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Radioguided Surgery for Breast Cancer

  • Francesco GiammarileEmail author
  • Federica Orsini
  • Renato A. Valdés Olmos
  • Sergi Vidal-Sicart
  • Armando E. Giuliano
  • Giuliano Mariani
Living reference work entry

Abstract

Sentinel lymph node biopsy is the standard surgical procedure for staging clinically tumor-free regional nodes in patients with early-stage breast cancer. This technique has spared the additional morbidity of axillary lymph node dissection without compromising diagnostic accuracy and prognostic information. However, it is still important to discuss current techniques and some controversies. Current data indicate that the combined radiocolloid injection approach (both superficial and deep injections) results in a higher identification rate of sentinel lymph nodes. Routine preoperative scintigraphic imaging helps the intraoperative search for sentinel lymph nodes and is vital for detecting extra-axillary or aberrant nodes, as well as for patients who have had prior core breast biopsy or surgery. SPECT/CT imaging, in addition to conventional lymphoscintigraphy, leads to improved preoperative visualization and localization of sentinel lymph nodes, especially if performed for specific indications. The combined use of radioactive tracers and blue dyes is more effective in detecting sentinel lymph nodes than either modality used alone and is therefore recommended for routine use.

Intraoperative imaging with portable gamma cameras is being increasingly employed, enhancing the reliability of the gamma probe by adding clear imaging of the surgical fields, especially when the injection site is close to the lymphatic basin. Portable gamma cameras can also be useful during radioguided occult lesion localization procedures in patients with non-palpable breast lesions.

Advances in radiopharmaceuticals and computer technology make it possible to integrate optical, hybrid tracers and 3D rendering systems that facilitate intraoperative sentinel lymph node identification.

Keywords

Breast cancer Sentinel lymph node biopsy Nuclear medicine Axillary lymph node dissection Radiocolloid injection Radioguided occult lesion localization 

Glossary

[18F]FDG

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

99mTc-MAA

99mTc-macroaggregated albumin

ALND

Axillary lymph node dissection

ART

Axillary radiotherapy

ASCO

Americal Society of Clinical Oncology

CT

X-ray computed tomography

DCIS

Ductal carcinoma in situ

FOV

Field of view

GOSTT

Guided intraoperative scintigraphic tumor targeting

H&E

Hematoxylin and eosin staining

ICG

Indocyanine green

IHC

Immunohistochemistry staining

IMC

Lymph nodes of the internal mammary chain

IMN

Internal mammary lymph nodes

LEHR

Low-energy high-resolution

LEUHR

Low-energy ultra-high resolution

LN

Lymph node

MRI

Magnetic resonance imaging

NACT

Neoadjuvant systemic chemotherapy

PET

Positron emission tomography

PET/CT

Positron emission tomography/computed tomography

ROLL

Radioguided occul lesion localization

SLN

Sentinel lymph node

SLNB

Sentinel lymph node biopsy

SNOLL

Sentinel node occult lesion localization (a combined procedure of simultaneous SLNB and ROLL in the same surgical session)

SPECT

Single photon emission computed tomography

SPECT/CT

Single photon emission computed tomography/computed tomography

SPIO

Superparamagnetic iron oxide

US

Ultrasonography

Introduction

General Background

Radioguided surgery constitutes a wide range of procedures which involve close collaboration between different specialties (nuclear medicine and surgery, often pathology) [1].

“Radioguided surgery” includes a set of pre-, intra-, and postoperative techniques and procedures that are designed to optimize oncologic surgery. All these technologies and applications can be encompassed in the recently coined concept of guided intraoperative scintigraphic tumor targeting (GOSTT) [2]. The basic feature that most obviously characterizes GOSTT is the preoperative administration of a radiopharmaceutical (either interstitially or systemically), associated with the intraoperative use of a handheld radioactivity counting probe (most often the so-called gamma probe) that facilitates the task of the surgeon – that is, the identification and removal of the target tissue, either a lymph node or the tumor itself – by virtue of preferential radioactivity accumulation in the target tissue. Intraoperative exploration of the surgical field with the gamma probe (which has recently evolved to allow intraoperative imaging as well) is made possible by a set of preoperative techniques employed by the nuclear medicine physician to achieve accumulation of the radiopharmaceutical in the specific target lesion. In this scenario, the most recent advances are based on growing interaction among different components of the complex armamentarium now available to the imaging community (including hybrid imaging, hybrid imaging agents, and/or virtual navigation systems) and to the surgical community (including robot-assisted surgery) [2, 3, 4, 5, 6].

The concentration of a radiopharmaceutical in a target lesion can be achieved by three main mechanisms: (1) interstitial administration of an adequate radiopharmaceutical, typically a radiocolloid, that scintigraphically depicts the pattern of lymphatic drainage from the site of a solid epithelial tumor, i.e., performing lymphoscintigraphy to identify the sentinel lymph node(s) (SLN) of the tumor; (2) systemic administration of a radiopharmaceutical that preferentially accumulates in the target lesion, e.g., 99mT-sestamibi for localization of parathyroid adenomas or [18F]FDG for [18F]FDG-avid tumor lesions; and (3) direct intralesional administration of a radiopharmaceutical such as 99mTc-macroaggregated human albumin (99mTc-MAA, comprised of particles that, by virtue of their relatively large size, are virtually indefinitely retained at the injection site) for the so-called radioguided occult lesion localization (ROLL) for non-palpable breast tumors.

In the last few years, GOSTT applications have rapidly expanded especially to perform sentinel lymph node biopsy (SLNB) . The sentinel lymph node (SLN) procedure is a diagnostic staging procedure that is applied in a variety of tumor types. The procedure aims to determine the tumor status of the SLN(s). Although historically the term “sentinel lymph node” was used to describe a group of nodes seen in patients with penile carcinoma [7], an SLN is currently defined as a lymph node on a direct drainage pathway from the primary tumor [8, 9]. The concept is based on the premise that lymph flow from the primary tumor travels sequentially to the SLN and then onto the other regional lymph nodes (Fig. 1). The SLN is the node most likely to harbor metastases.
Fig. 1

Schematic representation of the sentinel lymph node concept. Assuming that lymph drainage from a solid tumor proceeds in an orderly way from lower-echelon to higher-echelon lymph nodes, the first node(s) encountered in such pathway, that is, the sentinel node(s), should be the site where tumor cells migrating through lymphatic channels are most likely to be entrapped and possibly originate metastasis before spreading to higher-echelon lymph nodes. As illustrated in the figure, even in any given lymphatic basin, there can be more than one sentinel lymph node, as lymph can drain from the site of the primary tumor via different lymphatic channels toward the same basin. The diagram also illustrates the complex interconnections that can exist at higher levels, with variable directions of lymph flow at intermediate levels within the general pattern of overall centripetal flow. The pattern of lymph flow is even more complex when considering that lymph from the tumor site can drain to more than one lymphatic basin, each one repeating the basic pattern represented here for a single basin

The histopathologic status of this node should reflect the histopathologic status of the entire nodal basin, and additional treatment of the nodal basin (e.g., surgery) is routinely performed in case of metastatic involvement of the SLN – although the presence per se of metastatic tumor cells in the SLN is not the only factor determining lymph node dissection of the basin of interest (see further below in this chapter). A negative SLN, however, would justify a wait-and-see policy avoiding unnecessary elective lymph node dissections and the associated morbidity, hospital stay, and costs.

In addition to being continually applied in patients with breast cancer and cutaneous melanoma, radioguided SLNB is being explored in patients with a wide variety of other solid epithelial cancers. In particular, malignancies where the feasibility and/or clinical impact of radioguided SLNB is increasingly being investigated include head and neck cancers, gynecological cancers (vulvar, cervical, and endometrial), gastrointestinal cancers (esophagus, stomach, colorectal, anus), prostate cancer, non-small cell lung cancer, differentiated thyroid carcinoma, and others [10, 11, 12, 13, 14, 15].

Breast Cancer

Breast cancer is the most frequent cancer diagnosed in women worldwide [16]. In patients with breast cancer, accurate lymph node (LN) staging is essential for both prognosis (of early-stage disease) and treatment both for regional control of disease and for adjuvant therapies [17].

Clinical examination (i.e., palpation) is not accurate enough for assessing the axillary status, and preoperative imaging modalities including PET/CT with [18F]FDG and ultrasound have low sensitivity, especially in case of micrometastatic disease [18, 19, 20, 21, 22, 23, 24]. Thus, in breast cancer, the traditional staging approach has been axillary LN dissection (ALND). However, ALND results in a high incidence (about 25–30%) of postoperative complications that can reduce quality of life, such as delayed wound healing; lymphedema; peripheral nerve injury or even brachial plexus injury, with sensory/motor impairment; and pain. Furthermore, in early breast cancer, nearly 80% of axillary dissections reveal no metastasis and, therefore, could have been avoided [25].

Based on the definition of SLNs as those regional nodes that directly drain lymph from the primary tumor, SLNs are the first nodes to potentially receive the seeding of lymph-borne metastatic cells [26, 27]. After the initial description by Morton et al. of a method of SLNB in the management of melanoma patients, more than two decades ago [28, 29], SLN mapping and biopsy were applied in breast cancer [30, 31]. Since then, SLN mapping and biopsy have become routine techniques in breast cancer management, contributing to the development of less invasive surgical procedures [32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44]. Sentinel node biopsy is extremely accurate and effective. A systematic review showed an axillary 0.6% relapse rate in negative SLN patients and no benefits to completion ALND in terms of survival after negative SLNB [42, 45]. Thus, when the SLN is free of metastasis, the patient can be spared an ALND that until a few years ago was considered the standard staging procedure for breast cancer [31, 46, 47].

Despite the widespread application of SLNB for early-stage breast cancer, there is significant variation in performance characteristics reported for such procedures. Differences in institutional experience and in lymphatic mapping techniques are two of the main contributing factors to variations in the proportions of successful mappings [48, 49, 50]. The ranges of rates for false-negative findings and for SLN identifications emphasize the variability of this procedure. Learning curves for this technical procedure also vary [48]. Nevertheless, once a multidisciplinary team is experienced with the procedure, reasonable levels of accuracy are achieved, with identification rates of more than 95% reported routinely [25, 47, 51, 52, 53, 54].

Sentinel Lymph Node in Breast Cancer

Pathophysiological Aspects

The breast embryologically originates from ectodermal tissue, as a skin appendage, and therefore shares a pattern of lymphatic drainage with the overlying skin. The mammary gland is interposed between the superficial (subdermal) and the deep (subcutaneous) lymphatic plexuses, the two systems being interconnected by a dense network of lymphatic vessels (Fig. 2a). Lymphatic vessels surrounding the mammary lobules predominantly drain to the subareolar Sappey’s plexus, which is part of the superficial plexus of the skin. Most of the lymph produced in the breast is therefore drained to the subareolar region, progressing then toward the ipsilateral axillary nodes (Fig. 2b). A small fraction of the lymph produced in the breast (about 3%) is instead drained to lymph nodes of internal mammary chain, while an even smaller amount drains to other lymph nodes such as the intercostal, pectoral muscles, contralateral breast, or even abdominal nodes [55].
Fig. 2

(a) Schematic structure of cutaneous blood and lymph vessels. For easier comprehension, the lymph and blood vessel networks (which are actually embedded in each other) are represented separately, respectively, on the right (yellow) and on the left (red and blue). Due to its embryologic origin in the ectoderm, the mammary gland can be placed in an ideal space between the subcutaneous plexus and the deep lymphatic collectors (magnified insert in the figure). Branches of the periductal plexus drain lymph mostly toward the skin surface (via the subareolar plexus), while a minor component drains toward the deep collectors (which in turn drain toward the internal mammary chain). Radiocolloids injected intradermally over the mammary gland drain to the subcutaneous plexus that also receives most of the lymph draining from the mammary gland. (b) Pathways of the lymphatic vessels and lymph node stations draining the mammary gland. Most of the lymph produced in the breast drains to the subareolar plexus, then merges with the subcutaneous plexus of overlying skin, and flows mostly toward the axilla. Lymph from deeper portion of mammary gland drains either through the same pathway or through deep lymphatics that reach the parasternal, internal mammary chain (and even the contralateral side). abdom abdominal (From [38] with permission)

By following these routes of drainage, lymph and cancer cells entering the lymph space spread initially to the first node, which is the SLN. If the SLN is free of metastasis, the probability of tumor cells skipping that lymph node and metastasizing to second- or third-echelon nodes is an exceptionally rare event [39, 46, 56, 57, 58, 59, 60, 61, 62, 63, 64].

Indications

The main objective of SLN mapping and SLNB in breast cancer patients is axillary staging. These procedures are an appropriate alternative to routine staging axillary LN dissection for patients with early-stage biopsy-proven breast carcinoma without cytologically or histologically proven axillary lymph node metastases [65]. Appropriately identified patients with negative SLN biopsy do not need to undergo axillary LN dissection.

Currently, the SLNB procedure is recognized as the standard treatment for stage I and stage II breast cancer patients [40, 66, 67]. In these stages, the results showed that SLNB has a positive LN rate similar to that observed after ALND [40, 68, 69], yet with a significant reduction in morbidity [68] and similar gold standard (i.e., axillary LN recurrence rates at 5 years) [40]. The technique is validated if SLNs are found in more than 95% of the cases (i.e., the probability of detecting tumor cells in non-sentinel nodes is less than 5%). False-negative rates are higher in grade 3 lesions and in cases with a single SLN, compared to cases with multiple SLNs [70].

The recognized indications for SLNB, together with recommendations as to whether an SLN procedure is the established standard of care, are listed in Table 1 [71].
Table 1

Recommendations on the use of SLN biopsy (Modified from [71])

Clinical circumstance

Use of SLN biopsy

T1 or T2 tumor

Established

T3 or T4 tumor

Controversial

Multicentric or multifocal tumor

Controversial

Inflammatory breast cancer

Not recommended

DCIS with mastectomy

Established

DCIS without mastectomy, but with suspected or proven microinvasion

Established

DCIS without mastectomy

Controversial

Suspicious, palpable axillary nodes

Controversial

Older age

Established

Obesity

Established

Male breast cancer

Established

Pregnancy

Controversial

Evaluation of internal mammary lymph nodes

Controversial

Prior diagnostic or excisional breast biopsy

Controversial

Prior axillary surgery

Controversial

Prior non-oncologic breast surgery

Controversial

After preoperative systemic therapy

Controversial

Before preoperative systemic therapy

Established

Controversial indications are those for which SLN biopsy is not universally accepted or for which the evidence behind the practice is limited or entirely missing

DCIS ductal carcinoma in situ

Procedures

Generally, the procedure for SLN mapping and SLNB involves interstitial tracer injection, preoperative scintigraphic imaging, and intraoperative gamma probe localization for surgical removal of the detected LNs. Although there is consensus on some broad aspects of SLN protocols for breast cancer, consensus does not exist on all details. Controversies exist with regard to the particle size of the radiotracer, the optimal route for injection, timing and type of scintigraphy and intraoperative detection, and whether or not extra-axillary LNs should be considered for harvesting and analysis. The specific radiotracer and technique used are additionally guided by local availabilities, regulations, and practices [71].

Procedures in Nuclear Medicine

Three main parameters define an optimal tracer administration technique for radioguided SLNB: injection site, injected volume, and injected activity. A fourth parameter to be taken into account is the time elapsed between injection and surgery, as it specifically influences the amount of radioactivity to be injected [72, 73].

Radiopharmaceuticals
Several 99mTc-based agents have been used for radioguided SLNB for breast cancer (see Table 2) [74]. The radiopharmaceuticals most widely used are 99mTc-sulfur colloid (particle size: 15–5,000 nm, but usually filtered to select a more restricted range of particles’ size), 99mTc-nanocolloid (5–100 nm), and 99mTc-antimony trisulfide (3–30 nm).
Table 2

Radiopharmaceutical characteristics (Modified from [74])

99mTc-based agents

Particle size max (nm)

Particle size mean (nm)

Sulfur colloid

350–5,000

100–220 (filtered)

Antimony trisulfide

80

3–30

Sulfide nanocolloid (Lymphoscint®)

80

10–50

Nanocolloidal albumin (Nanocoll®)

100

5–80

Rhenium sulfide nanocolloid (Nanocis®)

500

50–200

Tin colloid

800

30–250

Labeled dextran

800

10–400

Hydroxyethyl starch

1,000

100–1,000

Stannous phytate

1,200

200–400

Tilmanocept (Lymphoseek®)

~7 (equivalence)

~7 (equivalence)

The ideal radiotracer should show rapid transit to SLNs with prolonged retention in the nodes. In general, the drainage, distribution, and clearance of radioactive colloids by the lymphatic system may vary and are dependent on the size of the particles. Small particles are drained and cleared first; large particles are drained and cleared last and may be retained longer at the injection site. Studies have shown the success rate of identification of axillary SLNs is not significantly affected by the particle size of the radiotracer [38, 75, 76, 77]. Thus, the selection of radiotracer is based more on local availability than on differences in SLN detection. However, there is general agreement that a 100–200nm sized radiocolloid should be considered the best compromise between fast lymphatic drainage and optimal retention in SLNs [78].

New tracers have been developed in recent years. The tracer most recently made commercially available is Lymphoseek®, which is composed of a dextran backbone with multiple glucose and mannose residues attached to DTPA for 99mTc-labeling. The potential advantages of its small molecular size (7.1 nm) and the receptor-targeted nature of the mannose moieties in 99mTc-Tilmanocept include rapid transit from the primary site to the SLN as well as selective accumulation in that node, with limited pass-through to second-echelon nodes [79, 80, 81, 82].

Activities and Volumes

Literature supports the use of small volumes with high specific activity to improve SLN detection. Nevertheless, consensus on the activity to be administered in an SLN procedure has not been reached. Activities as low as 3.7 MBq (0.1 mCi) [83] and as high as 370 MBq (10 mCi) [84] have been used. In current practice, a total injected activity of 5–30 MBq (depending on the elapsed time between scintigraphy and surgery) is generally considered sufficient for surgery planned for the same day. Prior day injection has been shown to be technically feasible by adequately increasing the amount of radioactivity injected (up to 150 MBq) [85].

Injection of large volumes may disrupt local lymphatics; therefore, a quantity of 0.2–0.5 mL should be injected. Moreover, the syringe should also contain a sufficient amount of air to clear any dead space within the syringe and the needle.

Injection Procedure
The injection site of the mapping agent is another controversial issue, mainly because lymphatic drainage of the breast is not completely understood [86]. The most commonly used injection sites can be classified into two categories: deep (intratumoral and peritumoral) and superficial (intradermal, subdermal, subareolar, and periareolar) injection (see Fig. 3).
Fig. 3

Modalities of interstitial radiocolloid injection for SLNM in breast cancer. Superficial injections (ad) and deep injections (e, f): intradermal (a), subcutaneous (b), subareolar (c), periareolar (d), peritumoral (e), and intratumoral (f)

All injection modalities enable axillary sentinel nodes to be identified accurately, and satisfactory SLN detection rates have been reported for all injection approaches [87]. Lymphatic circulation within solid tumors (including breast cancer) is generally grossly abnormal, disrupted, and inefficient. Thus, intratumoral administration requires the injection of high activities (up to 370 MBq or 10 mCi) and large volumes (even up to over 1 mL). Injection of such large volumes can substantially increase interstitial pressure at the injection site, thus possibly altering the pattern of lymphatic drainage and forcing drainage routes different from those prevailing in baseline conditions. Furthermore, most of the injected radioactivity is retained at the injection site, often causing interference – the so-called “shine-through” effect – in scintigraphic and intraoperative sentinel lymph node detection. Finally, the slow drainage from the tumor can cause poor scintigraphic visualization of the lymphatic channels and possibly lead to failure of lymphoscintigraphic imaging and of intraoperative identification of the sentinel lymph node.

All the above considerations explain why, at present, most nuclear medicine centers prefer peritumoral or superficial injections versus the originally proposed intratumoral route of administration, although the high reproducibility of intratumoral injection has been well demonstrated [88].

