Breast Cancer Lymphoscintigraphy (Sentinel Lymph Node Mapping)

Lymphoscintigraphy (sentinel lymph node mapping) is an imaging technique that is used to identify the lymph drainage basin, determine the number of sentinel nodes, differentiate sentinel nodes from subsequent nodes, locate the sentinel node in an unexpected location, and mark the sentinel node over the skin for biopsy. Lymphoscintigraphy is indicated for proven palpable or nonpalpable invasive breast carcinoma for which removal of the primary tumor and axillary node dissection would be indicated. ^{[1, 2, 3, 4]}

The sentinel lymph node, which can be identified by a radioisotope, visual dye, or both, is based on the principle that primary tumors drain to one or or more lymph nodes before they spread widely. If the sentinel lymph node is negative for metastasis, it is likely that the neoplasm is still within the location of the primary tumor. Lymph nodes are the most common location for metastasis, with a strong correlation between metastasis in the lymphatic system and prognosis. Systemic therapy is more likely to be needed if a distant metastasis is identified. Advances include MR lymphangiography and intranodal lymphangiogram. ^[1]

Sentinel node mapping is rapidly becoming an alternative staging procedure for the axilla in managing early breast cancer. ^[5] Several well-conducted studies have provided high-quality evidence for its usefulness. ^[6] Sentinel node scanning was initially studied in cutaneous melanomas to detect lymphatic drainage patterns before surgery. ^[2] The procedure is applicable to almost all regions of the body, but the greatest impetus to the technique came with the application of the procedure to identify breast sentinel nodes.

The sentinel node is the first node to receive metastatic deposits in a malignancy. Lymphoscintigraphy is an important procedure because if the sentinel node is free of metastasis, subsequent nodes are also likely to be free of disease. The sentinel node is generally defined as follows:

• The node closest to the primary lesion

• The node with a radioactive channel leading to it

• The node with the highest count rate on lymphoscintigraphic imaging and probe counting

• The first node visible on lymphoscintigraphic imaging

• The blue node on dye injection technique

• The node with a blue channel leading to it

Lymphoscintigraphy allows the patient to avoid axillary clearance surgery (axillary lymph node dissection) if the sentinel node is negative for metastatic disease. Given the high prevalence of breast cancer worldwide, the possibility of avoiding axillary clearance surgery in a significant number of patients makes this an extremely valuable procedure.

Lymphoscintigraphy is the staging modality of choice for early breast cancer, and breast cancer trials with 5- to 10-year outcome data have shown no significant differences in disease-free survival rates or overall survival rates between lymphoscintigraphy and axial lymph node dissection but have shown significantly lower morbidity with lymphoscintigraphy. ^[7]

Absolute contraindications to lymphoscintigraphy include clinically positive (N1) axilla and allergy to component used. ^[5]

Relative contraindications to lymphoscintigraphy include the following ^[8] :

• Prior biopsy (especially excisional biopsy)

• Previous breast and axillary surgery

• Advanced disease (associated with fatty degeneration of nodes with reduced function)

• Neoadjuvant chemotherapy

• Multicentric and multifocal disease

• Ductal carcinoma in situ

• High body mass index and old age

• Pregnancy

• Surgeon’s experience and skills

Lymphoscintigraphy has become widely accepted in several other applications besides breast cancer, ^{[9, 10]} including malignant melanoma (stage I and II disease). ^{[11, 7, 12]} Technetium-99m tilmanocept is also used for intradermal or SC injection for melanoma mapping. ^[13] The Multicenter Selective Lymphadenectomy Trial concluded that sentinel node scanning is a low-morbidity procedure for evaluating the regional nodal basin in early melanoma and should become the standard of care. ^[14] Other applications include head and neck cancer, thyroid cancer, non–small cell lung cancer, gastric cancer, ^[10] penile cancer, ^[15] and vulvar cancers. ^[16]

Equipment

Lymphoscintigraphy equipment includes the following:

• Syringes with needles of appropriate gauge, usually 25-G insulin syringes (see the image below)

  Injecting syringe.

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• Syringe shields

• Tc-99m radiopharmaceutical: antimony trisulphide, particle size 0.015-0.3 µm; nanocolloid, particle size 0.05-0.8 µm; sulfur colloid, particle size 0.22 µm; or tilmanocept (Lymphoseek) ^[17]

• Alcohol swabs and other material used during and after injections (see the image below)

  Injection tray containing the radioactive dose in a syringe shield, alcohol swabs, bandage, and dry cotton.

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• Gamma camera and imaging system

• Gamma-detecting probe (see the image below)

  Gamma probe with a highly collimated handheld detecting wand, which is covered with a sterile cover for use within the surgical field.

