Techniques that accurately identify the sentinel lymph node in cancer

Table 1 Characteristics of common tracers

Blue dyes	Inherent low molecular weight of blue dyes translates into a very rapid migration into and subsequently out of the lymphatics with fairly low SLN retention, relying on surgeon expertize to identify, locate and remove the SLN before the dye spreads to other nodes[111] Better for localization of superficial lymph nodes Methylene blue (tetramethylthionine chloride, C16H18ClN3S) is a heterocyclic aromatic dye, a member of thiazine dyes[112] First line of treatment in methemoglobinemias, is used frequently in the treatment of ifosfamide-induced encephalopathy and has applications in the treatment of memory loss[112]. Has risk of skin necrosis observed with intradermal injection[113]. Excreted primarily in the urine and causes a green-blue discoloration of the urine which can also be observed in saliva and bile that disappears within a few days. Better safety profile when compared to Isosulfan Blue[114] Patent blue (Isosulfan Blue, Lymphazurin) has a vivid affinity for the lymphatics, with particle size small enough to travel through the lymph vessel but large to be trapped in the lymph nodes[115]
Radiolabelled colloid	Variable size, from 100-400 nm[24] Sulphide-based nanoparticles conjugated with Tc-99m are the most commonly used and available[116] Half life is approximately 6 h[116] As the radiocolloid emits high energy gamma radiation (140 keV) which is highly penetrating, allowing for its use in variable tissue depth, density and coloration[116] Gamma detection instruments are needed to localize tracer (hand held gamma probes, gamma cameras, SPECT)
Indocyanine green	ICG is a negatively charged ion tricarbocyanine dye belonging to the large family of cyanine dyes ICG fluoresces at about 800 nm and longer wavelengths, confines to the vascular compartment through binding with plasma proteins, has low toxicity and rapid excretion, almost exclusively into the bile[117] ICG is a low molecular weight contrast agent, and is both rapidly taken up into the lymphatics but also can diffuse from the lymphatics, reducing the local concentrations and contributing to background signal[116] and needs to be readministered
Tilmanocept (99mTc, Lymphoseek)	Radiopharmaceutical that accumulates in lymphatic tissues by binding to a mannose-binding protein on the surface of macrophages[101] The molecule, 99mTc-DTPA-mannosyl-dextran, is composed of a dextran backbone to which multiple units of mannose and DTPA are synthetically attached[101]

DTPA: Diethylenetriamine pentaacetic acid; SLN: Sentinel lymph node; ICG: Indocyanine green; SPECT: Single-photon emission computerized tomography.

Table 2 National Comprehensive Cancer Network Guidelines for sentinel lymph node biopsy by cancer type

Melanoma (version 4.2014)	In general, SLN biopsy is not recommended for primary melanomas ≤ 0.75 mm thick, unless there is significant uncertainty about the adequacy of microstaging For melanomas 0.76-1.0 mm thick, SLN biopsy may be considered in the appropriate clinical context In patients with thin melanomas ( ≤ 1.0 mm), apart from primary tumor thickness, there is little consensus as to what should be considered “high-risk features” for a positive SLN. Conventional risk factors for a positive SLN, such as ulceration, high mitotic rate, and LVI, are very uncommon in melanomas ≤ 0.75 mm thick; when present, SLN biopsy may be considered on an individual basis For melanomas > 1 mm thick, discuss and offer SLN biopsy
Breast (version 3.2014)	Performance of SLN mapping and resection in the surgical staging of the clinically negative axilla is recommended for assessment of the pathologic status of the axillary lymph nodes in patients with clinical stage I or II breast cancer. This recommendation is supported by results of randomized clinical trials showing decreased arm and shoulder morbidity (pain, lymphedema, sensory loss) in patients with breast cancer undergoing SLN biopsy compared with patients undergoing standard axillary lymph node dissection. The patient must be a candidate for SLN biopsy and an experienced SLN team is mandatory for the use of SLN mapping and excision Axillary staging following preoperative systemic therapy may include SLN biopsy or level I/II dissection SLN mapping injections may be peritumoral, subareolar, or subdermal. However, only peritumoral injections map to the internal mammary lymph node(s) The performance of a SLN procedure should be strongly considered if the patient with apparent pure DCIS is to be treated with mastectomy or with excision in an anatomic location compromising the performance of a future SLN procedure In women with a local breast recurrence after breast conserving surgery who had a prior SNB, a repeat SNB may be technically possible. The accuracy of repeat SNB is unproven and the prognostic significance of repeat SNB after mastectomy is unknown and its use is discouraged The use of blue dye is contraindicated in pregnancy; radiolabelled sulfur colloid appears to be safe for SNB in pregnancy
Esophagus and Esophagogastric Junction (version 1.2014)	No guidelines for SLN biopsy exist
Stomach (version 1.2014)	No guidelines for SLN biopsy exist
Colon (version 3.2014)	Examination of the SLN allows an intense histologic and/or immunohistochemical investigation to detect the presence of metastatic carcinoma. At the present time the use of SLNs should be considered investigational, and results should be used with caution in clinical management decisions
Rectum (version 3.2014)	Examination of the SLN allows an intense histologic and/or immunohistochemical investigation to detect the presence of metastatic carcinoma. At the present time the use of SLNs should be considered investigational, and results should be used with caution in clinical management decisions
Head and Neck (version 2.2014)	SLN biopsy is an alternative to elective neck dissections for identifying occult cervical metastasis in patients with early (T1 or T2) oral cavity carcinoma in centers where expertise for this procedure is available. Patients with metastatic disease in their sentinel nodes must undergo a completion neck dissection while those without may be observed
Penis (version 1.2014)	Dynamic SLN biopsies are recommended only in patients with nonpalpable inguinal lymph nodes treated at tertiary care centers that perform greater than 20 per year
Cervix (version 1.2015)	Consider SLN mapping in stage IA1 (with LVSI), IA2 and IB1 Consider SLN mapping for positive margins or dysplasia or carcinoma on cone biopsy for stage IA1 without LVSI
Endometrium (version 1.2015)	SLN mapping can be considered for the surgical staging of apparent uterine-confined malignancy when there is no metastasis demonstrated by imaging studies or no obvious extrauterine disease at exploration Cervical injection with dye has emerged as a useful and validated technique for identification of LNs that are at high risk for metastasis The combination of a superficial (1-3 mm) and deep (1-2 cm) cervical injection leads to dye delivery to the main layers of the lymphatic channel origins in the cervix and corpus

SLN: Sentinel lymph node; SNB: Sentinel node biopsy; LVSI: Lymphovascular space invasion; LVI: Lymphovascular invasion; DCIS: Ductal carcinoma in situ; LN: Lymph node.