Lymphatic circulation in the peritumoral area is normal and actually represents the entrance site to lymph vessels of cancer cells detached from the growing edge of the tumor, which eventually gives rise to lymph nodal metastasis. Indeed, any drainage pattern from any quadrant of the breast can occur, and most of the lymph from the breast flows toward the nodal basins with a direct course, not necessarily passing through the subareolar plexus [87, 89]. Peritumoral injection is considered the gold standard for accurate SLN detection, because the tracer is injected near the same lymph vessels draining the tumor and is able to reveal extra-axillary drainage [90]. However, this approach has been criticized especially in non-palpable and multicentric tumors. Peritumoral administration is usually performed by depositing two aliquots on each side of the tumor, while intra-/subdermal administration is performed in or just under the skin overlying the tumor. Intradermal injection should produce a small wheal. More than one injection could be performed in adjacent sites. Periareolar administration is generally performed with two to four aliquots, each one at the edge of the areola at Sappey’s plexus.

The rationale of intra-/subdermal administration stems from the fact that lymph is drained from the intra-/subdermal space to the subcutaneous plexus, which is the merging point for lymph originating from the underlying breast parenchyma (see Fig. 2a). Thus, a tracer injected intra-/subdermally displays the same pathways of lymphatic drainage as the underlying breast gland and of cancer cells entering the lymphatic space. Similar considerations apply to the periareolar route of administration: the lymph produced in the breast flows to the periareolar Sappey’s plexus, before draining to axillary LNs (see Fig. 2b).

Superficial injection sites have numerous advantages, including simplicity, shorter time between injection and SLN identification, and increased radiotracer nodal uptake which may result in improved nodal identification rates. Nevertheless, superficial injection allows almost exclusive identification of axillary nodes. The use of peritumoral injections requires careful investigation of a patient’s prior imaging and medical records, particularly if the tumor is non-palpable. Tumor location and injection sites may be identified by ultrasound and/or x-ray stereotactic guidance. If a tumor is in the upper outer quadrant, the relatively intense activity at the injection site may make it difficult to localize of a nearby SLN with less intense uptake [91, 92].

Regardless of the injection site, after injection, the patient is asked to gently massage the breast to facilitate lymphatic drainage of the tracer. Massage can also be employed if the passage of activity from the injection site is delayed at any time during the study [93, 94].

Results of multiple studies support the validity of both the deep and the superficial injection approaches; in particular, all injection modalities enable axillary SLN to be identified accurately, and satisfactory SLN detection rates have been reported for all injection approaches [87]. A clinical trial comparing the injection routes demonstrated, in 400 breast cancer patients, the superior intraoperative gamma probe localization of the axillary SLNs for the intradermal route (100%) compared to the subareolar route (95%) and the intraparenchymal route (90%) [95]. A preferential drainage to the same few axillary SLNs has been postulated for most of the breast tissue and its overlying skin, after merging initially to the retroareolar Sappey plexus; therefore, accurate identification of axillary SLNs is supposed not to be affected by the injection route [93, 94, 96, 97]. Thus, if the goal is axillary staging only, a superficial tracer injection (periareolar, subareolar, subdermal, intradermal) may be preferable to a deep injection (peritumoral, intratumoral) due to better and quicker visualization of axillary SLNs [98]. On the other hand, an important advantage of deep injection is the improved detection of extra-axillary SLNs: after peritumoral administration, lymphoscintigraphy shows drainage to the internal mammary chain in 20–30% of the cases, while this fraction is much lower (<3%) after intra-/subdermal or periareolar administration [66, 99, 100]. Thus, if one’s aim is to stage extra-axillary nodal basins as well as the axilla, deep injection is recommended.

The superficial routes of administration are generally preferred in the case of superficial, easily palpable tumors and the peritumoral route for deeply seated tumors. The periareolar route can be used mainly in upper quadrant tumors to avoid possible cross talk owing to the short distance between the peritumoral depot and the axillary SLNs and is particularly recommended in cases of non-palpable or multifocal tumors [101, 102]. The combination of both injection techniques (deep and superficial) in the same patient may improve SLN detection [90].

Imaging Procedures

Lymphatic mapping allows to determine the number of LNs that are on a direct drainage pathway and to locate the SLNs [71] [103]. Preoperative imaging is strongly recommended due to variability in breast lymphatic drainage into the axilla and extra-axillary nodes [104]. Thus, preoperative lymphatic mapping has the potential to both improve accuracy (especially in extra-axillary LN) and reduce morbidity relative to the use of handheld gamma probes alone [34, 71]. Preoperative imaging also serves as quality control on the use of the appropriate tracer, failure of the injection, failure of the radiopharmaceutical, and management of the appropriate breast and axilla – injection of the proper side (L/R). Reasons not to use preoperative lymphoscintigraphy are logistical or because there is no definite evidence of a higher intraoperative success rate in the harvesting of axillary SLNs [105, 106].

Timing: In order to identify all SLNs and to avoid confusion with radiocolloid stasis in a lymphatic vessel, images are acquired with an adequate delay after injection. This delay may vary according to the radiopharmaceutical used, the injection site, and the patient’s characteristics (lymphatic drainage can be slower in elderly or overweight patients). While smaller particles allow quick visualization of SLNs, larger particles have slow transit in the lymphatic system that tends to minimize visualization of non-sentinel second-tier nodes (lymph nodes downstream of SLNs) [107]. After superficial tracer administration, lymphatic drainage and subsequent lymph node visualization is usually quicker than after peritumoral injection (20–30 min compared to 2–3 h on average). After 15–18 h, during surgery, the amount of radiocolloid migrated to LNs represents about 1% of the injected activity after superficial administration, while it is about 0.1% after peritumoral administration.

SLNs are generally visualized within 1–2 h, and the patient should be in the operating theater within 2–30 h of radiocolloid injection , depending on the facility’s schedule [71, 107]. In the event a surgery is scheduled for early morning, injection and imaging may be safely performed the afternoon prior to the surgery [108].

Gamma camera parameters: A single- or dual-head gamma camera system with large field-of-view (FOV) detectors is generally used to acquire planar emission and, if desired, single-photon computed tomographic (SPECT) or SPECT/computed tomographic (SPECT/CT) images. Low-energy, high-resolution, or low-energy high-resolution collimators should be used. The energy window should be 15% (±5%) centered on the 140 keV photopeak of 99mTc.

Image acquisition: Dynamic (flow) imaging is not often used in SLN procedures for breast cancer, but can provide information useful to SLN localization.

Planar (static) imaging should be performed 15–30 min, and 2–4 h post injection, and as needed thereafter up to 18–30 h. At least two, preferably all three, of the following images should be acquired: anterior, 45° anterior oblique, and lateral. Each image is typically 3–5 min in duration. For a system with large FOV detectors, the pixel size is recommended to be approximately 2 mm and the matrix size 256 × 256 with zoom 1 or, rarely, 128 × 128 with zoom 2. If 2 mm pixel size is not feasible on the system, the smallest pixel size available should be used.

Figure 4 shows different patterns of lymphatic drainage and SLN distribution as obtained by planar scintigraphic imaging in preparation for radioguided SLNB. Although conventional planar imaging certainly enables identification of the draining pattern to SLNs, it does not provide the exact anatomic location of the detected LNs, an information that is instead very useful intraoperatively [109]. By combining tomographic functional lymphoscintigrams registered with anatomic data from CT, SPECT/CT imaging provides better contrast and resolution than planar imaging and has the possibility to correct for attenuation and scatter. Fused SPECT/CT imaging considerably improves the topographic localization of the SLN within an anatomical landscape, thus providing a valuable surgical road map [110].
Fig. 4

Variable lymphoscintigraphic patterns visualized between 30 and 60 min after intradermal injection of 99mTc-nanocolloidal albumin in patients with breast cancer. (a) Single lymphatic vessel leading to a single sentinel lymph node, with faint visualization of subsequent-tier lymph nodes (right anterior oblique view). (b) Two separate lymphatic vessels widely diverging in their initial pathway, eventually leading to two separate but adjacent sentinel lymph nodes, with faint visualization of subsequent-tier nodes (left anterior oblique view). (c) Three separate lymphatic vessels widely diverging in their initial pathway, eventually leading to two separate but very close sentinel nodes (left anterior oblique view). (d) Multiple lymphatic vessels leading to at least three separate sentinel lymph nodes (right anterior oblique view) (From [38] with permission)

SPECT acquisition for SLN detection should be performed with a dual-detector SPECT system equipped with LEHR or LEUHR collimators. Acquisition parameters should include matrix size of 128 × 128 (4–5 mm pixels) and 120 or 128 projections over 360° with 20−25 s/projection.

Both low-dose CT (140 kVp, 2.5 mA) and conventional CT (140 kVp, 30–150 mA) can provide useful anatomical detail that can be used for anatomical localization and, if desired, attenuation correction.

Mapping of all direct tumor-draining LNs requires knowledge of the number and location of these SLNs, which will be provided by SPECT/CT in addition to planar images. SPECT/CT imaging provides significant information in the large majority of patients, with useful preoperative complimentary information to the surgeons: better location, reduced surgical time, and greater confidence of the surgeons with the technique [111].

It has been shown that SPECT/CT images can detect additional SLNs not visualized on planar images in a substantial number of patients in whom the conventional images are difficult to interpret [110, 111, 112]. In the majority of cases, the surgical team appreciates the anatomic information provided by the fused SPECT/CT images and the surgical time is reduced [113]. However, because the current conventional approach based on combined radiocolloid and blue dye injection, preoperative planar scintigraphic imaging, and intraoperative gamma probe counting has proven very successful (with SLN detection rates over 95%), the added value of SPECT/CT imaging seems to be limited to a small fraction of breast cancer patients undergoing SLNB. Current recognized indications for SPECT/CT imaging in breast cancer patients are non-visualization of SLNs at conventional imaging, obesity, and presence of extra-axillary SLNs or otherwise unusual drainage (e.g., in cases of previous breast surgery) [71]. SPECT/CT imaging might also be performed if the conventional images are difficult to interpret (e.g., if contamination is suspected or an SLN is located near to the injection area) [112, 113].

When acquiring planar imaging, a 57Co flood source can be positioned between the patient’s body and the collimator in order to obtain some reference anatomic landmarks in the scintigraphic image (see Fig. 5). Alternatively, the body contour can be delineated by moving a 57Co point source during scintigraphic acquisition (see Fig. 6). SPECT/CT acquisitions obviate the problem of identifying anatomic landmarks as a reference for topographic location of the SLN(s) (see Figs. 7 and 8) [109, 114, 115, 116, 117, 118].
Fig. 5

Anatomical information in lymphatic mapping. (a) The use of a 57Co flood phantom placed opposite to the gamma camera head (black arrows) provides body contour delineation in the anterior planar image (b) in a patient with cancer of the right breast and drainage to the right axilla and right internal mammary chain. In the same patient, subsequent SPECT/CT acquisition (c) leads to anatomically identify the axillary and parasternal sentinel lymph nodes after reconstruction of the fused SPECT/CT using volume rendering (d)

Fig. 6

Body contour delineation obtained by moving a 57Co point source along the body of the patient during acquisition of the planar scintigraphic images. In this patient with cancer of the left breast, 99mTc-nanocolloidal albumin was injected at four spots periareorally. Images acquired both in the anterior projection (left panel) and in the left anterior oblique projection (right panel) visualize migration of the radiocolloid to a single sentinel lymph node in the axilla

Fig. 7

Anatomical sentinel lymph node localization in breast cancer. Following deep injection of 99mTc-nanocolloidal albumin in the left breast, lymphatic drainage to the axilla, periclavicular area, and internal mammary chain is observed on anterior planar image (a) and on SPECT/CT fused imaging displayed with volume rendering (b). Lymph nodes are subsequently localized in the second intercostal space, level I of the left axilla, and behind the left clavicle (cf)

Fig. 8

Multidirectional lymphatic drainage after deep injection of 99mTc-nanocolloidal albumin on anterior planar image (a) in a patient with breast cancer in the medial inferior quadrant of the right breast. SPECT/CT with volume rendering (b) and axial fused SPECT/CT sections (ce) depict ipsilateral sentinel lymph nodes in the breast, in the axilla, and in the internal mammary chain

Surface marks that provide a method to triangulate SLNs and to estimate their depths are desired by some surgeons. Surface locations should be marked on the skin with a small spot of indelible ink, and the depth of the node should be described. When marking the skin in the imaging process, an attempt should be made to position the patient’s arm in the same position as it will be placed during surgery.

Image Interpretation

Early and delayed lymphoscintigraphic planar images identify SLNs in a majority of cases [71]. Major criteria to identify LNs as SLNs are the time of appearance and, occasionally, visualization of lymphatic channels (if dynamic imaging was performed). Usually, SLNs cannot be readily distinguished from second-tier LNs. The SLN is not necessarily the hottest node, although that is often the case. Separate lymphatic channels that drain to different LNs identify each of those as distinct SLNs, even though they may be located in the same anatomic region. When drainage to more than one anatomic region is seen, each of those regions has at least one SLN.

In current protocols SPECT/CT is performed following delayed planar images. This sequential acquisition is helpful to clarify the role of both modalities. For imaging interpretation the major criteria to identify LNs visualized on lymphoscintigraphy as SLNs are the visualization of lymphatic ducts, the time of appearance, the lymph node basin, and the intensity of lymph node uptake [105, 119]. Following these criteria visualized radioactive lymph nodes may be classified as:
  1. (A)

    Definitively SLNs: this category concerns all LNs draining from the site of the primary tumor through their own lymphatic vessel or a single radioactive LN in a certain lymphatic basin.

     
  2. (B)

    Highly probable SLNs: this category includes LNs appearing between the injection site and a first draining node or LNs with increasing uptake appearing in other lymph node stations.

     
  3. (C)

    Less probable SLNs: all higher-echelon LNs may be included in this category.

     

Axillary LNs represent the main basin for breast lymphatic drainage, but different patterns can also occur in some cases. Drainage to the internal mammary basin is present in up to 35–40% of patients after intratumoral/peritumoral radiocolloid injection . Other unusually located SLNs are also observed in a non-negligible fraction of patients: intramammary (prepectoral) in 6%, interpectoral in 2%, and infraclavicular in 3% [120, 121].

The report to the referring physician should describe the orientations of the images acquired, the radiopharmaceutical, the method of administration, the amount and volume of activity injected, the location of the SLNs on each image, and any source of error or inaccuracy of the procedure.

The images and report should be available by the time the patient arrives in the surgical suite – in electronic form or as hard copy. If this is not possible, the critical information should be relayed directly to the surgeon. A close working relationship between the imaging department and the surgeon is critical for accurate dissemination of information regarding numbers and locations of sentinel lymph nodes.

Procedures in the Surgical Suite

Blue Dye Lymph Node Localization

Regarding the use of blue dye for optical guidance during surgery, there is general agreement that combined administration of radiocolloid and blue dye using both superficial injection and deep injection enhances SLN detection [38, 94, 97]. A possible advantage of the combined technique is where macrometastasis in the SLN may inhibit tracer accumulation [122, 123].

Blue dye can be injected around the primary tumor 10–20 min prior to surgery in a volume of 2–5 mL. The site of injection can be gently massaged after the administration or if the drainage of activity from the injection site is delayed at any time during the study [94]. Within 5–15 min, the SLNs are colored. Washout is evident after approximately 45 min.

Multiple studies have established the validity of blue dyes as markers for SLNs with reasonably high detection rates (ranging from 75% to 80%) [124]; nevertheless such rates are slightly lower than those achieved with radiocolloids. In most cases, the same SLNs are detected by the two methods. Disadvantages of using blue dyes are as follows: (i) impossibility to evaluate extra-axillary nodes, (ii) temporary blue tattooing of the skin or areola (for patients with breast conservation surgery), and (iii) induction of anaphylactic reactions (which require resuscitation in 0.5–1.0% of patients and that contraindicate its use in pregnant women) [124, 125, 126, 127, 128, 129, 130, 131].

Radioguided Surgery

Intraoperative detection of SLNs is usually radioguided by a gamma-detection probe. Such probes should be designed and constructed to be suitable for intraoperative use, in order to be able to detect the SLN from the skin surface as well as within the exposed surgical cavity [26]. The probe is placed in a sterile bag to be used in the sterile surgical field. A display capable of providing clear instantaneous and cumulative counts is a major requirement. It is helpful if the instantaneous count rate is fed to an audio signal that conveys count rate information.

The count rates obtained with the gamma probe during surgery are recorded per unit time with the probe in the surgical field, over the node before excision (in vivo) and after excision (ex vivo). A background tissue count is also recorded with the probe pointing away from the injection site, nodal activity, or other physiological accumulation sites (i.e., liver) [71].

Just before starting surgery and with the patient positioned on the operating table, using the images and skin markings as guides, the gamma probe scans the axilla or any other region where tracer accumulation has been visualized in order to confirm correct identification and localization of the SLN(s) and to select the optimum location for incision. This task requires the sensitivity of the detector to be sufficient to identify a weakly active SLN when attenuated by, typically, up to 5 cm of soft tissue. The surgeon then introduces the probe through the skin incision to guide dissection to the hot node(s). Discriminating activity counts within the SLN from those originating from nearby sites requires the probe to be well collimated with a small angle of view. The detector should offer a high level of shielding against radiation hitting the side of the probe assembly. However, when working with the probe, it is important to direct the probe away from activity at the injection sites.

When a hot SLN has been removed, the surgical bed should be checked to confirm removal of the hot node(s) and to evaluate remaining activity. Owing to the limited spatial resolution of the gamma camera, LNs closer than approximately 15–20 mm may appear on lymphoscintigraphy as one single hot spot; so, in some cases another hot node may still be present at a close location after removal of the hottest SLN. In this regard, the use of SPECT/CT imaging is very helpful because it may provide information about the actual presence of a cluster of LNs rather than a single SLN. When other sources of activity are found in the lymphatic basin, the decision of whether to remove them will depend upon the report from lymphoscintigraphy and the working definition of “nodes to remove” [132, 133]. In principle, SLNB requires the removal of all SLNs receiving direct lymphatic drainage from the site of the primary tumor. In practice, this is not always achieved. In cases with multiple radiolabeled LNs, it is often difficult to distinguish between SLNs and second-tier LNs. The issue of how many SLNs should be biopsied when multiple radioactive LNs are found is still debated. In this regard, while removing too few nodes may miss potential metastases in regional LNs, indiscriminate removal of all radioactive axillary nodes may cause morbidity similar to that experienced after conventional ALND (in addition to the unnecessarily increased burden for histopathological analysis).

Several operational definitions of the SLN have evolved over time in order to decide exactly which nodes should be removed to maximize the likelihood of locating the “true” biologic SLN and to minimize the superfluous removal of non-SLNs. Some authors base SLN identification on the absolute number of counts per second recorded for the presumed nodes, while others consider the ratio of the “in vivo” or “ex vivo” radioactive counts in the SLNs relative to background or to neighboring non-SLNs. Empiric thresholds corresponding to (i) 10% or 20% of the counting rate in the first LN removed (which is usually the most radioactive) or (ii) at least ten times the background count, taken at a location remote from the injection site, are widely reported in the literature [98, 134, 135, 136, 137]. It is generally accepted that removing more than five LNs from the axilla does not result in marked improvement in the sensitivity of axillary SLNB [138, 139, 140, 141, 142, 143]. If blue dye is used, it can be a useful adjunct for aiding SLN localization and harvesting. Blue dye generally results in a lower SLN detection rate than radiotracers, but it can be used in addition to radiocolloids. Following injection, the blue dye drains to the SLNs, staining the channels, which can be followed to the first-echelon nodes. Direct visualization and dissection of these channels facilitate SLN localization.

Deeply located SLNs are difficult to detect intraoperatively because of tissue attenuation; furthermore, the large amount of radioactivity retained at the injection site may cause nearby located SLNs to be hidden because of the shine-through effect. Patients who have undergone previous breast surgery or radiation may demonstrate nodes in locations not typically seen in patients without a history of prior surgery. The lymphatic duct to the original SLN may be obstructed by tumor growth or the original SLN may be entirely replaced by disease. Consequently, lymphatic drainage may be either diverted to a non-sentinel node or no lymph nodes may be visualized, increasing false-negative results.