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The camera should be equipped with a low-energy, high-resolution collimator and should be peaked at 140 KeV with a 20% window centered over the peak. A small magnification (1.35) is often used.

Patient Preparation

Anesthesia

No anesthesia is required.

Positioning

The patient must be imaged in the same position used for surgery, so that there is no shift when the sentinel node is marked on the skin. The patient is usually supine with the ipsilateral arm abducted at 90 degrees and suitably supported.

False-Positive and False-Negative Results

A false-positive result may be caused by contamination of the skin or residual activity from another nuclear medicine procedure done recently.

A false-negative result (absent or faint lymph node uptake) may be caused by a low radiopharmaceutical dose, poor radiopharmaceutical quality, insufficient radiocolloid particles, imaging time that is too early or too late, advanced patient age, or tumor replacement of nodes.

One way of reducing false-positive and false-negative results is to combine the visual assessment of nodes with intraoperative gamma counting and digital palpation through the surgical incision. ^[18]

Approach Considerations

Injection techniques can be divided into superficial and deep methods. The superficial techniques include intradermal, subcutaneous, subareolar, and periareolar injections. Deep techniques include peritumoral or intratumoral injections. Subcutaneous, periareolar, and subareolar techniques are associated with a low yield of nonaxillary nodes.

The combination of radiocolloid injection and blue-dye injection immediately before surgery gives the highest sensitivity and specificity of the technique.  However, numerous studies have also found that SLN biopsy with radiotracer alone is successful. ^{[19, 20]}  A meta-analysis found that mapping sentinel lymph node locations with methylene blue alone results in an acceptable identification rate but an excessive false-negative rate. ^[21]

SLN biopsy with near-infrared (NIR) fluorescence imaging using indocyanine green (ICG) has been reported to be a highly sensitive method for SLN detection. In this method, ICG is injected and then tracked through the lymphatic ducts to SLNs using an excitation illumination system and a high-sensitivity camera. ^[22]  

According to a study by Freebody et al, multisite (triple-site) injection is associated with a high axillary sentinel lymph node identification rate. In the study, simultaneous injections of radiotracer at peritumoral, subcutaneous, and subareolar regions had an axillary sentinel lymph node identification rate of 98% in 123 breast lymphoscintigraphy patients. One axillary node was detected in 110 patients; 2 axillary nodes were detected in 10 patients; and no axillary nodes were detected in 3 patients. ^[23]  

Imaging and Interpretation

Imaging techniques must be meticulous and of a high standard. The camera should be equipped with a low-energy, high-resolution collimator and should be peaked at 140 KeV with a 20% window centered over the peak. Shielding of the injection site is usually not needed. A small magnification (1.35) is often used.

Imaging times for the various injection techniques are given in the table below.

Table. Acquisition Protocols and Imaging Times for Various Injection Types (Open Table in a new window)

An anterior oblique view with a 30-degree lateral tilt is used. If a dual-head camera is used, simultaneous lateral images are also acquired.

Transmission images, radioactive markers to identify the nipple, and flexible line sources to outline the breast contour may be used to provide additional anatomic localization.

Once a sentinel node is identified, a radioactive marker is moved over skin while the patient is under the gamma camera detector, keeping the sentinel node in the field of view. With real-time imaging mode, the marker is moved until the 2 sources coincide (the marker and sentinel node). This area is marked with waterproof ink.

It is useful to add late images before the patient is taken for surgery to ensure that the sentinel node identified is indeed retaining the radiopharmaceutical and also to see if subsequent tier nodes have appeared.

The sentinel node is the one that appears first, is closer to the injection, and/or has a lymphatic duct connecting the injection site with the node.

Axillary nodes are seen in almost all patients, but the appearance of nodes can take several patterns, as follows:

• One sentinel node, with or without a visible lymphatic duct; no second-tier nodes

• One sentinel and one or more second-tier nodes

• The simultaneous appearance of 2 nodes with same uptake intensity (twin sentinel nodes)

• A node closer to the injection site that appears later than other more distant nodes (the closer node is the sentinel node)

Differentiation of the sentinel node from second-tier nodes can be made by the following:

• The presence of a lymphatic channel leading to the sentinel node

• The sequence of appearance (the sentinel node appears first)

• The intensity of uptake (the sentinel node has more activity)

Confirmation needs blue-dye corroboration.