The use of SPECT/CT images can help localization of focal activity [144] as can the use of intraoperative imaging with portable gamma cameras; the latter imaging equipment is generally used simply to verify that all radioactive lymph nodes of interest are removed [4]. Finally, to minimize false-negative results, the open axilla should be palpated and suspicious lymph nodes harvested, even if these are neither hot nor blue.

SLN Non-visualization or Failed Intraoperative Detection

It is important to consider that when an SLN is not detected intraoperatively, this corresponds to a failure of the method and not to a false-negative case (better defined as when an axillary relapse is observed despite a prior negative SLNB). The majority of patients with preoperative lymphoscintigraphic SLN non-visualization will have at least one SLN detected intraoperatively, either by a gamma probe alone or by a gamma probe combined with blue dye. While logistically difficult in most centers, a second radiocolloid injection, following perhaps a different injection route, may be useful to visualize previously non-visualized SLNs.

In approximately 1–2% of the patients, SLNs will not be detected preoperatively or intraoperatively, and the status of axillary LNs cannot be determined. Old age, obesity, tumor location other than in the upper outer quadrant and non-visualization of SLNs on preoperative lymphoscintigraphy may be associated with failed SLN localization [142]. The significance of preoperative scintigraphic SLN non-visualization is not yet known. Some studies have suggested that patients with unsuccessful axillary mapping may have an increased risk of metastatic axillary involvement [145]. There is no definitive consensus on what to do if an SLN cannot be visualized. However, current standards of care recommend axillary LN dissection when intraoperative SLN identification is not achieved [146].

New approaches and strategies have been proposed in case of failure to visualize SLN(s) with conventional lymphoscintigraphy. Recently, Pouw et al. demonstrated in a large cohort of patients that SPECT/CT provided SLN visualization in 23.2% of cases with non-visualization of the SLN on planar imaging (66/284). In those patients receiving reinjection after persistent SPECT/CT non-visualization, the SLN visualization rate reached 62.1% (36/58). Thus, an adjustment of the clinical protocols (logistically not easy) may be proposed when no SLN is visualized during planar imaging [147].

Histopathology of SLNs

Detailed histopathological analysis of the SLN is the standard procedure on which to base selection of the postoperative management strategy of breast cancer patients. By focusing on only a few lymph nodes rather than on 15–20 nodes as generally harvested during an axillary dissection, the pathologist can completely dissect and examine at 50–100 μm intervals each SLN. However, protocols for SLN analysis have not yet been standardized; therefore, high variability in procedures still exists among different centers.

Immunohistochemistry (IHC) considerably improves sensitivity by identifying micrometastases and even isolated tumor cells, which are generally missed with conventional hematoxylin and eosin (H&E) staining alone [148, 149]. Methods for molecular biology analysis, such as those based on the reverse transcription polymerase chain reaction, are also being used for SLN analysis, although they are generally characterized by relatively poor reproducibility and longer time for analysis. Nevertheless, equipment for fast, even intraoperative, analysis has recently been made commercially available; a potential disadvantage of such new techniques is that the whole SLN is usually homogenized and processed for molecular analysis, without parallel conventional histopathologic analysis being conducted [150, 151].

Different procedures for intraoperative SLN analysis have been developed, including the touch imprint of one or more slices (relatively low sensitivity, but very high specificity), staining of one or several intraoperative frozen sections, and even IHC for cytokeratins as the most exhaustive method. In this case, if the SLN has metastasis, it is possible to perform ALND immediately. On the other hand, if complete intraoperative histopathologic evaluation of the SLN is not performed, it is necessary to wait for definitive histology usually obtained within a week. If metastases are detected, ALND may be performed with a second procedure.

No significant difference exists in terms of 5-year survival rate between patients with SLN-positive and those with SLN-negative metastases by IHC. Consequently, it would seem that SLN micrometastases identified only by IHC are clinically insignificant and that IHC staining of SLNs appears to be unnecessary. IHC should be limited to particular cases, such as infiltrating lobular carcinoma, for which it is difficult to detect SLN metastases with H&E staining alone [78, 152, 153].

Qualifications and Responsibilities of Personnel

SLN studies should only be performed by surgeons and nuclear medicine specialists who have received specific training in such procedures [154].

An initial supervised learning phase is recommended to harmonize and optimize interaction between these specialists. The most important parameters to test such a multidisciplinary team are (a) percentage of SLNBs successfully identified and (b) percentage of false negatives.

It is often considered that 20–40 procedures under guidance are sufficient in order to implement radioguided SLNB into the routine clinical practice of a given hospital. These numbers, however, are highly variable, and SLNB should only be introduced to clinical practice where the team demonstrates high identification rate and accuracy [40, 71, 78, 98, 155, 156].

Clinical Controversial Aspects

T3–T4 Tumors

The evidence regarding the safety of sentinel node biopsy is mainly based on studies including T1 and small T2 tumors only [71, 78, 157, 158, 159, 160]. However, a few reports suggest that false-negative rate and axillary recurrence reported in larger tumors are similar [63, 161].

Multiple (Multifocal/Multicentric) Tumors

Multifocal breast cancer is defined as separate foci of ductal carcinoma more than 2 cm apart within the same quadrant, while multicentric breast cancer indicates the presence of separate independent foci of carcinoma in different quadrants [101]. Until recently, SLNB was contraindicated in patients with multicentric and multifocal breast cancer because it was believed that it was difficult to localize the true SLN, and a negative SLNB would not exclude the possibility of positive LN metastasis in basins draining from other regions of the breast. However, most of the mammary gland can actually be considered as a single unit with lymph drainage to only a few designated lymph nodes in the axilla [93, 162]. In this regard, the efficacy of SLNB in patients with multifocal/multicentric cancer has been shown to be equal to that in patients with unicentric breast cancer. This means that the presence of multiple tumors should not affect lymphatic drainage and the possibility to perform SLNB with superficial injection [163, 164]. Nevertheless, it should be noted that the prevalence of axillary metastases seems higher in multifocal or multicentric tumors. Furthermore, high false-negative rates have been reported [165]. However, even if there are limited and heterogenic data on the efficacy and safety of SLNB in multiple breast cancer [102, 166], the reported axillary recurrence rates are acceptable, and the SLNb may be performed in patients with multifocal or multicentric tumors [63, 101, 163].

Ductal Carcinoma In Situ (DCIS) and Breast Conservation Surgery

By definition, DCIS does not metastasize to regional lymph nodes. However, controversy exists over the use of SLNB in patients with preoperative diagnosis of DCIS [167]. In fact, core needle/vacuum-assisted minimally invasive biopsy may be affected by sampling error; invasive disease is found at surgery in about 15–30% of patients with DCIS [168, 169]. Because of the low prevalence of metastatic involvement and the feasibility of SLNB after breast-conserving surgery, SLNB should not be considered a standard procedure in the treatment of all patients with DCIS, but only recommended in those patients undergoing mastectomy [170, 171, 172]. However, wide local excision before SLNB can alter lymphatic drainage, especially to the internal mammary nodes (IMNs) [173, 174]. Thus, SLNB could also be an option in women treated with breast-conserving surgery when there is a high risk of invasive cancer at final diagnosis (i.e., palpability of the lesion or presence of a mammographic mass) [175].

Suspicious Palpable Axillary Nodes

Palpable axillary LN may be tumor negative in up to 40% of the patients [176, 177]. The proportion is lower when considering suspected LN identified by noninvasive techniques during preoperative staging (US, CT, MRI, or [18F]FDG-PET). In any case, axillary ultrasound with fine needle aspiration cytology or core needle biopsy from the suspicious nodes is a widely accepted policy. In that case, SLNB can be performed in patients with palpable LNs, if negative in the preoperative diagnosis. However, the suspicious, palpable LNs should be harvested for histopathological evaluation, even when neither hot nor blue.

Evaluation of Internal Mammary and Other Extra-Axillary Nodes

Although the IMNs, in the same way as the axilla, are a first-echelon nodal drainage site in breast cancer, the importance of their treatment has long been debated [71, 178]. Randomized trials have failed to demonstrate a survival benefit from surgical internal mammary chain (IMC) dissection, and several retrospective studies have shown that IMNs are rarely the first site of recurrence [179, 180, 181, 182, 183, 184]. However, the recent widespread adoption of SLNB has stimulated a critical reappraisal of such early results. Furthermore, the virtually systematic application of adjuvant systemic and/or locoregional radiotherapy encourages reexamination of the significance of IMN metastases [185]. There is strong evidence that postmastectomy radiotherapy to chest wall and nodal basins (including IMC) reduces both recurrence and breast cancer mortality in axilla-positive patients, even when systemic therapy is given [186]. However, internal mammary radiation remains controversial, mainly because of the difficulties in selecting patients at risk of occult internal mammary involvement [187, 188].

It is generally recognized that mapping of IMNs requires deep injection of the lymphatic mapping agent, either peritumorally or intratumorally [99, 100, 189]. Moreover, the fused SPECT/CT images represent a further technical solution to increase the identification rate of IMNs. Nevertheless, the rates of detection and intraoperative harvesting of IMNs are much lower than those for axillary LNs. Visualization of the IMNs has been detected in approximately one third of patients with breast cancer receiving deep radiocolloid injection, of which about 63–92% could be harvested during surgery, and 11–27% of them had metastases [178, 190, 191, 192].

In conclusion, there is no doubt that IMN metastasis has prognostic significance similar to prognostic importance to axillary nodal involvement [193, 194, 195]. However, the significance of IMN biopsy is not clear. There is evidence that IMN mapping leads to upstage migration and to modifications of treatment planning with respect to radiotherapy and systemic therapy, but more evidence is necessary to support the idea that IMN mapping will improve the outcome of treatment and survival, perhaps because IMN drainage at lymphoscintigraphy is more difficult to demonstrate than axillary drainage [178, 196]. Thus, an “integrated and multidisciplinary technique” is required to evaluate IMN drainage [192, 197].

Previous Surgery

Although the lymph drainage is probably changed in patients who have undergone previous breast surgery, current data indicate that lymphatic mapping is feasible with accuracies comparable to the results obtained in the general population [198, 199, 200].

Prior excisional biopsy: The lymph drainage pattern may be altered in patients who have undergone prior procedures, as non-axillary drainage has been identified more often in reoperative SLNB than in primary SLNB. In 73% of such patients, migration to the regional nodal drainage basins has been noted in ipsilateral axillary, supraclavicular, internal mammary, interpectoral, and contralateral axillary nodes [173, 201, 202, 203]. However, there is evidence that sentinel node biopsy performed in the area of previous breast biopsy is not affected significantly by the prior procedure as regards success of the second procedure [204, 205].

Prior other breast surgeries: SLNB can be performed in patients undergoing breast surgery due to a local recurrence after breast conservation surgery in patients with DCIS. Although plastic surgery for breast augmentation or reduction requires major tissue movements, it does not contraindicate the SLN procedure [206, 207].

Prior axillary surgery: A second SLNB can be performed in patients with a local recurrence after breast conservation surgery and negative axillary SLN biopsy, although the success rate may be lower when compared with a primary SLN biopsy. Furthermore, extra-axillary SLNs are visualized more frequently in this group of patients. Encouraging results have been reported regarding axillary recurrences but, due to the rarity of the cases, the evidence is not solid. On the other hand, there is no evidence that these patients benefit from diagnostic axillary lymph node dissection [208].

Axillary Lymph Node Dissection

Review of surveillance, epidemiology, and end-result data has shown that the use of ALND for SLN metastasis has decreased in recent years [53, 209]. Actually, the management of breast cancer continues to advance toward more minimally invasive approaches, and the role of ALND for patients whose SLNs contain metastases is likely to become less important in the future. Cancer biology is much better understood now than it was when ALND was introduced. Consequently, the decision to administer systemic therapy is influenced by a variety of patient- and tumor-related factors, with lymph node tumor status influencing [210, 211, 212], but not necessarily dictating the use of chemotherapy [213, 214, 215].

Indeed, a high rate of locoregional control is achieved with modern multimodality therapy, including axillary radiotherapy (ART), even without ALND. Likewise, no significant difference is observed in disease-free survival or in overall survival between SLN plus ALND and SLN-only groups for selected patients with early nodal metastases, suggesting that ALND might not be required for all SLN-positive breast cancer women [216, 217, 218, 219].

Thus, the ASCO Update Committee recommended that clinicians should avoid ALND in cases of women affected by early-stage breast cancer with one or two SLN metastases, who will receive breast-conserving surgery with conventionally fractionated whole-breast radiotherapy. Instead, clinicians might offer ALND to women suffering from early-stage breast cancer with nodal metastases found on SLNB who will receive mastectomy [43, 44, 50, 220, 221, 222].

Neoadjuvant Chemotherapy

Neoadjuvant systemic chemotherapy (NACT) is established for locally advanced breast cancer and is increasingly used for early-stage disease as well [223, 224]. Debate is ongoing on whether SLNB is accurate enough after NACT or whether it should be performed before starting NACT. Performing SLNB before or after primary systemic treatment has advantages and disadvantages in both cases. Before NACT, SLNB yields a more precise axillary staging, with useful information about possible nodal spread. Nevertheless, the procedure can postpone the beginning of treatment, and two surgeries may be necessary. After NACT, SLNB may lead to an underestimation of the initial stage of the disease because the tumor regression pattern in the axilla is unknown [225, 226, 227]. On the other hand, axillary nodal status after NACT is a highly significant prognostic factor. Pathologic complete response in the axilla can be achieved in up to 40% of patients. These patients can be spared ALND and the associated morbidity. Available data show that SLNB following NACT in cN0 patients is acceptable [226, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238].

A second issue concerns the possibility to perform SLNB in patients with initial node-positive disease who are downstaged by NACT to cN0. At present, SLNB may not be routinely recommended after NACT in patients with prior metastatic nodes. Changes in approach and patient selection would be necessary to support the use of SLN surgery as an alternative to ALND in this patient population [160, 239, 240, 241, 242, 243].

Pregnancy

Many studies have demonstrated that prenatal doses from sentinel node imaging, when properly performed, are low enough that they do not significantly increase the risk of prenatal death, malformation, or mental impairment (see further below in the “Radioprotection” section) [244, 245, 246, 247]. Thus, pregnancy is not an absolute contraindication for SLNB, in patients with early lesions and clinically/US negative axilla, but it is recommended to reduce the time interval between lymphoscintigraphy and surgery in order to reduce the injected activity (i.e., using a single day protocol). Furthermore, since small quantities of the radioactive colloid may be excreted with breast milk, lactation should be suspended for 24 h after radiopharmaceutical administration. It is also important to consider that vital dyes may have some contraindications in pregnancy [248, 249, 250]. Pregnant women with breast cancer should be followed by a multidisciplinary team and be clearly informed about the potential risks of radioactive tracers balanced against the risk of delaying therapy or omitting nodal staging [248, 251].

Primary Localizing Techniques

ROLL

Screening programs for breast cancer have led to an increase in detection of non-palpable breast tumors. Current approaches to breast cancer surgery aim at removing the lesion with an adequate clearance margin while, at the same time, accurately assessing the risk of distant metastases. Effective localization procedures are required to ensure complete excision of small non-palpable lesions detected on either symptomatic mammography or screening mammography. Several localization techniques have been developed for this purpose.

Hook-wire localization of non-palpable lesions has been the most widely used preoperative technique for many years. Although this is a reasonably effective technique, it involves a number of disadvantages. First, the entry site of the wire is often not at the ideal location for surgical incision at the time of operation. This may lead to additional unnecessary dissection and suboptimal cosmetic results. In addition, the wire must be placed on the day of operation, necessitating the coordination of radiology and operative schedules. The most important disadvantage, however, is the inaccuracy of localizing the target lesion percutaneously and during dissection. This results in high rates of reoperation for tissue margins involved in carcinoma [252, 253].

Intraoperative US imaging without preoperative wire localization has been used to map excision of non-palpable breast lesions; however, this technique has limitations, as it is feasible only in patients whose breast lesion is visible at US imaging [254, 255, 256, 257, 258, 259].

The “radioguided occult lesion localization” (ROLL) approach [260, 261, 262] has gained popularity for non-palpable tumor lesions, including breast cancer. ROLL involves injection, into the center of the lesion, of a small amount of radioactive tracer that does not migrate from the site of interstitial injection, typically 99mTc-MAA. Injection is performed on the same day or on the day before surgery, under mammographic or US guidance (activity injected ranges from 2 to 150 MBq). Surgeons identify the lesion intraoperatively as a hot spot by using a handheld gamma probe, which allows accurate lesion localization and removal with minimal excision of healthy tissue (the skin incision is made at the site with highest counts or at a site suitable for oncoplastic breast surgery). After specimen resection, residual activity in the surgical field must be checked to avoid the possibility of missing some residual involved tissue [263]. This technique enables a good cosmetic outcome.

ROLL is a well-tolerated and feasible technique for localizing early-stage breast cancer in the course of breast-conserving surgery and is a suitable replacement for wire-guided localization [264, 265, 266, 267, 268]. Reported advantages of the ROLL technique include (i) easy and precise intraoperative localization of the breast lesion; (ii) complete lesion resection, with free margins and reduced needs for second operations; (iii) an increased capacity to center the lesion within the specimen; and (iv) a surgical approach (skin incision) that is independent from the intralesional radiotracer injection procedure [269, 270, 271, 272, 273]. Some potential pitfalls have been described; these are related to possible radiotracer spillage, contamination of the skin, or the injection path or ductal diffusion, as well as the presence of microcalcifications or DCIS [270, 271]. However, a systematic review of the ROLL technique concluded that this approach compares favorably to conventional wire localization for non-palpable breast lesions (Table 3) [267].
Table 3

Studies comparing ROLL and hook-wire techniques [266]

Authors

n (ROLL–hook wire)

Detection (%)

Free margins (ROLL versus hook wire) (%)

p

Gallegos, 2004

132 (65–67)

100

83 versus 64

0.014

Macmillan, 2004

95 (48–47)

100

61 versus 72

NS

Nadeem, 2004

130 (65–65)

100

83 versus 57

0.001

Thind, 2005

140 (70–70)

100

84 versus 60

0.002

Zgajnar, 2004

143 (51–92)

100

70 versus 44

 

Rönkä, 2005

78 (64–14)

100

89 versus 79

0.05

Fraile, 2005

233 (65–168)

100

80 versus 70

NS

Strnad, 2006

33 (21–12)

100

Hook wire < ROLL

NS

It is important to notice that radiation doses at the injection site and patient and staff absorbed doses are maintained well within the recommended limits established by the International Commission on Radiological Protection (ICRP) [274]. Finally, the possibility of performing ROLL after systemic intravenous administration of 99mTc-sestamibi (as a nonspecific, tumor-seeking agent) on the day of surgery has also been described [275].

SNOLL

As ROLL is an excellent technique enabling the removal of small breast cancers, the possibility to simultaneously perform SLNB without compromising oncological safety and the SLN detection rate is very important. Different techniques have been described to identify the SLNs in combination with ROLL, the so-called sentinel node occult lesion localization (SNOLL) [269, 276, 277, 278, 279, 280, 281, 282, 283, 284].

An intratumoral injection of 99mTc-MAA for ROLL of a tumor may be associated with a subdermal injection of 99mTc-nanocolloid for SLN mapping and SLNB. When the lesions are located near to the areola, intraoperative interference between the tracers could be avoided by elevation of the dermis and the subdermal area after skin incision [276]. Another possibility is to use a single intratumoral injection for both ROLL and SNOLL in the same session [280]. As a single procedure for localization of breast lesions and sentinel nodes, SNOLL may improve the entire surgical procedure. The majority of the studies published so far show a high percentage of successful tumor resection and intraoperative SLN localization with reduced failure [267, 269, 276, 279, 280, 281, 282, 283, 284].

Radioactive Seeds

Alternatives to hook-wire localization of occult breast lesions include carbon trace as well as the use of sealed radioactive seeds. The seeds are essentially the same as the ones used in brachytherapy for cancer of the prostate, namely, a 4.5–0.8 mm titanium capsule containing a ceramic cylinder enriched with 125I-iodine. Iodine-125 has a long decay time (half-life of 59.4 days) and emits low-energy photons (27 keV). The use of one or two seeds with this low photon energy has a negligible effect on the surrounding tissue. The radioactive seed is placed in the center of the breast lesion using an 18 G needle fixed in a needle holder under mammographic or ultrasonographic guidance; after successful positioning, the exact location is confirmed by mammography. During surgery, excision of the lesion is guided by using a handheld gamma probe [285].

If a SNOLL technique is scheduled, the 99mTc-colloid is subsequently injected, around the tumor or through a superficial route. Thus, the handheld gamma probe can be switched between the 27 keV energy window of the 125I source and the 140 keV of 99mTc, allowing discrimination between the emissions of the two radioisotopes. Effective seed removal is verified by the absence of 125I activity in the breast and its presence in the specimen. X-ray of the surgical specimen may confirm the presence of the seed and the relation of the lesion to the resection margins.

It has been shown that radioguided seed localization in non-palpable breast lesions is at least equivalent to the hook-wire technique in terms of ease of procedure, removing the target lesion, volume of breast tissue excised, obtaining negative margins, avoiding a second operative intervention, and allowing for simultaneous axillary staging [285, 286, 287, 288, 289].

Added Value of Intraoperative Portable Gamma Cameras

Recently, several types of portable or handheld mini gamma cameras have become available for clinical practice; while some of these portable gamma cameras are not specifically designed for radioguided surgery, other models are focused on different applications of SLNB [4, 5, 290, 291].

Appropriate use of a portable gamma camera enhances the reliability of the gamma probe by adding a clear image of the surgical field. The use of an intraoperative imaging device implies the possibility to better plan the surgical approach, to localize surgical targets in complex anatomical areas, to monitor the lymphatic basin before and after removal of the hot nodes, and, above all, to verify the correct SLN excision. Moreover, the use of point sources (e.g., 133Ba or 125I) facilitates SLN localization, as these sources can be depicted separately on the screen of the portable gamma camera, thus functioning as a pointer in the search for the SLNs. Nevertheless, their role in breast cancer surgery is still to be clarified. Intraoperative imaging using a portable gamma camera might be useful only when no conventional gamma camera is available for preoperative imaging, in particular in cases with extra-axillary drainage. Portable gamma cameras have also been used with promising results in other GOSTT environments regarding breast cancer, such as in ROLL or SNOLL procedures [290, 291, 292, 293, 294, 295, 296].

An interesting recent development of intraoperative imaging consists in combining conventional gamma probes with position and orientation tracking systems such as the so-called freehand SPECT, which permits a virtual reconstruction in a 3D environment (see Fig. 9) [4, 5, 293]. All these technologies will play an increasing role in the future extension of the GOSTT concept, in order to provide a better roadmap for radioguided surgery [2, 5].
Fig. 9

Radioguided sentinel lymph node and occult lesion localization (SNOLL) in a patient with breast cancer using a single intratumoral injection of 99mTc-nanocolloidal albumin. Using a freehand SPECT probe (a), first the axillary sentinel lymph node is removed (b). Subsequently, the primary lesion is detected (c) following an image-guided procedure (d). Finally, the freehand SPECT probe (e) is used to visualize the primary tumor in relation to the margins of the specimen (f)

Radioprotection

Nuclear medicine, surgery, and pathology professionals are involved if a radiopharmaceutical is used in a sentinel node procedure. Each involved practitioner (nuclear physician, surgeon, personnel in the surgical suite, pathologist) and the patient undergoing SLN and/or ROLL procedures are exposed to radiation. The exposures received by each, when radioactive activities standard for SLN procedures are administered, are well below recommended limits for both public and occupational exposures.

Estimates of radiation exposures for patients [244, 297, 298, 299, 300, 301, 302], surgeons [299, 300, 301, 303, 304, 305, 306, 307, 308, 309], and pathologists [299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311] have been reported by several investigators. Table 4 presents a summary and interpretation of most of the available data. The estimates in the second column were extracted or derived from information in the included references. The values in the third column assume that SLN procedures were conducted on 100 patients in a year and assume that each patient was injected with an activity of 18.5 MBq. Columns four and five are International Commission on Radiological Protection (ICRP) recommended public and occupational limits [310].
Table 4

Ranges of estimates of radiation exposures (Modified from [71])

Radiation exposure

Range of estimates (mSv/MBq)

×18.5 MBq

×100 patients/year (mSv/year)

Public limit (mSv/year)

Occupational limit (mSv/year)

Injection site absorbed dose

1–50

<925

   

Injected breast equivalent dose

0.03–0.8

<15

   

Patient effective dose

0.002–0.03

<0.56

 

<1

 

Fetus/uterus equivalent dose

0.00003–0.0009

<0.017

 

<1

 

Surgeon lens-of-eye equivalent dose

0.00009

 

<0.17

<15

<150

Surgeon hand equivalent dose

0.0004–0.01

 

<19

<50

<500

Surgeon effective dose

0.00004–0.0003

 

<0.56

<1

<20

Pathologist lens-of-eye equivalent dose

0.00001–0.00003

 

<0.056

<15

<150

Pathologist hand equivalent dose

0.00001–0.001

 

<1.9

<50

<500

Pathologist effective dose

0.000004–0.0002

 

<0.37

<1

<20

Repeated measurements have clearly demonstrated that exposures to patients and personnel involved in radioguided SLN procedures (surgeon, nurse, pathologist) are minimal. Since exposures in SLN procedures of all nonnuclear medicine personnel are sufficiently low, none need be monitored routinely for occupational radiation exposure. Low patient effective doses and very low fetus/uterus equivalent doses [244, 299, 312, 313, 314] indicate that exposure to radiation is not a contraindication for an SLN procedure on any patient, including pregnant women. However, prudence dictates care should be exhibited when conducting an SLN procedure on any patient. For patients who are breastfeeding, nursing should be suspended for 24 h following radiopharmaceutical administration. Obviously, when using a 57Co flood transmission source or SPECT/CT imaging, the total exposure is the emission-generated dose plus the transmission-generated dose [315].

Although the dose absorbed at the injection site can be relevant (see Table 4), there are no known negative consequences at the injection site. In fact, the site is often, though not always, excised. Furthermore, the radiation dose caused by the radionuclide-based procedure is very small relative to that received from postoperative radiation therapy.

Because exposures in SLN procedures of all nonnuclear medicine personnel are sufficiently low, none need be monitored routinely for radiation exposure. Finally, contamination with residual radioactivity of material from the operating room (surgical gauzes, liquids, and biological tissues of the patient) is minimal already at the time of surgery. Due to the fast physical decay of 99mTc, it is sufficient to wait only a few hours before disposal of operating room material to ensure an almost nonexistent radioactivity exposure to personnel [299].

Future Perspectives

The possibility of combining currently used radiotracers with other imaging agents opens new avenues for further developments. In this regard, hybrid tracers containing both a radioactive and a fluorescence label have recently been introduced (see Fig. 10), thus enabling the direct integration of conventional preoperative imaging with intraoperative radio- and fluorescence guidance to the SLN via one single tracer injection [54].
Fig. 10

Resection of an infraclavicular sentinel lymph node in a patient with high-risk breast cancer using the hybrid tracer ICG-99mTc-nanocolloid. The sentinel lymph node is first located on the skin projection using a portable gamma camera (a) and a handheld gamma probe (b). Subsequently, a portable near-infrared camera (c) is used to depict the fluorescence signal on the screen (d). This enables to remove the node (e) and to perform ex vivo control of the fluorescence signal (f, g)

Competitive methods are emerging: the techniques for SLNB that are not radioactivity-dependent or that refine the existing method (i.e., indocyanine green fluorescence, contrast-enhanced ultrasound using microbubbles, and superparamagnetic iron oxide nanoparticles) are particularly interesting [316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332]. In particular, the SentiMAG Multicentre Trial demonstrated that the magnetic technique with superparamagnetic iron oxide (SPIO) is feasible for SLNb, with an identification rate that is not inferior to the standard technique [333, 334, 335, 336, 337]. Recently, it has been shown that the SLN status can be evaluated with high accuracy preoperatively using contrast-enhanced color Doppler ultrasonography [338, 339].

However, a systematic review suggested that these new methods have clinical potential but yield high levels of false-negative results and presently cannot challenge the existing standard procedure. Further assessment of these techniques against the standard dual technique in randomized trials is thus needed [340].

Concluding Remarks

The development and wide acceptance of SLNB has deeply affected the management of breast cancer. Several technical and clinical controversies have been raised during the development of this technique. The resolution of these controversies should result in the standardization of the procedure and in the expansion of the number of patients evaluated with SLNB in the future. The modern approach in breast cancer care, which includes more detailed screening diagnostics, pathological evaluation, improved planning of surgical and radiation therapy, and more effective systemic treatment, emphasizes the need for ongoing reevaluation of the “standard” locoregional therapy [341, 342].