Radiocolloid Injection Method

Intradermal Injection Technique

Many experts contend that this method offers the best results. ^[24] The injection is made 24 hours before the surgery, with 10-15 MBq (0.3-0.4 mCi) of the appropriate Tc-99m-labeled radiopharmaceutical used in a volume of 0.2 mL. The Tc-99m tilmanocept dose is 0.5 mCi administered at least 15 minutes before initiating intraoperative lymphatic mapping. Do not delay mapping more than 15 hours after injection of Tc-99m tilmanocept.

A 25-G needle is used, and 0.2 mL of air bubble is drawn into the syringe behind the radiopharmaceutical. The air ensures that the whole radiopharmaceutical is injected and that none of the dose is left behind in the needle; it also minimizes the risk of spillage as the syringe is withdrawn, which can lead to false-positive and false-negative results.

The injection is made in the skin overlying the tumor, and the needle is inserted at an acute angle into the skin. Proper injection technique is confirmed by the appearance of a skin bleb at the injection site. (See the image below.)

After the injection, dry cotton is applied over the injection site, and the site is sealed with an adhesive bandage. The patient is asked to massage over the injection site with dry cotton wool. This massage should continue for 1-2 minutes. (See the image below.)

Peritumoral Injection Technique

In the peritumoral injection technique, the injection is made deeper into the breast parenchyma around the mass. (See the image below.)

Usually, 4 injections are made around the tumor. The volume of injectate is larger, with 1-2 mL injected at each injection site to make a total volume of 4-8 mL. The injections are made superior, inferior, lateral, and medial to the mass. Another technique is to inject in a semicircle along the axillary side of the mass.

If the mass is nonpalpable, ultrasound guidance can be used for needle placement.

The patient is asked to massage over the injection site and between the injection site and axilla for at least 1-2 minutes. (See the image below.)

Intratumoral Injection Technique

Although some authors have advocated injection inside the tumor, there are concerns about tumor spread, especially along the needle track. Proponents claim 100% reproducibility and sentinel node visualization. ^[25] A small volume of radiopharmaceutical (0.2 mL), with 0.1 mL of air bubble behind it, is injected into the center of the tumor.

If the mass is nonpalpable, ultrasound guidance can be used for needle placement.

The patient is asked to massage over the injection site and between the injection site and axilla for at least 1-2 minutes.

Dye Injection Method

Methylene blue, patent blue, or isosulfan blue injections are used alone or in conjunction for sentinel node identification. ^[26] The injection is given in the operation theater 5 minutes before the surgical incision. The injection is subdermal, peritumoral, or subareolar. (See the image below.)

A volume of approximately 1.5-2 mL is used for subdermal injections, whereas a larger volume of about 5 mL (divided into 2 aliquots) is used for peritumoral injections. The injection site is massaged as it is for the radiopharmaceutical injection.

A positive test is when a node is colored blue, often with a blue channel leading to it.

Note that there may be generalized blue coloration of the body, and some patients may experience allergic reaction to the dye.

Intraoperative Sentinel Node Detection Technique

Imaging the sentinel node allows the surgeon to have an idea of where to explore to retrieve the sentinel node. However, the addition of radioguidance using a gamma probe is the true strength of the technique. This also introduces a multidisciplinary element to the procedure, with breast surgeons and nuclear medicine physicians operating in close cooperation.

By using sentinel node imaging, the surgeon can determine the area where the sentinel node lies. Complete excision can be confirmed by counting the area after removing the purported sentinel node to see if the counts have fallen to background levels. The probe also guides the surgeon into the right direction and allows removal of invisible non-blue nodes that are recognizable due to their radioactive signature.

The gamma probe is covered in sterile sheath that extends to cover the connecting wire up to the display console. The display console is placed where the surgeon can easily see the display. (See the image below.)

The skin mark is confirmed to actually overlie the hottest node by placing the probe tip over the area and moving it to the surrounding areas. The hottest area is identified by the pitch of the audible signal and the count rate on the digital display. (See the images below.)

Background is acquired. One practice is to acquire the background over the suprasternal notch.

The line of sight ^[27] is established by angling the probe at the site of maximum count to determine the angle that allows the shortest distance from the skin to the sentinel node. The node is approached along the line of sight, correcting the direction with periodic input from the probe. If a blue channel is seen, this reinforces the direction.

Once the node is exposed, the probe is applied to it again to ensure that this has a high count rate (in vivo counting). If a blue dye is used and the same node is colored, this corroborates the probe data.

Once the node is removed, it is placed on the probe surface to confirm the counts (ex vivo counting). (See the image below.)

The probe is reapplied to the surgical field to confirm that the radioactive node(s) have been removed. If all radioactive nodes have been removed, the activity in the surgical bed should fall to 10% of the most active node. ^[27]  (See the images below.)