References

  1. 1.
    Mariani G, Giuliano AE, Strauss HW, editors. Radioguided surgery – a comprehensive team approach. New York: Springer; 2008.Google Scholar
  2. 2.
    Zaknun JJ, Giammarile F, Valdés Olmos R, Vidal-Sicart S, Mariani G. Changing paradigms in radioguided surgery and intraoperative imaging: the GOSTT concept. Eur J Nucl Med Mol Imaging. 2012;39:1–3.PubMedCrossRefGoogle Scholar
  3. 3.
    Chin PT, Welling MM, Meskers SC, Valdes Olmos RA, Tanke H, van Leeuwen FW. Optical imaging as an expansion of nuclear medicine: cerenkov-based luminescence vs fluorescence-based luminescence. Eur J Nucl Med Mol Imaging. 2013;40:1283–91.PubMedCrossRefGoogle Scholar
  4. 4.
    Vidal-Sicart S, Rioja ME, Paredes P, Keshtgar MR, Valdés Olmos RA. Contribution of perioperative imaging to radioguided surgery. Q J Nucl Med Mol Imaging. 2014;58:140–60.PubMedGoogle Scholar
  5. 5.
    Valdés Olmos RA, Vidal-Sicart S, Giammarile F, Zaknun JJ, Van Leeuwen FW, Mariani G. The GOSTT concept and hybrid mixed/virtual/augmented reality environment radioguided surgery. Q J Nucl Med Mol Imaging. 2014;58:207–15.PubMedGoogle Scholar
  6. 6.
    KleinJan GH, van den Berg NS, de Jong J, Wit EM, Thygessen H, Vegt E, van der Poel HG, van Leeuwen FW. Multimodal hybrid imaging agents for sentinel node mapping as a means to (re)connect nuclear medicine to advances made in robot-assisted surgery. Eur J Nucl Med Mol Imaging. 2016;43:1278–87.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Cabañas RM. An approach for the treatment of penile carcinoma. Cancer. 1977;39:456–66.PubMedCrossRefGoogle Scholar
  8. 8.
    Ollila DW, Brennan MB, Giuliano AE. The role of intraoperative lymphatic mapping and sentinel lymphadenectomy in the management of patients with breast cancer. Adv Surg. 1999;32:349–64.PubMedGoogle Scholar
  9. 9.
    Nieweg OE, Tanis PJ, Kroon BBR. The definition of a sentinel node. Ann Surg Oncol. 2001;9:538–41.CrossRefGoogle Scholar
  10. 10.
    Mariani G, Manca G, Valdés AR, Orsini F, Vidal-Sicart S, editors. Atlas of lymphoscintigraphy and sentinel node mapping – a pictorial case-based approach. Milan: Springer; 2013.Google Scholar
  11. 11.
    de Bree R, Nieweg OE. The history of sentinel node biopsy in head and neck cancer: from visualization of lymphatic vessels to sentinel nodes. Oral Oncol. 2015;51:819–23.PubMedCrossRefGoogle Scholar
  12. 12.
    Smith B, Backes F. The role of sentinel lymph nodes in endometrial and cervical cancer. J Surg Oncol. 2015;112:753–60.PubMedCrossRefGoogle Scholar
  13. 13.
    Yashiro M, Matsuoka T. Sentinel node navigation surgery for gastric cancer: overview and perspective. World J Gastrointest Surg. 2015;27(7):1–9.Google Scholar
  14. 14.
    Jakobsen JK. Sentinel node biopsy in uro-oncology: a history of the development of a promising concept. Urol Oncol. 2015;33:486–93.PubMedCrossRefGoogle Scholar
  15. 15.
    Shersher DD, Liptay MJ. Status of sentinel lymph node mapping in non-small cell lung cancer. Cancer J. 2015;21:17–20.PubMedCrossRefGoogle Scholar
  16. 16.
    Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin. 2015;65:5–29.PubMedCrossRefGoogle Scholar
  17. 17.
    Zurrida S, Veronesi U. Milestones in breast cancer treatment. Breast J. 2015;21:3–12.PubMedCrossRefGoogle Scholar
  18. 18.
    Veronesi U, De Cicco C, Galimberti VE, et al. A comparative study on the value of FDG-PET and sentinel node biopsy to identify occult axillary metastases. Ann Oncol. 2007;18:473–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Liu Y. Role of FDG PET-CT in evaluation of locoregional nodal disease for initial staging of breast cancer. World J Clin Oncol. 2014;5:982–9.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Futamura M, Asano T, Kobayashi K, et al. Prediction of macrometastasis in axillary lymph nodes of patients with invasive breast cancer and the utility of the SUV lymph node/tumor ratio using FDG-PET/CT. World J Surg Oncol. 2015;13:49.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Krammer J, Schnitzer A, Kaiser CG, et al. 18F-FDG PET/CT for initial staging in breast cancer patients – is there a relevant impact on treatment planning compared to conventional staging modalities? Eur Radiol. 2015;25:2460–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Boone BA, Huynh C, Spangler ML, et al. Axillary lymph node burden in invasive breast cancer: a comparison of the predictive value of ultrasound-guided needle biopsy and sentinel lymph node biopsy. Clin Breast Cancer. 2015;15:e243–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Hyun SJ, Kim EK, Yoon JH, Moon HJ, Kim MJ. Adding MRI to ultrasound and ultrasound-guided fine-needle aspiration reduces the false-negative rate of axillary lymph node metastasis diagnosis in breast cancer patients. Clin Radiol. 2015;70:716–22.PubMedCrossRefGoogle Scholar
  24. 24.
    You S, Kang DK, Jung YS, An YS, Jeon GS, Kim TH. Evaluation of lymph node status after neoadjuvant chemotherapy in breast cancer patients: comparison of diagnostic performance of ultrasound, MRI and 18F-FDG PET/CT. Br J Radiol. 2015;88(1052):20150143.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Beek MA, Verheuvel NC, Luiten EJ, et al. Two decades of axillary management in breast cancer. Br J Surg. 2015;102:1658–64.PubMedCrossRefGoogle Scholar
  26. 26.
    Keshtgar MRS, Ell PJ. Sentinel lymph node detection and imaging. Eur J Nucl Med. 1999;26:57–67.PubMedCrossRefGoogle Scholar
  27. 27.
    Chatterjee A, Serniak N, Czerniecki BJ. Sentinel lymph node biopsy in breast cancer: a work in progress. Cancer J. 2015;21:7–10.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg. 1992;127:392–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Nieweg OE, Uren RF, Thompson JF. The history of sentinel lymph node biopsy. Cancer J. 2015;21:3–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Krag DN, Weaver D, Alex JC, Fairbank JT. Surgical resection and radiolocalization of sentinel lymph node in breast cancer using a gamma probe. Surg Oncol. 1993;2:335–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Giuliano AE, Kirgan D, Guenther JM. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg. 1994;220:391–401.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Noguchi M, Katev N, Miyazaki I. Diagnosis of axillary lymph node metastases in patients with breast cancer. Breast Cancer Res Treat. 1996;40:283–93.PubMedCrossRefGoogle Scholar
  33. 33.
    Taylor A, Murray D, Herda S, Vansant J, Alazraki N. Dynamic lymphoscintigraphy to identify the sentinel and satellite nodes. Clin Nucl Med. 1996;21:755–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Pijpers R, Meijer S, Hoekstra OS, et al. Impact of lymphoscintigraphy on sentinel node identification with technetium-99m-colloid albumin in breast cancer. J Nucl Med. 1997;38:366–8.PubMedGoogle Scholar
  35. 35.
    Giuliano AE. Lymphatic mapping and sentinel node biopsy in breast cancer. JAMA. 1997;277:791–2.PubMedCrossRefGoogle Scholar
  36. 36.
    Veronesi U, Paganelli G, Galimberti V, et al. Sentinel node biopsy to avoid axillary dissection in breast cancer patients with clinically negative lymph-nodes. Lancet. 1997;349:1864–7.PubMedCrossRefGoogle Scholar
  37. 37.
    International Breast Cancer Consensus Conference. Image-detected breast cancer: state of the art diagnosis and treatment. International Breast Cancer Consensus Conference. J Am Coll Surg. 2001;193:297–302.CrossRefGoogle Scholar
  38. 38.
    Mariani G, Moresco L, Viale G, et al. Radioguided sentinel lymph node biopsy in breast cancer surgery. J Nucl Med. 2001;42:1198–215.PubMedGoogle Scholar
  39. 39.
    Veronesi U, Paganelli G, Viale G, et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med. 2003;349:546–53.PubMedCrossRefGoogle Scholar
  40. 40.
    Veronesi U, Paganelli G, Viale G, et al. Sentinel-lymph-node biopsy as a staging procedure in breast cancer: update of a randomized controlled study. Lancet Oncol. 2006;7:983–90.PubMedCrossRefGoogle Scholar
  41. 41.
    Benson JR, Della Rovere GQ, Axilla Management Consensus Group. Management of the axilla in women with breast cancer. Lancet Oncol. 2007;8:331–48.PubMedCrossRefGoogle Scholar
  42. 42.
    Giuliano AE, Gangi A. Sentinel node biopsy and improved patient care. Breast J. 2015;21:27–31.PubMedCrossRefGoogle Scholar
  43. 43.
    Lopez Penha TR, van Roozendaal LM, Smidt ML, et al. The changing role of axillary treatment in breast cancer: who will remain at risk for developing arm morbidity in the future? Breast. 2015;24:543–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Layeequr Rahman R, Crawford SL, Siwawa P. Management of axilla in breast cancer – the saga continues. Breast. 2015;24:343–53.PubMedCrossRefGoogle Scholar
  45. 45.
    Pepels MJ, Vestjens JH, de Boer M, et al. Safety of avoiding routine use of axillary dissection in early stage breast cancer: a systematic review. Breast Cancer Res Treat. 2011;125:301–13.PubMedCrossRefGoogle Scholar
  46. 46.
    Atalay C. New concepts in axillary management of breast cancer. World J Clin Oncol. 2014;10:895–900.CrossRefGoogle Scholar
  47. 47.
    Sledge GW, Mamounas EP, Hortobagyi GN, Burstein HJ, Goodwin PJ, Wolff AC. Past, present, and future challenges in breast cancer treatment. J Clin Oncol. 2014;32:1979–86.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Buscombe J, Paganelli G, Burak ZE, European Association of Nuclear Medicine Oncology Committee and Dosimetry Committee, et al. Sentinel node in breast cancer procedural guidelines. Eur J Nucl Med Mol Imaging. 2007;34:2154–9.PubMedCrossRefGoogle Scholar
  49. 49.
    Lizarraga IM, Weigel RJ. Axillary lymph node dissection for breast cancer: primum non nocere. Eur J Surg Oncol. 2015;41:955–7.PubMedCrossRefGoogle Scholar
  50. 50.
    van den Hoven I, Voogd AC, Roumen RM. A paradigm shift in axillary breast cancer treatment; from “treat all-except” toward “treat none-unless”. Clin Breast Cancer. 2015;15:399–402.PubMedCrossRefGoogle Scholar
  51. 51.
    Galimberti V, Manika A, Maisonneuve P, et al. Long-term follow-up of 5262 breast cancer patients with negative sentinel node and no axillary dissection confirms low rate of axillary disease. Eur J Surg Oncol. 2014;40:1203–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Han HJ, Kim JR, Nam HR, Keum KC, Suh CO, Kim YB. Clinical outcomes after sentinel lymph node biopsy in clinically node-negative breast cancer patients. Radiat Oncol J. 2014;32:132–7.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Joyce DP, Manning A, Carter M, et al. Meta-analysis to determine the clinical impact of axillary lymph node dissection in the treatment of invasive breast cancer. Breast Cancer Res Treat. 2015;153:235–40.PubMedCrossRefGoogle Scholar
  54. 54.
    Tsujimoto M. Recent advances in sentinel node biopsy in breast surgery. Breast Cancer. 2015;22:211.PubMedCrossRefGoogle Scholar
  55. 55.
    Suami H, Pan WR, Taylor GI. Historical review of breast lymphatic studies. Clin Anat. 2009;22:531–6.PubMedCrossRefGoogle Scholar
  56. 56.
    Torrenga H, Fabry H, van der Sijp JR, van Diest PJ, Pijpers R, Meijer S. Omitting axillary lymph node dissection in sentinel node negative breast cancer patients is safe: a long term follow-up analysis. J Surg Oncol. 2004;88:4–7.PubMedCrossRefGoogle Scholar
  57. 57.
    Carlo JT, Grant MD, Knox SM, Jones RC, Hamilton CS, Livingston SA, Kuhn JA. Survival analysis following sentinel lymph node biopsy: a validation trial demonstrating its accuracy in staging early breast cancer. BUMC Proc. 2005;18:103–7.Google Scholar
  58. 58.
    Fuhrman GM, Gambino J, Bolton JS, Farr G, Jiang X. Five-year follow-up after sentinel node mapping for breast cancer demonstrates better than expected treatment outcomes. Am Surg. 2005;71:564–9.PubMedGoogle Scholar
  59. 59.
    Sanjuàn A, Vidal-Sicart S, Zanón G, et al. Clinical axillary recurrence after sentinel node biopsy in breast cancer: a follow-up study of 220 patients. Eur J Nucl Med Mol Imaging. 2005;32:932–6.PubMedCrossRefGoogle Scholar
  60. 60.
    Smidt ML, Janssen CM, Kuster DM, Bruggink ED, Strobbe LJ. Axillary recurrence after a negative sentinel node biopsy for breast cancer: incidence and clinical significance. Ann Surg Oncol. 2005;12:29–33.PubMedCrossRefGoogle Scholar
  61. 61.
    Veronesi U, Galimberti V, Mariani L, et al. Sentinel node biopsy in breast cancer: early results in 953 patients with negative sentinel node biopsy and no axillary dissection. Eur J Cancer. 2005;41:197–8.CrossRefGoogle Scholar
  62. 62.
    de Kanter AY, Menke-Pluymers MM, Wouters MW, Burgmans I, van Geel AN, Eggermont AM. Five-year follow-up of sentinel node negative breast cancer patients. Eur J Surg Oncol. 2006;32:282–6.PubMedCrossRefGoogle Scholar
  63. 63.
    Veronesi U, Galimberti V, Paganelli G, et al. Axillary metastases in breast cancer patients with negative sentinel nodes: follow-up of 3,548 cases. Eur J Cancer. 2009;45:1381–8.PubMedCrossRefGoogle Scholar
  64. 64.
    Veronesi U, Viale G, Paganelli G, et al. Sentinel lymph node biopsy in breast cancer: ten-year results of a randomized control study. Ann Surg. 2010;251:595–600.PubMedCrossRefGoogle Scholar
  65. 65.
    Kaufmann M, Morrow M, von Minckwitz G, Harris JR, Biedenkopf Expert Panel Members. Locoregional treatment of primary breast cancer: consensus recommendations from an International Expert Panel. Cancer. 2010;116:1184–91.PubMedCrossRefGoogle Scholar
  66. 66.
    van der Ploeg IM, Nieweg OE, van Rijk MC, Valdés Olmos RA, Kroon BB. Axillary recurrence after a tumour-negative sentinel node biopsy in breast cancer patients: a systematic review and meta-analysis of the literature. Eur J Surg Oncol. 2008;34:1277–84.PubMedCrossRefGoogle Scholar
  67. 67.
    Krag DN, Anderson SJ, Julian TB, et al. Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial. Lancet Oncol. 2010;11:927–33.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Purushotham AD, Upponi S, Klevesath MB, et al. Morbidity after sentinel lymph node biopsy in primary breast cancer: results from a randomized controlled trial. J Clin Oncol. 2005;23:4312–21.PubMedCrossRefGoogle Scholar
  69. 69.
    Mansel RE, Fallowfield L, Kissin M, et al. Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: the ALMANAC Trial. J Natl Cancer Inst. 2006;98:599–609.PubMedCrossRefGoogle Scholar
  70. 70.
    Goyal A, Newcombe RG, Chhabra A, Mansel RE, ALMANAC Trialists Group. Factors affecting failed localisation and false-negative rates of sentinel node biopsy in breast cancer – results of the ALMANAC validation phase. Breast Cancer Res Treat. 2006;99:203–8.PubMedCrossRefGoogle Scholar
  71. 71.
    Giammarile F, Alazraki N, Aarsvold JN, et al. The EANM and SNMMI practice guideline for lymphoscintigraphy and sentinel node localization in breast cancer. Eur J Nucl Med Mol Imaging. 2013;40:1932–47.PubMedCrossRefGoogle Scholar
  72. 72.
    Mount MG, White NR, Nguyen CL, Orr RK, Hird RB. Evaluating one day versus two days preoperative lymphoscintigraphy protocols for sentinel lymph node biopsy in breast cancer. Am Surg. 2015;81:454–7.PubMedGoogle Scholar
  73. 73.
    Wang H, Heck K, Pruitt SK, et al. Impact of delayed lymphoscintigraphy for sentinel lymph node biopsy for breast cancer. J Surg Oncol. 2015;111:931–4.PubMedCrossRefGoogle Scholar
  74. 74.
    Wilhelm AJ, Mijnhout GS, Franssen EJF. Radiopharmaceuticals in sentinel lymph-node detection – an overview. Eur J Nucl Med. 1999;26:S36–42.PubMedCrossRefGoogle Scholar
  75. 75.
    Clarke D, Khoni N, Mansel ER. Sentinel node biopsy in breast cancer. ALMANAC trial. World J Surg. 2001;25:819–22.PubMedCrossRefGoogle Scholar
  76. 76.
    Burak WE, Agnese DM, Povoski SP. Advances in the surgical management of early stage invasive breast cancer. Curr Probl Surg. 2004;41:877–936.CrossRefGoogle Scholar
  77. 77.
    Bourgeois P. Scintigraphic investigations of the lymphatic system: the influence of injected volume and quantity of labeled colloidal tracer. J Nucl Med. 2007;48:693–5.PubMedCrossRefGoogle Scholar
  78. 78.
    Lyman GH, Giuliano AE, Somerfield MR, et al. American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in early-stage breast cancer. J Clin Oncol. 2005;23:7703–20.PubMedCrossRefGoogle Scholar
  79. 79.
    Vera DR, Wallace AM, Hoh CK. A synthetic macromolecule for sentinel node detection: 99mTc-DTPA-mannosyl-dextran. J Nucl Med. 2001;42:951–9.PubMedGoogle Scholar
  80. 80.
    Wallace AM, Han LK, Povoski SP, et al. Comparative evaluation of [99mTc]tilmanocept for sentinel lymph node mapping in breast cancer patients: results of two phase 3 trials. Ann Surg Oncol. 2013;20:2590–9.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Dambros Gabbi MC, Masiero PR, Uchoa D, Moraes IV, Biazus JV, Edelweiss MI. Comparison between preoperative and intraoperative injection of 99mTc Dextran-500 for sentinel lymph node localization in breast cancer. Am J Nucl Med Mol Imaging. 2014;4:602–10.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Baker JL, Pu M, Tokin CA, et al. Comparison of [99mTc]tilmanocept and filtered [99mTc]sulfur colloid for identification of SLNs in breast cancer patients. Ann Surg Oncol. 2015;22:40–5.PubMedCrossRefGoogle Scholar
  83. 83.
    McCarter MD, Yeung H, Yeh S, et al. Localization of the sentinel node in breast cancer: identical results with same-day and day-before isotope injection. Ann Surg Oncol. 2001;8:682–6.PubMedCrossRefGoogle Scholar
  84. 84.
    van der Ent FW, Kengen RA, van der Pol HA, Hoofwijk AG. Sentinel node biopsy in 70 unselected patients with breast cancer: increased feasibility by using 10 mCi radiocolloid in combination with a blue dye tracer. Eur J Surg Oncol. 1999;25:24–9.PubMedCrossRefGoogle Scholar
  85. 85.
    Gray RJ, Pockaj BA, Roarke MC. Injection of 99mTc-labeled sulfur colloid the day before operation for breast cancer sentinel lymph node mapping is as successful as injection the day of operation. Am J Surg. 2004;188:685–9.PubMedCrossRefGoogle Scholar
  86. 86.
    Suami H, Pan WR, Mann GB, Taylor GI. The lymphatic anatomy of the breast and its implications for sentinel lymph node biopsy: a human cadaver study. Ann Surg Oncol. 2008;15:863–71.PubMedCrossRefGoogle Scholar
  87. 87.
    Ahmed M, Purushotham AD, Horgan K, Klaase JM, Douek M. Meta-analysis of superficial versus deep injection of radioactive tracer and blue dye for lymphatic mapping and detection of sentinel lymph nodes in breast cancer. Br J Surg. 2015;102:169–81.PubMedCrossRefGoogle Scholar
  88. 88.
    Tanis PJ, Valdés Olmos RA, Muller SH, Nieweg OE. Lymphatic mapping in patients with breast carcinoma: reproducibility of lymphoscintigraphic results. Radiology. 2003;228:546–51.PubMedCrossRefGoogle Scholar
  89. 89.
    Tanis PJ, Nieweg OE, Valdes Olmos RA, Kroon BB. Anatomy and physiology of lymphatic drainage of the breast from the perspective of sentinel node biopsy. J Am Coll Surg. 2001;192:399–409.PubMedCrossRefGoogle Scholar
  90. 90.
    Hindie E, Groheux D, Espie M, et al. Sentinel node biopsy in breast cancer. Bull Cancer. 2009;96:713–25.PubMedGoogle Scholar
  91. 91.
    Pelosi E, Bello M, Griors M, et al. Sentinel lymph node detection in patients with early-stage breast cancer: comparison of periareolar and subdermal/peritumoral injection techniques. J Nucl Med. 2004;45:220–5.PubMedGoogle Scholar
  92. 92.
    Chakera AH, Friis E, Hesse U, et al. Factors of importance for scintigraphic non-visualization of sentinel nodes in breast cancer. Eur J Nucl Med Mol Imaging. 2005;32:286–93.PubMedCrossRefGoogle Scholar
  93. 93.
    Nieweg OE, Estourgie SH, van Rijk MC, Kroon BB. Rationale for superficial injection techniques in lymphatic mapping in breast cancer patients. J Surg Oncol. 2004;87:153–6.PubMedCrossRefGoogle Scholar
  94. 94.
    Noguchi M, Inokuchi M, Zen Y. Complement of peritumoral and subareolar injection in breast cancer sentinel lymph node biopsy. J Surg Oncol. 2009;100:100–5.PubMedCrossRefGoogle Scholar
  95. 95.
    Povoski SP, Olsen JO, Young DC, et al. Prospective randomized clinical trial comparing intradermal, intraparenchymal, and subareolar injection routes for sentinel lymph node mapping and biopsy in breast cancer. Ann Surg Oncol. 2006;13:1412–21.PubMedCrossRefGoogle Scholar
  96. 96.
    Linehan DC, Hill ADK, Akhurst T, et al. Intradermal radiocolloid and intraparenchymal blue dye injection optimize sentinel node identification in breast cancer patients. Ann Surg Oncol. 1999;6:286–93.CrossRefGoogle Scholar
  97. 97.
    Pesek S, Ashikaga T, Krag LE, Krag D. The false-negative rate of sentinel node biopsy in patients with breast cancer: a meta-analysis. World J Surg. 2012;36:2239–51.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Martin 2nd RC, Edwards MJ, Wong SL, et al. Practical guidelines for optimal gamma probe detection of sentinel lymph nodes in breast cancer: results of a multi-institutional study. Surgery. 2000;128:139–44.PubMedCrossRefGoogle Scholar
  99. 99.
    Paganelli G, Galimberti V, Trifirò G, et al. Internal mammary node lymphoscintigraphy and biopsy in breast cancer. Q J Nucl Med. 2002;46:138–44.PubMedGoogle Scholar
  100. 100.
    Krynyckyi BR, Chun H, Kim HH, Eskandar Y, Kim CK, Machac J. Factors affecting visualization rates of internal mammary sentinel nodes during lymphoscintigraphy. J Nucl Med. 2003;44:1387–93.PubMedGoogle Scholar
  101. 101.
    Kumar R, Jana S, Heiba SI, et al. Retrospective analysis of sentinel node localization in multifocal multicentric, palpable, or non palpable breast cancer. J Nucl Med. 2003;44:7–10.PubMedGoogle Scholar
  102. 102.
    Knauer M, Konstantiniuk P, Haid A, et al. Multicentric breast cancer: a new indication for sentinel node biopsy – a multi-institutional validation study. J Clin Oncol. 2006;24:3374–80.PubMedCrossRefGoogle Scholar
  103. 103.
    Uren RF, Howman-Giles R, Chung D, Thompson JF. Imaging sentinel lymph nodes. Cancer J. 2015;21:25–32.PubMedCrossRefGoogle Scholar
  104. 104.
    Moncayo VM, Aarsvold JN, Alazraki NP. Lymphoscintigraphy and sentinel nodes. J Nucl Med. 2015;56:901–7.PubMedCrossRefGoogle Scholar
  105. 105.
    McMasters KM, Wong SL, Tuttle TM, et al. Preoperative lymphoscintigraphy for breast cancer does not improve the ability to identify axillary sentinel lymph nodes. Ann Surg. 2000;231:724–31.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Marchal F, Rauch P, Morel O, et al. Results of preoperative lymphoscintigraphy for breast cancer are predictive of identification of axillary sentinel lymph nodes. World J Surg. 2006;30:55–62.PubMedCrossRefGoogle Scholar
  107. 107.
    De Cicco C, Cremonesi M, Luini A, et al. Lymphoscintigraphy and radioguided biopsy of the sentinel axillary node in breast cancer. J Nucl Med. 1998;39:2080–4.PubMedGoogle Scholar
  108. 108.
    Babiera GV, Delpassand ES, Breslin TM, et al. Lymphatic drainage patterns on early versus delayed breast lymphoscintigraphy performed after injection of filtered Tc-99m sulfur colloid in breast cancer patients undergoing sentinel lymph node biopsy. Clin Nucl Med. 2005;30:11–5.PubMedCrossRefGoogle Scholar
  109. 109.
    Lerman H, Metser U, Lievshitz G, et al. Lymphoscintigraphic sentinel node identification in patients with breast cancer: the role of SPECT-CT. Eur J Nucl Med Mol Imaging. 2006;33:329–37.PubMedCrossRefGoogle Scholar
  110. 110.
    Keidar Z, Israel O, Krausz Y. SPECT/CT in tumor imaging: technical aspects and clinical applications. Semin Nucl Med. 2003;33:205–18.PubMedCrossRefGoogle Scholar
  111. 111.
    Vermeeren L, van der Ploeg IM, Valdes Olmos RA, et al. SPECT/CT for preoperative sentinel node localization. J Surg Oncol. 2010;101:184–90.PubMedGoogle Scholar
  112. 112.
    van der Ploeg IM, Nieweg OE, Kroon BB, et al. The yield of SPECT/CT for anatomical lymphatic mapping in patients with breast cancer. Eur J Nucl Med Mol Imaging. 2009;36:903–9.PubMedCrossRefGoogle Scholar
  113. 113.
    Jimenez-Heffernan A, Ellman A, et al. Results of a prospective International Atomic Energy Ahency (IAEA) sentinel node trial on the value of SPECT/CT over planar imaging in various malignancies. J Nucl Med. 2015;56:1338–44.PubMedCrossRefGoogle Scholar
  114. 114.
    Even-Sapir E, Lerman H, Lievshitz G, et al. Lymphoscintigraphy for sentinel node mapping using a hybrid SPECT/CT system. J Nucl Med. 2003;44:1413–20.PubMedGoogle Scholar
  115. 115.
    Lerman H, Lievshitz G, Zak O, Metser U, Schneebaum S, Even-Sapir E. Improved sentinel node identification by SPECT/CT in overweight patients with breast cancer. J Nucl Med. 2007;48:201–6.PubMedGoogle Scholar
  116. 116.
    Valdés Olmos RA, Rietbergen DD, Vidal-Sicart S, Manca G, Giammarile F, Mariani G. Contribution of SPECT/CT imaging to radioguided sentinel lymph node biopsy in breast cancer, melanoma, and other solid cancers: from “open and see” to “see and open”. Q J Nucl Med Mol Imaging. 2014;58:127–39.PubMedGoogle Scholar
  117. 117.
    Serrano-Vicente J, Rayo-Madrid JI, Domínguez-Grande ML, et al. Role of SPECT-CT in breast cancer sentinel node biopsy when internal mammary chain drainage is observed. Clin Transl Oncol. 2016;18:418–25.PubMedCrossRefGoogle Scholar
  118. 118.
    Tomiguchi M, Yamamoto-Ibusuki M, Yamamoto Y, et al. Prediction of sentinel lymph node status using single-photon emission computed tomography (SPECT)/computed tomography (CT) imaging of breast cancer. Surg Today. 2016;46:214–23.PubMedCrossRefGoogle Scholar
  119. 119.
    Vidal-Sicart S, Brouwer OR, Valdés-Olmos RA. Evaluation of the sentinel lymph node combining SPECT/CT with the planar image and its importance for the surgical act. Rev Esp Med Nucl. 2011;30:331–7.PubMedCrossRefGoogle Scholar
  120. 120.
    Uren RF, Howman-Giles R, Chung D, Thompson JF. Nuclear medicine aspects of melanoma and breast lymphatic mapping. Semin Oncol. 2004;31:338–48.PubMedCrossRefGoogle Scholar
  121. 121.
    van Rijk MC, Tanis PJ, Nieweg OE, et al. Clinical implications of sentinel nodes outside the axilla and internal mammary chain in patients with breast cancer. J Surg Oncol. 2006;94:281–6.PubMedCrossRefGoogle Scholar
  122. 122.
    Estourgie SH, Nieweg OE, Valdés Olmos RA, Rutgers EJ, Peterse JL, Kroon BB. Eight false-negative sentinel lymph node procedures in breast cancer: what went wrong? Eur J Surg Oncol. 2003;29:336–40.PubMedCrossRefGoogle Scholar
  123. 123.
    OʼReilly EA, Prichard RS, Al Azawi D, et al. The value of isosulfan blue dye in addition to isotope scanning in the identification of the sentinel lymph node in breast cancer patients with a positive lymphoscintigraphy: a randomized controlled trial (ISRCTN98849733). Ann Surg. 2015;262:243–8.PubMedCrossRefGoogle Scholar
  124. 124.
    Anan K, Mitsuyama S, Kuga H, et al. Double mapping with subareolar blue dye and peritumoral green dye injections decreases the false negative rate of dye only sentinel node biopsy for early breast cancer: 2 site injection is more accurate than 1-site injection. Surgery. 2006;139:624–9.PubMedCrossRefGoogle Scholar
  125. 125.
    Albo D, Wayne JD, Hunt KK, et al. Anaphylactic reactions to isosulfan blue dye during sentinel lymph node biopsy for breast cancer. Am J Surg. 2001;182:393–8.PubMedCrossRefGoogle Scholar
  126. 126.
    Borgen PI. Isosulfan blue dye reactions during sentinel lymph node mapping for breast cancer. Anesth Analg. 2002;95:385–8.PubMedGoogle Scholar
  127. 127.
    Montgomery LL, Thorne AC, Van Zee KJ, et al. Incidence of anaphylactoid reactions to isosulfan blue dye during breast carcinoma lymphatic mapping in patients treated with preoperative prophylaxis: results of a surgical prospective clinical practice protocol. Cancer. 2005;104:692–9. Dal.CrossRefGoogle Scholar
  128. 128.
    Scherer K, Studer W, Figueiredo V, Bircher AJ. Anaphylaxis to isosulfan blue and cross-reactivity to patent blue V: case report and review of the nomenclature of vital blue dyes. Ann Allergy Asthma Immunol. 2006;96:497–500.PubMedCrossRefGoogle Scholar
  129. 129.
    Rodier JF, Velten M, Wilt M, et al. Prospective multicentric randomized study comparing periareolar and peritumoral injection of radiotracer and blue dye for the detection of sentinel lymph node in breast sparing procedures: FRANSENODE trial. J Clin Oncol. 2007;25:3664–9.PubMedCrossRefGoogle Scholar
  130. 130.
    Varghese P, Abdel-Rahman AT, Akberali S, et al. Methylene blue dye – a safe and effective alternative for sentinel lymph node localization. Breast J. 2008;14:61–7.PubMedCrossRefGoogle Scholar
  131. 131.
    Iqbal FM, Basit A, Salem F, Vidya R. Feeling blue, going green and finding other attractive alternatives: a case of biphasic anaphylaxis to patent blue and a literature review of alternative sentinel node localisation methods. BMJ Case Rep. 2015;pii: bcr2015213107. doi: 10.1136/bcr-2015-213107.Google Scholar
  132. 132.
    Chung A, Yu J, Stempel M, Patil S, Cody H, Montgomery L. Is the “10% rule” equally valid for all subsets of sentinel-node-positive breast cancer patients? Ann Surg Oncol. 2008;15:2728.PubMedCrossRefGoogle Scholar
  133. 133.
    Liu LC, Lang JE, Jenkins T, et al. Is it necessary to harvest additional lymph nodes after resection of the most radioactive sentinel lymph node in breast cancer? J Am Coll Surg. 2008;207:853–8.PubMedCrossRefGoogle Scholar
  134. 134.
    Morton DL, Bostick PJ. Will the true sentinel node please stand? Ann Surg Oncol. 1999;6:12–4.PubMedCrossRefGoogle Scholar
  135. 135.
    Nathanson SD. Will the true sentinel node please stand? Ann Surg Oncol. 1999;6:514–6.PubMedCrossRefGoogle Scholar
  136. 136.
    McMasters KM, Reintgen DS, Ross MI, et al. Sentinel lymph node biopsy for melanoma: how many radioactive nodes should be removed? Ann Surg Oncol. 2001;8:192–7.PubMedCrossRefGoogle Scholar
  137. 137.
    Manca G, Romanini A, Pellegrino D, et al. Optimal detection of sentinel lymph node metastases by intraoperative radioactive threshold and molecular analysis in patients with melanoma. J Nucl Med. 2008;49:1769–75.PubMedCrossRefGoogle Scholar
  138. 138.
    Aarsvold JN, Alazraki NP. Update on detection of sentinel lymph nodes in patients with breast cancer. Semin Nucl Med. 2005;35:116–28.PubMedCrossRefGoogle Scholar
  139. 139.
    Goyal A, Newcombe RG, Mansel RE, Axillary Lymphatic Mapping Against Nodal Axillary Clearance (ALMANAC) Trialists Group. Clinical relevance of multiple sentinel nodes in patients with breast cancer. Br J Surg. 2005;92:438–42.PubMedCrossRefGoogle Scholar
  140. 140.
    Serrano Vicente J, Infante de la Torre JR, Domínguez Grande ML, et al. Optimization of sentinel lymph node biopsy in breast cancer by intraoperative axillary palpation. Rev Esp Med Nucl. 2010;29:8–11.PubMedCrossRefGoogle Scholar
  141. 141.
    Ban EJ, Lee JS, Koo JS, Park S, Kim SI, Park BW. How many sentinel lymph nodes are enough for accurate axillary staging in t1-2 breast cancer? J Breast Cancer. 2011;14:296–300.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Cheng G, Kurita G, Kurita S, Torigian DA, Alavi A. Current status of sentinel lymph-node biopsy in patients with breast cancer. Eur J Nucl Med Mol Imaging. 2011;38:562–75.PubMedCrossRefGoogle Scholar
  143. 143.
    Schuman S, Walker G, Avisar E. Processing sentinel nodes in breast cancer: when and how many? Arch Surg. 2011;146:389–93.PubMedCrossRefGoogle Scholar
  144. 144.
    Uren RF, Howman-Giles R, Chung DK, et al. SPECT/CT scans allow precise anatomical location of sentinel lymph nodes in breast cancer and redefine lymphatic drainage from the breast to the axilla. Breast. 2012;21:480–6.PubMedCrossRefGoogle Scholar
  145. 145.
    Brenot-Rossi I, Houvenaeghel G, Jacquemier J, et al. Nonvisualization of axillary sentinel node during lymphoscintigraphy: is there a pathologic significance in breast cancer? J Nucl Med. 2003;44:1232–7.PubMedGoogle Scholar
  146. 146.
    Leidenius MH, Krogerus LA, Toivonen TS, Leppänen EA, von Smitten KA. The sensitivity of axillary staging when using sentinel node biopsy in breast cancer. Eur J Surg Oncol. 2003;29:849–53.PubMedCrossRefGoogle Scholar
  147. 147.
    Pouw B, Hellingman D, Kieft M, Vogel WV, van Os KJ, Rutgers EJ, Valdés Olmos RA, Stokkel MP. The hidden sentinel node in breast cancer: reevaluating the role of SPECT/CT and tracer reinjection. Eur J Surg Oncol. 2016;42:497–503.PubMedCrossRefGoogle Scholar
  148. 148.
    Krishnamurthy S, Meric-Bernstam F, Lucci A, et al. A prospective study comparing touch imprint cytology, frozen section analysis, and rapid cytokeratin immunostain for intraoperative evaluation of axillary sentinel lymph nodes in breast cancer. Cancer. 2009;115:1555–62.PubMedCrossRefGoogle Scholar
  149. 149.
    Dixon JM, Rutgers E, Hunt KK. Intraoperative assessment of axillary lymph nodes in patients with breast cancer. BMJ. 2014;349:g6803.PubMedCrossRefGoogle Scholar
  150. 150.
    Bernet L, Cano R, Martinez M, et al. Diagnosis of the sentinel lymph node in breast cancer: a reproducible molecular method: a multicentric Spanish study. Histopathology. 2011;58:863–9.PubMedCrossRefGoogle Scholar
  151. 151.
    Castellano I, Macrì L, Deambrogio C, et al. Reliability of whole sentinel lymph node analysis by one-step nucleic acid amplification for intraoperative diagnosis of breast cancer metastases. Ann Surg. 2012;255:334–42.PubMedCrossRefGoogle Scholar
  152. 152.
    Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thurlimann B, Senn HJ. Strategies for subtypes – dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer. Ann Oncol. 2011;22:1736–47.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Shimazu K, Noguchi S. Clinical significance of breast cancer micrometastasis in the sentinel lymph node. Surg Today. 2016;46:155–60.PubMedCrossRefGoogle Scholar
  154. 154.
    Morita ET, Chang J, Leong SP. Principles and controversies in lymphoscintigraphy with emphasis on breast cancer. Surg Clin North Am. 2000;80:1721–39.PubMedCrossRefGoogle Scholar
  155. 155.
    Giuliano AE, Jones RC, Brennan M, Statman R. Sentinel lymphadenectomy in breast cancer. J Clin Oncol. 1997;15:2345–50.PubMedCrossRefGoogle Scholar
  156. 156.
    Krag D, Weaver D, Ashikaga T, et al. The sentinel node in breast cancer – a multi-center validation study. N Engl J Med. 1998;339:941–6.PubMedCrossRefGoogle Scholar
  157. 157.
    Tausch C, Konstantiniuk P, Kugler F, Austrian Sentinel Node Study Group, et al. Sentinel lymph node biopsy after preoperative chemotherapy for breast cancer: findings from the Austrian Sentinel Node Study Group. Ann Surg Oncol. 2008;15:3378–83.PubMedCrossRefGoogle Scholar
  158. 158.
    Zervoudis S, Iatrakis G, Tomara E, Bothou A, Papadopoulos G, Tsakiris G. Main controversies in breast cancer. World J Clin Oncol. 2014;5:359–73.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Assi H, Sbaity E, Abdelsalam M, Shamseddine A. Controversial indications for sentinel lymph node biopsy in breast cancer patients. Biomed Res Int. 2015;2015:405949.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Manca G, Rubello D, Tardelli E, et al. Sentinel lymph node biopsy in breast cancer: indications, contraindications, and controversies. Clin Nucl Med. 2016;41:126–33.PubMedCrossRefGoogle Scholar
  161. 161.
    Meretoja TJ, Leidenius MH, Heikkilä PS, Joensuu H. Sentinel node biopsy in breast cancer patients with large or multifocal tumors. Ann Surg Oncol. 2009;16:1148–55.PubMedCrossRefGoogle Scholar
  162. 162.
    Zavagno G, Rubello D, Franchini Z, et al. Axillary sentinel lymph nodes in breast cancer: a single lymphatic pathway drains the entire mammary gland. Eur J Surg Oncol. 2005;31:479–84.PubMedCrossRefGoogle Scholar
  163. 163.
    Goyal A, Newcombe RG, Mansel RE, et al. Sentinel lymph node biopsy in patients with multifocal breast cancer. Eur J Surg Oncol. 2004;30:475–9.PubMedCrossRefGoogle Scholar
  164. 164.
    Gentilini O, Trifirò G, Soteldo J, et al. Sentinel lymph node biopsy in multicentric breast cancer. The experience of the European Institute of Oncology. Eur J Surg Oncol. 2006;32:507–10.PubMedCrossRefGoogle Scholar
  165. 165.
    Spillane AJ, Brennan ME. Accuracy of sentinel lymph node biopsy in large and multifocal/multicentric breast carcinoma – a systematic review. Eur J Surg Oncol. 2011;37:371–85.PubMedCrossRefGoogle Scholar
  166. 166.
    Giard S, Chauvet MP, Penel N, et al. Feasibility of sentinel lymph node biopsy in multiple unilateral synchronous breast cancer: results of a French prospective multi-institutional study (IGASSU 0502). Ann Oncol. 2010;21:1630–5.PubMedCrossRefGoogle Scholar
  167. 167.
    Francis AM, Haugen CE, Grimes LM, et al. Is sentinel lymph node dissection warranted for patients with a diagnosis of ductal carcinoma in situ? Ann Surg Oncol. 2015;22:4270–9.PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Bruening W, Fontanarosa J, Tipton K, Treadwell JR, Launders J, Schoelles K. Systematic review: comparative effectiveness of core-needle and open surgical biopsy to diagnose breast lesions. Ann Intern Med. 2010;152:238–46.PubMedCrossRefGoogle Scholar
  169. 169.
    Brennan ME, Turner RM, Ciatto S, et al. Ductal carcinoma in situ at core-needle biopsy: meta-analysis of underestimation and predictors of invasive breast cancer. Radiology. 2011;260:119–28.PubMedCrossRefGoogle Scholar
  170. 170.
    Intra M, Rotmensz N, Veronesi P, et al. Sentinel node biopsy is not a standard procedure in ductal carcinoma in situ of the breast: the experience of the European Institute of Oncology on 854 patients in 10 years. Ann Surg. 2008;247:315–9.PubMedCrossRefGoogle Scholar
  171. 171.
    Virnig BA, Tuttle TM, Shamliyan T, Kane RL. Ductal carcinoma in situ of the breast: a systematic review of incidence, treatment, and outcomes. J Natl Cancer Inst. 2010;102:170–8.PubMedCrossRefGoogle Scholar
  172. 172.
    Kotani H, Yoshimura A, Adachi Y, et al. Sentinel lymph node biopsy is not necessary in patients diagnosed with ductal carcinoma in situ of the breast by stereotactic vacuum-assisted biopsy. Breast Cancer. 2016;23:190–4.Google Scholar
  173. 173.
    Taback B, Nguyen P, Hansen N, Edwards GK, Conway K, Giuliano AE. Sentinel lymph node biopsy for local recurrence of breast cancer after breast-conserving therapy. Ann Surg Oncol. 2006;13:1099–104.PubMedCrossRefGoogle Scholar
  174. 174.
    Tunon-de-Lara C, Chauvet MP, Baranzelli MC, et al. The role of sentinel lymph node biopsy and factors associated with invasion in extensive DCIS of the breast treated by mastectomy: The Cinnamome prospective multicenter study. Ann Surg Oncol. 2015;22:3853–60.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Schneider C, Trocha S, McKinley B, et al. The use of sentinel lymph node biopsy in ductal carcinoma in situ. Am Surg. 2010;76:943–6.PubMedGoogle Scholar
  176. 176.
    Specht MC, Fey JV, Borgen PI, Cody 3rd HS. Is the clinically positive axilla in breast cancer really a contraindication to sentinel lymph node biopsy? J Am Coll Surg. 2005;200:10–4.PubMedCrossRefGoogle Scholar
  177. 177.
    Usmani S, Ahmed N, Saleh NA, Huda FA, Amanguno HG, Amir T, Kandari FA. The clinical utility of combining pre-operative axillary ultrasonography and fine needle aspiration cytology with radionuclide guided sentinel lymph node biopsy in breast cancer patients with palpable axillary lymph nodes. Eur J Radiol. 2015;84:2515–20.PubMedCrossRefGoogle Scholar
  178. 178.
    Kim H, Shin MJ, Kim SJ, Kim IJ, Park I. The relation of visualization of internal mammary lymph nodes on lymphoscintigraphy to axillary lymph node metastases in breast cancer. Lymphat Res Biol. 2014;12:295–300.PubMedCrossRefGoogle Scholar
  179. 179.
    Veronesi U, Valagussa P. Inefficacy of internal mammary nodes dissection in breast cancer surgery. Cancer. 1981;47:170–5.PubMedCrossRefGoogle Scholar
  180. 180.
    Meier P, Ferguson DJ, Karrison T. A controlled trial of extended radical mastectomy. Cancer. 1985;55:880–91.PubMedCrossRefGoogle Scholar
  181. 181.
    Lacour J, Le MG, Hill C, Kramar A, Contesso G, Sarrazin D. Is it useful to remove internal mammary nodes in operable breast cancer? Eur J Surg Oncol. 1987;13:309–14.PubMedGoogle Scholar
  182. 182.
    Meier P, Ferguson DJ, Karrison T. A controlled trial of extended radical versus radical mastectomy. Ten-year results. Cancer. 1989;63:188–95.PubMedCrossRefGoogle Scholar
  183. 183.
    Morimoto T, Monden Y, Takashima S, et al. Five-year results of a randomized clinical trial comparing modified radical mastectomy and extended radical mastectomy for stage II breast cancer. Surg Today. 1994;24:210–4.PubMedCrossRefGoogle Scholar
  184. 184.
    Veronesi U, Marubini E, Mariani L, Valagussa P, Zucali R. The dissection of internal mammary nodes does not improve the survival of breast cancer patients. 30-year results of a randomised trial. Eur J Cancer. 1999;35:1320–5.PubMedCrossRefGoogle Scholar
  185. 185.
    Madsen EV, Aalders KC, van der Heiden-van der Loo M, et al. Prognostic significance of tumor-positive internal mammary sentinel lymph nodes in breast cancer: a multicenter cohort study. Ann Surg Oncol. 2015;22:4254–62.PubMedCrossRefGoogle Scholar
  186. 186.
    McGale P, Taylor C, Correa C, et al. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet. 2014;383:2127–35.PubMedCrossRefGoogle Scholar
  187. 187.
    Hennequin C, Fourquet A. Controversy about internal mammary chain irradiation in breast cancer. Cancer Radiother. 2014;18:351–5.PubMedCrossRefGoogle Scholar
  188. 188.
    Poortmans PM, Collette S, Kirkove C, et al. Internal mammary and medial supraclavicular irradiation in breast cancer. N Engl J Med. 2015;373:317–27.PubMedCrossRefGoogle Scholar
  189. 189.
    Estourgie SH, Tanis PJ, Nieweg OE, Valdés Olmos RA, Rutgers EJ, Kroon BB. Should the hunt for internal mammary chain sentinel nodes begin? An evaluation of 150 breast cancer patients. Ann Surg Oncol. 2003;10:935–41.PubMedCrossRefGoogle Scholar
  190. 190.
    Paredes P, Vidal-Sicart S, Zanón G, et al. Clinical relevance of sentinel lymph nodes in the internal mammary chain in breast cancer patients. Eur J Nucl Med Mol Imaging. 2005;32:1283–7.PubMedCrossRefGoogle Scholar
  191. 191.
    Bourre JC, Payan R, Collomb D, et al. Can the sentinel lymph node technique affect decisions to offer internal mammary chain irradiation? Eur J Nucl Med Mol Imaging. 2009;36:758–64.PubMedCrossRefGoogle Scholar
  192. 192.
    Manca G, Volterrani D, Mazzarri S, et al. Sentinel lymph node mapping in breast cancer: a critical reappraisal of the internal mammary chain issue. Q J Nucl Med Mol Imaging. 2014;58:114–26.PubMedGoogle Scholar
  193. 193.
    Singletary SE, Allred C, Ashley P, et al. Revision of the American Joint Committee on Cancer staging system for breast cancer. J Clin Oncol. 2002;20:3628–36.PubMedCrossRefGoogle Scholar
  194. 194.
    Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17:1471–4.PubMedCrossRefGoogle Scholar
  195. 195.
    Noushi F, Spillane AJ, Uren RF, Gebski V. Internal mammary node metastasis in breast cancer: predictive models to determine status and management algorithms. Eur J Surg Oncol. 2010;36:16–22.PubMedCrossRefGoogle Scholar
  196. 196.
    Leidenius MH, Krogerus LA, Toivonen TS, Leppänen EA, von Smitten KA. The clinical value of parasternal sentinel node biopsy in breast cancer. Ann Surg Oncol. 2006;13:321–6.PubMedCrossRefGoogle Scholar
  197. 197.
    Ozmen V, Ozcinar B, Bozdogan A, Eralp Y, Yavuz E, Dincer M. The effect of internal mammary lymph node biopsy on the therapeutic decision and survival of patients with breast cancer. Eur J Surg Oncol. 2015;41:1368–72.PubMedCrossRefGoogle Scholar
  198. 198.
    Bergkvist L, Frisell J, Liljegren G, Celebioglu F, Damm S, Thorn M. Multicentre study of detection and false-negative rates in sentinel node biopsy for breast cancer. Br J Surg. 2001;88:1644–8.PubMedCrossRefGoogle Scholar
  199. 199.
    Intra M, Trifirò G, Viale G, et al. Second biopsy of axillary sentinel lymph node for reappearing breast cancer after previous sentinel lymph node biopsy. Ann Surg Oncol. 2005;12:895–9.PubMedCrossRefGoogle Scholar
  200. 200.
    Newman EA, Cimmino VM, Sabel MS, et al. Lymphatic mapping and sentinel lymph node biopsy for patients with local recurrence after breast-conservation therapy. Ann Surg Oncol. 2006;13:52–7.PubMedCrossRefGoogle Scholar
  201. 201.
    Port ER, Garcia-Etienne CA, Park J, Fey J, Borgen PI, Cody 3rd HS. Reoperative sentinel lymph node biopsy: a new frontier in the management of ipsilateral breast tumor recurrence. Ann Surg Oncol. 2007;14:2209–14.PubMedCrossRefGoogle Scholar
  202. 202.
    Tasevski R, Gogos AJ, Mann GB. Reoperative sentinel lymph node biopsy in ipsilateral breast cancer relapse. Breast. 2009;18:322–6.PubMedCrossRefGoogle Scholar
  203. 203.
    Kaur P, Kiluk JV, Meade T, et al. Sentinel lymph node biopsy in patients with previous ipsilateral complete axillary lymph node dissection. Ann Surg Oncol. 2011;18:727–32.PubMedCrossRefGoogle Scholar
  204. 204.
    Luini A, Galimberti V, Gatti G, et al. The sentinel node biopsy after previous breast surgery; preliminary results on 543 patients treated at EIO. Breast Cancer Res Treat. 2005;89:159–63.PubMedCrossRefGoogle Scholar
  205. 205.
    Leidenius MH, Vironen JH, von Smitten KA, Heikkilä PS, Joensuu HJ. The outcome of sentinel node biopsy in breast cancer patients with preoperative surgical biopsy. Surg Oncol. 2009;99:420–3.CrossRefGoogle Scholar
  206. 206.
    Heuts EM, van der Ent FW, Kengen RA, van der Pol HA, Hulsewe KW, Hoofwijk AG. Results of sentinel node biopsy not affected by previous excisional biopsy. Eur J Surg Oncol. 2006;32:278–81.PubMedCrossRefGoogle Scholar
  207. 207.
    Rodriguez Fernandez J, Martella S, Trifirò G, et al. Sentinel node biopsy in patients with previous breast aesthetic surgery. Ann Surg Oncol. 2009;16:989–92.PubMedCrossRefGoogle Scholar
  208. 208.
    Kothari MS, Rusby JE, Agusti AA, MacNeill FA. Sentinel lymph node biopsy after previous axillary surgery: a review. Eur J Surg Oncol. 2012;38:8–15.PubMedCrossRefGoogle Scholar
  209. 209.
    Rescigno J, Zampell JC, Axelrod D. Patterns of axillary surgical care for breast cancer in the era of sentinel lymph node biopsy. Ann Surg Oncol. 2009;16:687–96.PubMedCrossRefGoogle Scholar
  210. 210.
    Goldhirsch A, Glick JH, Gelber RD, Senn HJ. Meeting highlights: international consensus panel on the treatment of primary breast cancer. J Natl Cancer Inst. 1998;90:1601–8.PubMedCrossRefGoogle Scholar
  211. 211.
    Abrams JS. Adjuvant therapy for breast cancer – results from the USA consensus conference. Breast Cancer. 2001;8:298–304.PubMedCrossRefGoogle Scholar
  212. 212.
    Fu Y, Chung D, Cao MA, Apple S, Chang H. Is axillary lymph node dissection necessary after sentinel lymph node biopsy in patients with mastectomy and pathological N1 breast cancer? Ann Surg Oncol. 2014;21:4109–23.PubMedCrossRefGoogle Scholar
  213. 213.
    van de Vijver MJ, He YD, van’t Veer LJ, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347:1999–2009.PubMedCrossRefGoogle Scholar
  214. 214.
    Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24:3726–34.PubMedCrossRefGoogle Scholar
  215. 215.
    Albain KS, Barlow WE, Shak S, et al. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol. 2010;11:55–65.PubMedCrossRefGoogle Scholar
  216. 216.
    Donker M, van Tienhoven G, Straver ME, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981–22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial. Lancet Oncol. 2014;15:1303–10.PubMedPubMedCentralCrossRefGoogle Scholar
  217. 217.
    Li CZ, Zhang P, Li RW, Wu CT, Zhang XP, Zhu HC. Axillary lymph node dissection versus sentinel lymph node biopsy alone for early breast cancer with sentinel node metastasis: a meta-analysis. Eur J Surg Oncol. 2015;41:958–66.PubMedCrossRefGoogle Scholar
  218. 218.
    Marrazzo A, Boscaino G, Marrazzo E, Taormina P, Toesca A. Breast cancer subtypes can be determinant in the decision making process to avoid surgical axillary staging: a retrospective cohort study. Int J Surg. 2015;21:156–61.PubMedCrossRefGoogle Scholar
  219. 219.
    van Roozendaal LM, de Wilt JH, van Dalen T, et al. The value of completion axillary treatment in sentinel node positive breast cancer patients undergoing a mastectomy: a Dutch randomized controlled multicentre trial (BOOG 2013-07). BMC Cancer. 2015;15:610.PubMedPubMedCentralCrossRefGoogle Scholar
  220. 220.
    Khatcheressian JL, Hurley P, Bantug E, et al. Breast cancer follow-up and management after primary treatment: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31:961–5.PubMedCrossRefGoogle Scholar
  221. 221.
    García-Fernández A, Chabrera C, García-Font M, et al. Breast cancer patients undergoing sentinel node biopsy: additional axillary tumor burden as a function of the total number of excised sentinel nodes – a multicenter study. Clin Breast Cancer. 2015;15:490–7.PubMedCrossRefGoogle Scholar
  222. 222.
    van la Parra RF, de Wilt JH, Mol SJ, Mulder AH, de Roos WK, Bosscha K. Is SLN biopsy alone safe in SLN positive breast cancer patients? Breast J. 2015;21:621–6.CrossRefGoogle Scholar
  223. 223.
    Kaufmann M, von Minckwitz G, Mamounas EP, et al. Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. Ann Surg Oncol. 2012;19:1508–16.PubMedCrossRefGoogle Scholar
  224. 224.
    Manguso N, Gangi A, Giuliano AE. Neoadjuvant chemotherapy and surgical management of the axilla in breast cancer: a review of current data. Oncology (Williston Park). 2015;29:733–8.Google Scholar
  225. 225.
    Schwartz GF, Giuliano AE, Veronesi U, Consensus Conference Committee. Proceedings of the consensus conference on the role of sentinel lymph node biopsy in carcinoma of the breast. Breast. 2002;11:362–73.CrossRefGoogle Scholar
  226. 226.
    Veronesi P, Gentilini O, Rodriguez-Fernandez J, Magnoni F. Breast conservation and sentinel lymph node after neoadjuvant systemic therapy. Breast. 2009;18:590–2.Google Scholar
  227. 227.
    Patten DK, Zacharioudakis KE, Chauhan H, Cleator SJ, Hadjiminas DJ. Sentinel lymph node biopsy after neo-adjuvant chemotherapy in patients with breast cancer: are the current false negative rates acceptable? Breast. 2015;24:318–20.PubMedCrossRefGoogle Scholar
  228. 228.
    Schwartz GF, Meltzer AJ. Accuracy of sentinel node biopsy following neoadjuvant (induction) chemotherapy for carcinoma of the breast. Breast J. 2003;9:374–9.PubMedCrossRefGoogle Scholar
  229. 229.
    Mamounas EP, Brown A, Anderson S, et al. Sentinel node biopsy after neoadjuvant chemotherapy in breast cancer: results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2005;23:2694–702.PubMedCrossRefGoogle Scholar
  230. 230.
    Tanaka Y, Maeda H, Ogawa Y, et al. Sentinel node biopsy in breast cancer patients treated with neoadjuvant chemotherapy. Oncol Rep. 2006;15:927–31.PubMedGoogle Scholar
  231. 231.
    Xing Y, Foy M, Cox DD, Kuerer HM, Hunt KK, Cormier JN. Meta-analysis of sentinel lymph node biopsy after preoperative chemotherapy in patients with breast cancer. Br J Surg. 2006;93:539–46.PubMedCrossRefGoogle Scholar
  232. 232.
    Kelly AM, Dwamena B, Cronin P, Carlos RC. Breast cancer sentinel node identification and classification after neoadjuvant chemotherapy – systematic review and metaanalysis. Acad Radiol. 2009;16:551–63.PubMedCrossRefGoogle Scholar
  233. 233.
    van Deurzen CH, Vriens BE, Tjan-Heijnen VC, et al. Accuracy of sentinel node biopsy after neoadjuvant chemotherapy in breast cancer patients: a systematic review. Eur J Cancer. 2009;45:3124–30.PubMedCrossRefGoogle Scholar
  234. 234.
    Dixon JM, Cody 3rd HS. Role of sentinel node biopsy in patients having neoadjuvant chemotherapy. Eur J Surg Oncol. 2010;36:511–3.PubMedCrossRefGoogle Scholar
  235. 235.
    Gilardi L, De Cicco C, Colleoni M, et al. Investigation of 18F-FDG PET in the selection of patients with breast cancer as candidates for sentinel node biopsy after neoadjuvant therapy. Eur J Nucl Med Mol Imaging. 2010;37:1834–41.PubMedCrossRefGoogle Scholar
  236. 236.
    Tan VK, Goh BK, Fook-Chong S, Khin LW, Wong WK, Yong WS. The feasibility and accuracy of sentinel lymph node biopsy in clinically node-negative patients after neoadjuvant chemotherapy for breast cancer – a systematic review and meta-analysis. J Surg Oncol. 2011;104:97–103.PubMedCrossRefGoogle Scholar
  237. 237.
    Reimer T, Hartmann S, Stachs A, Gerber B. Local treatment of the axilla in early breast cancer: concepts from the national surgical adjuvant breast and bowel project B-04 to the planned intergroup sentinel mamma trial. Breast Care (Basel). 2014;9:87–95.CrossRefGoogle Scholar
  238. 238.
    Lyman GH. Appropriate role for sentinel node biopsy after neoadjuvant chemotherapy in patients with early-stage breast cancer. J Clin Oncol. 2015;33:232–4.PubMedCrossRefGoogle Scholar
  239. 239.
    Rubio IT. Sentinel lymph node metastasis after neoadjuvant treatment in breast cancer: any size matters? World J Clin Oncol. 2015;6:202–6.PubMedPubMedCentralCrossRefGoogle Scholar
  240. 240.
    van der Heiden-van der Loo M, de Munck L, Sonke GS, et al. Population based study on sentinel node biopsy before or after neoadjuvant chemotherapy in clinically node negative breast cancer patients: identification rate and influence on axillary treatment. Eur J Cancer. 2015;51:915–21.PubMedCrossRefGoogle Scholar
  241. 241.
    van Nijnatten TJ, Schipper RJ, Lobbes MB, Nelemans PJ, Beets-Tan RG, Smidt ML. The diagnostic performance of sentinel lymph node biopsy in pathologically confirmed node positive breast cancer patients after neoadjuvant systemic therapy: a systematic review and meta-analysis. Eur J Surg Oncol. 2015;41:1278–87.PubMedCrossRefGoogle Scholar
  242. 242.
    Thorat MA. Sentinel lymph node assessment in breast cancer patients receiving neo-adjuvant chemotherapy: to biopsy before or after? Int J Cancer. 2016;138:267–70.PubMedCrossRefGoogle Scholar
  243. 243.
    Mocellin S, Goldin E, Marchet A, Nitti D. Sentinel node biopsy performance after neoadjuvant chemotherapy in locally advanced breast cancer: a systematic review and meta-analysis. Int J Cancer. 2016;138:472–80.PubMedCrossRefGoogle Scholar
  244. 244.
    Pandit-Taskar N, Dauer LT, Montgomery L, St Germain J, Zanzonico PB, Divgi CR. Organ and fetal absorbed dose estimates from 99mTc-sulfur colloid lymphoscintigraphy and sentinel node localization in breast cancer patients. J Nucl Med. 2006;47:1202–8.PubMedGoogle Scholar
  245. 245.
    Khera SY, Kiluk JV, Hasson DM, et al. Pregnancy-associated breast cancer patients can safely undergo lymphatic mapping. Breast J. 2008;14:250–4.PubMedCrossRefGoogle Scholar
  246. 246.
    Gentilini O, Cremonesi M, Toesca A, et al. Sentinel lymph node biopsy in pregnant patients with breast cancer. Eur J Nucl Med Mol Imaging. 2010;37:78–83.PubMedCrossRefGoogle Scholar
  247. 247.
    Gropper AB, Calvillo KZ, Dominici L, et al. Sentinel lymph node biopsy in pregnant women with breast cancer. Ann Surg Oncol. 2014;21:2506–11.PubMedCrossRefGoogle Scholar
  248. 248.
    Filippakis GM, Zografos G. Contraindications of sentinel lymph node biopsy: are there any really? World J Surg Oncol. 2007;5:10.PubMedPubMedCentralCrossRefGoogle Scholar
  249. 249.
    Barthelmes L, Goyal A, Newcombe RG, McNeill F, Mansel RE. Adverse reactions to patent blue V dye – the NEW START and ALMANAC experience. Eur J Surg Oncol. 2010;36:399–403.PubMedCrossRefGoogle Scholar
  250. 250.
    Bezu C, Coutant C, Salengro A, Darai E, Rouzier R, Uzan S. Anaphylactic response to blue dye during sentinel lymph node biopsy. Surg Oncol. 2011;20:e55–9.PubMedCrossRefGoogle Scholar
  251. 251.
    Rovera F, Chiappa C, Coglitore A, et al. Management of breast cancer during pregnancy. Int J Surg. 2013;11:S64–8.PubMedCrossRefGoogle Scholar
  252. 252.
    Chan BK, Wiseberg-Firtell JA, Jois RH, Jensen K, Audisio RA. Localization techniques for guided surgical excision of non-palpable breast lesions. Cochrane Database Syst Rev. 2015;12:CD009206.Google Scholar
  253. 253.
    Tóth D, Varga Z, Sebő É, Török M, Kovács I. Predictive factors for positive margin and the surgical learning curve in non-palpable breast cancer after wire-guided localization – prospective study of 214 consecutive patients. Pathol Oncol Res. 2016;22:209–15.PubMedCrossRefGoogle Scholar
  254. 254.
    Rahusen FD, Bremers AJ, Fabry HF, van Amerongen AH, Boom RP, Meijer S. Ultrasound-guided lumpectomy of nonpalpable breast cancer versus wire-guided resection: a randomized clinical trial. Ann Surg Oncol. 2002;9:994–8.PubMedCrossRefGoogle Scholar
  255. 255.
    Bennett IC, Greenslade J, Chiam H. Intraoperative ultrasound-guided excision of nonpalpable breast lesions. World J Surg. 2005;29:369–74.PubMedCrossRefGoogle Scholar
  256. 256.
    James TA, Harlow S, Sheehey-Jones J, et al. Intraoperative ultrasound versus mammographic needle localization for ductal carcinoma in situ. Ann Surg Oncol. 2009;16:1164–9.PubMedCrossRefGoogle Scholar
  257. 257.
    Krekel NM, Zonderhuis BM, Schreurs HW, et al. Ultrasound-guided breast-sparing surgery to improve cosmetic outcomes and quality of life. A prospective multicentre randomised controlled clinical trial comparing ultrasound-guided surgery to traditional palpation-guided surgery (COBALT trial). BMC Surg. 2011;11:8.PubMedPubMedCentralCrossRefGoogle Scholar
  258. 258.
    Ahmed D, Douek M. Intra-operative ultrasound versus wire-guided localization in the surgical management of non-palpable breast cancers: systematic review and meta-analysis. Breast Cancer Res Treat. 2013;140:435–46.PubMedCrossRefGoogle Scholar
  259. 259.
    Yu CC, Chiang KC, Kuo WL, Shen SC, Lo YF, Chen SC. Low re-excision rate for positive margins in patients treated with ultrasound-guided breast-conserving surgery. Breast. 2013;22:698–702.PubMedCrossRefGoogle Scholar
  260. 260.
    De Cicco C, Pizzamiglio M, Trifirò G, Luini A, Ferrari M, Prisco G, Galimberti V, Cassano E, Viale G, Intra M, Veronesi P, Paganelli G. Radioguided occult lesion localisation (ROLL) and surgical biopsy in breast cancer. Technical aspects. Q J Nucl Med. 2002;46:145–51.PubMedGoogle Scholar
  261. 261.
    Paganelli G, Luini A, Veronesi U. Radioguided occult lesion localization (ROLL) in breast cancer: maximizing efficacy, minimizing mutilation. Ann Oncol. 2002;13:1839–40.PubMedCrossRefGoogle Scholar
  262. 262.
    Paganelli G, Veronesi U. Innovation in early breast cancer surgery: radio-guided occult lesion localization and sentinel node biopsy. Nucl Med Commun. 2002;23:625–7.PubMedCrossRefGoogle Scholar
  263. 263.
    Landman J, Kulawansa S, McCarthy M, et al. Radioguided localisation of impalpable breast lesions using 99m-technetium macroaggregated albumin: lessons learnt during introduction of a new technique to guide preoperative localisation. J Med Radiat Sci. 2015;62:6–14.PubMedCrossRefGoogle Scholar
  264. 264.
    Rovera F, Frattini F, Marelli M, Corben AD, Vanoli C, Dionigi G, Boni L, Dionigi R. Radio-guided occult lesion localization versus wire-guided localization in non-palpable breast lesions. Int J Surg. 2008;1:S101–3.CrossRefGoogle Scholar
  265. 265.
    van der Ploeg IM, Hobbelink M, van den Bosch MA, Mali WP, Borel Rinkes IH, van Hillegersberg R. ‘Radioguided occult lesion localisation’ (ROLL) for non-palpable breast lesions: a review of the relevant literature. Eur J Surg Oncol. 2008;34:1–5.PubMedCrossRefGoogle Scholar
  266. 266.
    Sajid MS, Parampalli U, Haider Z, Bonomi R. Comparison of radioguided occult lesion localization (ROLL) and wire localization for non-palpable breast cancers: a meta-analysis. J Surg Oncol. 2012;105:852–8.PubMedCrossRefGoogle Scholar
  267. 267.
    Ahmed M, Douek M. Sentinel node and occult lesion localization (SNOLL): a systematic review. Breast. 2013;22:1034–40.PubMedCrossRefGoogle Scholar
  268. 268.
    Aydogan F, Velidedeoglu M, Kilic F, Yilmaz H. Radio-guided localization of clinically occult breast lesions: current modalities and future directions. Expert Rev Med Devices. 2014;11:53–63.PubMedCrossRefGoogle Scholar
  269. 269.
    Monti S, Galimberti V, Trifirò G, et al. Occult breast lesion localization plus sentinel node biopsy (SNOLL): experience with 959 patients at the European Institute of Oncology. Ann Surg Oncol. 2007;14:2928–31.PubMedCrossRefGoogle Scholar
  270. 270.
    Mariscal Martínez A, Solà M, de Tudela AP, Julián JF, Fraile M, Vizcaya S, Fernández J. Radioguided localization of nonpalpable breast cancer lesions: randomized comparison with wire localization in patients undergoing conservative surgery and sentinel node biopsy. AJR Am J Roentgenol. 2009;193:1001–9.PubMedCrossRefGoogle Scholar
  271. 271.
    Vernet-Tomas Mdel M, Ortega M, Vidal S, Corominas JM, Carreras R. Factors affecting surgical margins in nonpalpable breast tumors excised with the radioguided occult lesion localization approach. J Obstet Gynaecol Res. 2011;37:422–7.PubMedCrossRefGoogle Scholar
  272. 272.
    Ahmed M, van Hemelrijck M, Douek M. Systematic review of radioguided versus wire-guided localization in the treatment of non-palpable breast cancers. Breast Cancer Res Treat. 2013;140:241–52.PubMedCrossRefGoogle Scholar
  273. 273.
    Postma EL, Koffijberg H, Verkooijen HM, Witkamp AJ, van den Bosch MA, van Hillegersberg R. Cost-effectiveness of radioguided occult lesion localization (ROLL) versus wire-guided localization (WGL) in breast conserving surgery for nonpalpable breast cancer: results from a randomized controlled multicenter trial. Ann Surg Oncol. 2013;20:2219–26.PubMedCrossRefGoogle Scholar
  274. 274.
    Rampaul RS, Dudley NJ, Thompson JZ, Burrell H, Evans AJ, Wilson AR, Macmillan RD. Radioisotope for occult lesion localisation (ROLL) of the breast does not require extra radiation protection procedures. Breast. 2003;12:150–2.PubMedCrossRefGoogle Scholar
  275. 275.
    Duarte GM, dos Santos CC, Torresan RZ, et al. Radioguided surgery using intravenous 99mTc sestamibi associated with breast magnetic resonance imaging for guidance of breast cancer resection. Breast J. 2006;12:202–7.PubMedCrossRefGoogle Scholar
  276. 276.
    De Cicco C, Trifirò G, Intra M, et al. Optimised nuclear medicine method for tumour marking and sentinel node detection in occult primary breast lesions. Eur J Nucl Med Mol Imaging. 2004;31:349–54.PubMedCrossRefGoogle Scholar
  277. 277.
    Fraile M, Mariscal A, Lorenzo C, et al. Radio-guided occult lesion localization combined with sentinel node biopsy in women with breast cancer. Cir Esp. 2005;77:36–9.PubMedCrossRefGoogle Scholar
  278. 278.
    Strnad P, Rob L, Halaska MG, Chod J, Zuntova A, Moravcova Z. Radioguided occult lesion localisation in combination with detection of the sentinel lymph node in non-palpable breast cancer tumours. Eur J Gynaecol Oncol. 2006;27:236–8.PubMedGoogle Scholar
  279. 279.
    Intra M, De Cicco C, Gentilini O, Luini A, Paganelli G. Radioguided localisation (ROLL) of non-palpable breast lesions and simultaneous sentinel lymph node biopsy (SNOLL): the experience of the European Institute of Oncology. Eur J Nucl Med Mol Imaging. 2007;34:957–8.PubMedCrossRefGoogle Scholar
  280. 280.
    van Rijk MC, Tanis PJ, Nieweg OE, et al. Sentinel node biopsy and concomitant probe-guided tumor excision of nonpalpable breast cancer. Ann Surg Oncol. 2007;14:627–32.PubMedCrossRefGoogle Scholar
  281. 281.
    Lavoué V, Nos C, Clough KB, et al. Simplified technique of radioguided occult lesion localization (ROLL) plus sentinel lymph node biopsy (SNOLL) in breast carcinoma. Ann Surg Oncol. 2008;15:2556–61.PubMedCrossRefGoogle Scholar
  282. 282.
    Thind CR, Tan S, Desmond S, et al. SNOLL. Sentinel node and occult (impalpable) lesion localization in breast cancer. Clin Radiol. 2011;66:833–9.PubMedCrossRefGoogle Scholar
  283. 283.
    Bordea C, Plesca M, Condrea I, Gherghe M, Gociman A, Blidaru A. Occult breast lesion localization and concomitant sentinel lymph node biopsy in early breast cancer (SNOLL). Chirurgiae (Bucur). 2012;107:722–9.Google Scholar
  284. 284.
    Follacchio GA, Monteleone F, Anibaldi P, et al. A modified sentinel node and occult lesion localization (SNOLL) technique in non-palpable breast cancer: a pilot study. J Exp Clin Cancer Res. 2015;34:113.PubMedPubMedCentralCrossRefGoogle Scholar
  285. 285.
    Jakub JW, Gray RJ, Degnim AC, Boughey JC, Gardner M, Cox CE. Current status of radioactive seed for localization of non palpable breast lesions. Am J Surg. 2010;199:522–8.PubMedCrossRefGoogle Scholar
  286. 286.
    Sung JS, King V, Thornton CM, Brooks JD, Fry CW, El-Tamer M, Dauer LT, Brogi E, St Germain JM, Morris EA. Safety and efficacy of radioactive seed localization with I-125 prior to lumpectomy and/or excisional biopsy. Eur J Radiol. 2013;82:1453–7.PubMedCrossRefGoogle Scholar
  287. 287.
    Jackson L, Bourke AG, Abdul Aziz F, Taylor D. Radioactive seed localisation to guide removal of impalpable lymph nodes (radioguided occult lesion localisation using iodine-125 seeds, “ROLLIS”). BMJ Case Rep. 2014; pii: bcr-2013-203267. doi: 10.1136/bcr-2013-203267.Google Scholar
  288. 288.
    Parvez E, Cornacchi SD, Hodgson N, et al. A cosmesis outcome substudy in a prospective, randomized trial comparing radioguided seed localization with standard wire localization for nonpalpable, invasive, and in situ breast carcinomas. Am J Surg. 2014;208:711–8.PubMedCrossRefGoogle Scholar
  289. 289.
    van der Noordaa ME, Pengel KE, Groen E, et al. The use of radioactive iodine-125 seed localization in patients with non-palpable breast cancer: a comparison with the radioguided occult lesion localization with 99m technetium. Eur J Surg Oncol. 2015;41:553–8.PubMedCrossRefGoogle Scholar
  290. 290.
    Vermeeren L, Valdes Olmos RA, Klop WM, Balm AJ, van den Brekel MW. A portable gamma-camera for intraoperative detection of sentinel nodes in the head and neck region. J Nucl Med. 2010;51:700–3.PubMedCrossRefGoogle Scholar
  291. 291.
    Bricou A, Duval MA, Charon Y, Barranger E. Mobile gamma cameras in breast cancer care – a review. Eur J Surg Oncol. 2013;39:409–16.PubMedCrossRefGoogle Scholar
  292. 292.
    Bluemel C, Cramer A, Grossmann C, Kajdi GW, et al. iROLL: does 3-D radioguided occult lesion localization improve surgical management in early-stage breast cancer? Eur J Nucl Med Mol Imaging. 2015;42:1692–9.PubMedCrossRefGoogle Scholar
  293. 293.
    Engelen T, Winkel BM, Rietbergen DD, et al. The next evolution in radioguided surgery: breast cancer related sentinel node localization using a freehand SPECT-mobile gamma camera combination. Am J Nucl Med Mol Imaging. 2015;5:233–45.PubMedPubMedCentralGoogle Scholar
  294. 294.
    Lombardi A, Nigri G, Scopinaro F, et al. High-resolution, handheld camera use for occult breast lesion localization plus sentinel node biopsy (SNOLL): a single-institution experience with 186 patients. Surgeon. 2015;13:69–72.PubMedCrossRefGoogle Scholar
  295. 295.
    Taylor D, Landman J. ‘Rolling out radioguided occult lesion localisation for breast tumours’: moving from ROLL to ROLLIS. J Med Radiat Sci. 2015;62:175–6.PubMedPubMedCentralCrossRefGoogle Scholar
  296. 296.
    Bricou A, Duval MA, Bardet L, et al. Is there a role for a handheld gamma camera (TReCam) in the SNOLL breast cancer procedure? Q J Nucl Med Mol Imaging. 2015 Mar 31 [Epub ahead of print].Google Scholar
  297. 297.
    Bergqvist L, Strand SE, Persson B, Hafström L, Jönsson PE. Dosimetry in lymphoscintigraphy of Tc-99m antimony sulfide colloid. J Nucl Med. 1982;23:698–705.PubMedGoogle Scholar
  298. 298.
    Cremonesi M, Ferrari M, Sacco E, et al. Radiation protection in radioguided surgery of breast cancer. Nucl Med Commun. 1999;20:919–24.PubMedCrossRefGoogle Scholar
  299. 299.
    Waddington WA, Keshtgar MRS, Taylor I, Lakhani SR, Short MD, Ell PJ. Radiation safety of the sentinel node technique in breast cancer. Eur J Nucl Med. 2000;27:377–91.PubMedCrossRefGoogle Scholar
  300. 300.
    Law M, Cheng KC, Wu PM, Ho WY, Chow LW. Patient effective dose from sentinel lymph node lymphoscintigraphy in breast cancer: a study using a female humanoid phantom and thermoluminescent dosimeters. Br J Radiol. 2003;76:818–23.PubMedCrossRefGoogle Scholar
  301. 301.
    Law M, Chow LW, Kwong A, Lam CK. Sentinel lymph node technique for breast cancer: radiation safety issues. Semin Oncol. 2004;31:298–303.PubMedCrossRefGoogle Scholar
  302. 302.
    Sata S, Knesaurek K, Krynyckyi BR. Effective dose in sentinel lymph node imaging. Br J Radiol. 2004;77:709. author reply 709.PubMedCrossRefGoogle Scholar
  303. 303.
    Glass EC, Basinski JE, Krasne DL, Giuliano AE. Radiation safety considerations for sentinel node techniques. Ann Surg Oncol. 1999;6:10–1.PubMedCrossRefGoogle Scholar
  304. 304.
    Miner TJ, Shriver CD, Flicek PR, Miner FC, Jaques DP, Maniscalco-Theberge ME, Krag DN. Guidelines for the safe use of radioactive materials during localization and resection of the sentinel lymph node. Ann Surg Oncol. 1999;6:75–82.PubMedCrossRefGoogle Scholar
  305. 305.
    Stratmann SL, McCarty TM, Kuhn JA. Radiation safety with breast sentinel node biopsy. Am J Surg. 1999;178:454–7.PubMedCrossRefGoogle Scholar
  306. 306.
    Morton R, Horton PW, Peet DJ, Kissin MW. Quantitative assessment of the radiation hazards and risks in sentinel node procedures. Br J Radiol. 2003;76:117–22.PubMedCrossRefGoogle Scholar
  307. 307.
    de Kanter AY, Arends PP, Eggermont AM, Wiggers T. Radiation protection for the sentinel node procedure in breast cancer. Eur J Surg Oncol. 2003;29:396–9.PubMedCrossRefGoogle Scholar
  308. 308.
    Klausen TL, Chakera AH, Friis E, Rank F, Hesse B, Holm S. Radiation doses to staff involved in sentinel node operations for breast cancer. Clin Physiol Funct Imaging. 2005;25:196–202.PubMedCrossRefGoogle Scholar
  309. 309.
    Nejc D, Wrzesień M, Piekarski J, Olszewski J, Pluta P, Kuśmierek J, Jeziorski A. Sentinel node biopsy in patients with breast cancer – evaluation of exposure to radiation of medical staff. Eur J Surg Oncol. 2006;32:133–8.PubMedCrossRefGoogle Scholar
  310. 310.
    Ckarke RH, Bines W. Evolution of ICRP recommendations 1977, 1990, 2007 – Publications 26 to 60 to 103. OECD NEA, No 6920, 2011. http://www.oecd-nea.org/rp/reports/2011/nea6920-ICRP-recommendations.pdf
  311. 311.
    Singleton M, Firth M, Stephenson T, Morrison G, Baginska J. Radiation-guided breast sentinel lymph node biopsies – is a handling delay for radiation protection necessary? Histopathology. 2012;61:277–82.PubMedCrossRefGoogle Scholar
  312. 312.
    Gentilini O, Cremonesi M, Trifirò G, et al. Safety of sentinel node biopsy in pregnant patients with breast cancer. Ann Oncol. 2004;15:1348–51.PubMedCrossRefGoogle Scholar
  313. 313.
    Keleher A, Wendt 3rd R, Delpassand E, Stachowiak AM, Kuerer HM. The safety of lymphatic mapping in pregnant breast cancer patients using Tc-99m sulfur colloid. Breast J. 2004;10:492–5.PubMedCrossRefGoogle Scholar
  314. 314.
    Spanheimer PM, Graham MM, Sugg SL, Scott-Conner CE, Weigel RJ. Measurement of uterine radiation exposure from lymphoscintigraphy indicates safety of sentinel lymph node biopsy during pregnancy. Ann Surg Oncol. 2009;16:1143–7.PubMedCrossRefGoogle Scholar
  315. 315.
    Law M, Ma WH, Leung R, Li S, Wong KK, Ho WY, Kwong A. Evaluation of patient effective dose from sentinel lymph node lymphoscintigraphy in breast cancer: a phantom study with SPECT/CT and ICRP-103 recommendations. Eur J Radiol. 2012;81:717–20.CrossRefGoogle Scholar
  316. 316.
    Winter A, Woenkhaus J, Wawroschek F. A novel method for intraoperative sentinel lymph node detection in prostate cancer patients using superparamagnetic iron oxide nanoparticles and a handheld magnetometer: the initial clinical experience. Ann Surg Oncol. 2014;21:4390–6.PubMedPubMedCentralCrossRefGoogle Scholar
  317. 317.
    Rubio IT, Diaz-Botero S, Esgueva A, Rodriguez R, Cortadellas T, Cordoba O, Espinosa-Bravo M. The superparamagnetic iron oxide is equivalent to the Tc99 radiotracer method for identifying the sentinel lymph node in breast cancer. Eur J Surg Oncol. 2015;41:46–51.PubMedCrossRefGoogle Scholar
  318. 318.
    Pitsinis V, Provenzano E, Kaklamanis L, Wishart GC, Benson JR. Indocyanine green fluorescence mapping for sentinel lymph node biopsy in early breast cancer. Surg Oncol. 2015;24:375–9.PubMedCrossRefGoogle Scholar
  319. 319.
    Koslow Mautner S, Cody 3rd HS. Sentinel node biopsy after neoadjuvant chemotherapy for node-positive breast cancer: does axillary ultrasound improve performance? J Clin Oncol. 2015;33:3375–8.CrossRefGoogle Scholar
  320. 320.
    Toh U, Iwakuma N, Mishima M, Okabe M, Nakagawa S, Akagi Y. Navigation surgery for intraoperative sentinel lymph node detection using indocyanine green (ICG) fluorescence real-time imaging in breast cancer. Breast Cancer Res Treat. 2015;153:337–44.PubMedCrossRefGoogle Scholar
  321. 321.
    Tian P, Zhang W, Zhao H, Lei Y, Cui L, Zhang Y, Xu Z. Intraoperative detection of sentinel lymph node metastases in breast carcinoma by Fourier transform infrared spectroscopy. Br J Surg. 2015;102:1372–9.PubMedCrossRefGoogle Scholar
  322. 322.
    Stoffels I, Dissemond J, Pöppel T, Schadendorf D, Klode J. Intraoperative fluorescence imaging for sentinel lymph node detection: prospective clinical trial to compare the usefulness of indocyanine green vs Technetium Tc 99m for identification of sentinel lymph nodes. JAMA Surg. 2015;150:617–23.PubMedCrossRefGoogle Scholar
  323. 323.
    Piñero-Madrona A, Torró-Richart J, de León-Carrillo J, et al. Superparamagnetic iron oxide as a tracer for sentinel node biopsy in breast cancer: a comparative non-inferiority study. Eur J Surg Oncol. 2015;41:991–7.PubMedCrossRefGoogle Scholar
  324. 324.
    Kuijs VJ, Moossdorff M, Schipper RJ, Beets-Tan RG, Heuts EM, Keymeulen KB, Smidt ML, Lobbes MB. The role of MRI in axillary lymph node imaging in breast cancer patients: a systematic review. Insights Imaging. 2015;6:203–15.PubMedPubMedCentralCrossRefGoogle Scholar
  325. 325.
    Tsuyuki S, Yamaguchi A, Kawata Y, Kawaguchi K. Assessing the effects of neoadjuvant chemotherapy on lymphatic pathways to sentinel lymph nodes in cases of breast cancer: usefulness of the indocyanine green-fluorescence method. Breast. 2015;24:298–301.PubMedCrossRefGoogle Scholar
  326. 326.
    Kida K, Ishikawa T, Yamada A, et al. A prospective feasibility study of sentinel node biopsy by modified indigo carmine blue dye methods after neoadjuvant chemotherapy for breast cancer. Eur J Surg Oncol. 2015;41:566–70.PubMedCrossRefGoogle Scholar
  327. 327.
    Samorani D, Fogacci T, Panzini I, et al. The use of indocyanine green to detect sentinel nodes in breast cancer: a prospective study. Eur J Surg Oncol. 2015;41:64–70.PubMedCrossRefGoogle Scholar
  328. 328.
    Caudle AS, Yang WT, Mittendorf EA, et al. Selective surgical localization of axillary lymph nodes containing metastases in patients with breast cancer: a prospective feasibility trial. JAMA Surg. 2015;150:137–43.PubMedPubMedCentralCrossRefGoogle Scholar
  329. 329.
    Inoue T, Nishi T, Nakano Y, Nishimae A, Sawai Y, Yamasaki M, Inaji H. Axillary lymph node recurrence after sentinel lymph node biopsy performed using a combination of indocyanine green fluorescence and the blue dye method in early breast cancer. Breast Cancer. 2016;23:295–300.Google Scholar
  330. 330.
    Nakagawa M, Morimoto M, Takechi H, Tadokoro Y, Tangoku A. Preoperative diagnosis of sentinel lymph node (SLN) metastasis using 3D CT lymphography (CTLG). Breast Cancer. 2016;23:519–24.Google Scholar
  331. 331.
    Sugie T, Kinoshita T, Masuda N, et al. Evaluation of the clinical utility of the ICG fluorescence method compared with the radioisotope method for sentinel lymph node biopsy in breast cancer. Ann Surg Oncol. 2016;23:44–50.PubMedCrossRefGoogle Scholar
  332. 332.
    Benson J. Indocyanine green fluorescence for sentinel lymph node detection in early breast cancer. Ann Surg Oncol. 2016;23:6–8.PubMedCrossRefGoogle Scholar
  333. 333.
    Pouw JJ, Grootendorst MR, Bezooijen R, et al. Pre-operative sentinel lymph node localization in breast cancer with superparamagnetic iron oxide MRI: the SentiMAG multicentre trial imaging subprotocol. Br J Radiol. 2015;88:20150634.PubMedPubMedCentralCrossRefGoogle Scholar
  334. 334.
    Li C, Meng S, Yang X, Zhou D, Wang J, Hu J. Sentinel lymph node detection using magnetic resonance lymphography with conventional gadolinium contrast agent in breast cancer: a preliminary clinical study. BMC Cancer. 2015;15:213.PubMedPubMedCentralCrossRefGoogle Scholar
  335. 335.
    Ahmed M, Anninga B, Goyal S, et al. Magnetic sentinel node and occult lesion localization in breast cancer (MagSNOLL Trial). Br J Surg. 2015;102:646–52.PubMedCrossRefGoogle Scholar
  336. 336.
    Ghilli M, Carretta E, Di Filippo F, et al. The superparamagnetic iron oxide tracer: a valid alternative in sentinel node biopsy for breast cancer treatment. Eur J Cancer Care (Engl). 2015 Sep 14 [Epub ahead of print].Google Scholar
  337. 337.
    Motomura K, Izumi T, Tateishi S, Tamaki Y, Ito Y, Horinouchi T, Nakanishi K. Superparamagnetic iron oxide-enhanced MRI at 3 T for accurate axillary staging in breast cancer. Br J Surg. 2015;17 [Epub ahead of print].Google Scholar
  338. 338.
    Dellaportas D, Koureas A, Contis J, et al. Contrast-enhanced color Doppler ultrasonography for preoperative evaluation of sentinel lymph node in breast cancer patients. Breast Care (Basel). 2015;10:331–5.CrossRefGoogle Scholar
  339. 339.
    Rautiainen S, Sudah M, Joukainen S, Sironen R, Vanninen R, Sutela A. Contrast-enhanced ultrasound-guided axillary lymph node core biopsy: diagnostic accuracy in preoperative staging of invasive breast cancer. Eur J Radiol. 2015;84:2130–6.PubMedCrossRefGoogle Scholar
  340. 340.
    Ahmed M, Purushotham AD, Douek M. Novel techniques for sentinel lymph node biopsy in breast cancer: a systematic review. Lancet Oncol. 2014;15:e351–62.PubMedCrossRefGoogle Scholar
  341. 341.
    Chung A, Gangi A, Amersi F, Zhang X, Giuliano AE. Not performing a sentinel node biopsy for older patients with early-stage invasive breast cancer. JAMA Surg. 2015;150:683–4.PubMedCrossRefGoogle Scholar
  342. 342.
    Jacobson GM, Partin JF, Salkeni MA. Optimal management of sentinel lymph node positive biopsy patients in early breast cancer. Ann Transl Med. 2015;3:87.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Francesco Giammarile
    • 1
    • 2
    Email author
  • Federica Orsini
    • 3
  • Renato A. Valdés Olmos
    • 4
    • 5
  • Sergi Vidal-Sicart
    • 6
  • Armando E. Giuliano
    • 7
  • Giuliano Mariani
    • 8
  1. 1.Médecine Nucléaire – Groupement Hospitalier EstUniversité Claude Bernard Lyon 1Bron CedexFrance
  2. 2.Biophysique – Faculté Charles Mérieux LyonOullins CedexFrance
  3. 3.Section of Nuclear Medicine«Maggiore della Carità» University HospitalNovaraItaly
  4. 4.Nuclear Medicine Section and Interventional Molecular Imaging Laboratory, Department of RadiologyLeiden University Medical CentreLeidenThe Netherlands
  5. 5.Nuclear Medicine Department, Antoni van Leeuwenhoek HospitalThe Netherlands Cancer InstituteAmsterdamThe Netherlands
  6. 6.Nuclear Medicine DepartmentHospital Clinic BarcelonaBarcelonaSpain
  7. 7.Surgical Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars-SinaiLos AngelesUSA
  8. 8.Regional Center of Nuclear MedicineUniversity of PisaPisaItaly

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