# Sentinel Lymph Node Mapping

## Introduction

Sentinel lymph node mapping identifies the first lymph node or nodes that receive lymphatic drainage from a primary tumor, enabling targeted biopsy and sparing patients unnecessary complete lymph node dissection. The procedure involves injecting Tc-99m sulfur colloid or Tc-99m tilmanocept peritumorally, then using lymphoscintigraphy and an intraoperative gamma probe to guide the surgeon to the sentinel node. This technique is the standard of care for staging melanoma and breast cancer.

## Principles of Sentinel Lymph Node Biology

The sentinel node concept rests on the orderly nature of lymphatic drainage. The first echelon node receiving drainage from a tumor site is the sentinel node, and if that node is free of metastatic disease, skip metastasis to higher-echelon nodes is rare, occurring in fewer than 2-5% of cases. Multiple sentinel nodes may be identified in a single patient because parallel lymphatic channels can drain to different first-station nodes simultaneously.

## Radiopharmaceuticals

### Tc-99m Sulfur Colloid

Tc-99m sulfur colloid is the most widely used sentinel lymph node agent in North America. The unfiltered preparation has a particle size of 100-1000 nm, which results in slower transit and prolonged retention at the injection site. When passed through a 0.22 micrometer filter, the particle size drops to 15-100 nm, allowing faster migration to sentinel nodes. Filtered preparations are preferred for breast cancer lymphoscintigraphy, while unfiltered colloid remains acceptable for melanoma.

### Tc-99m Tilmanocept (Lymphoseek)

Tc-99m tilmanocept is a receptor-targeted agent that binds to mannose receptors (CD206) on macrophages and dendritic cells within lymph nodes. It clears the injection site rapidly and is retained avidly in sentinel nodes with minimal migration to distal nodes. This low distal-node accumulation reduces shine-through and the risk of misidentifying second-echelon nodes as sentinel nodes. Tilmanocept holds FDA approval for breast cancer, melanoma, and head and neck squamous cell carcinoma.

| Agent | Particle Size | Mechanism | Key Feature |
|---|---|---|---|
| Tc-99m sulfur colloid (unfiltered) | 100–1000 nm | Phagocytosis by nodal macrophages | Slow transit; prolonged injection-site retention |
| Tc-99m sulfur colloid (filtered) | 15–100 nm | Phagocytosis by nodal macrophages | Faster transit; preferred for breast |
| Tc-99m tilmanocept (Lymphoseek) | ~7 nm | CD206 mannose receptor binding | Minimal distal migration; FDA-approved |
| Tc-99m nanocolloid (Nanocoll) | 5–80 nm | Phagocytosis | Widely used in Europe |
| ICG (indocyanine green) | N/A (optical) | Fluorescence | Real-time intraoperative visualization |

### Other Agents

Tc-99m nanocolloid (Nanocoll), with a particle size of 5-80 nm, is widely used in Europe. Tc-99m phytate is available in some countries. Indocyanine green (ICG) is an optical agent used alone or combined with a radiotracer. Hybrid tracers that pair ICG with Tc-99m nanocolloid combine radioactive and fluorescent signals, enabling both preoperative imaging and intraoperative optical guidance.

![Comparison of sentinel lymph node radiopharmaceuticals by particle size and mechanism](images/sln-radiopharmaceuticals-comparison.png)

## Lymphoscintigraphy Protocol

### Injection Technique

For breast cancer, the injection is given periarteolarly or peritumorally via intradermal or subdermal routes. A typical activity is 18.5-74 MBq (0.5-2 mCi) in a volume of 0.1-0.5 mL. Periareolar injection is technically simpler and achieves equivalent sentinel node identification rates because breast lymphatics converge toward the subareolar plexus regardless of tumor location. For melanoma, intradermal injection is administered at two to four sites surrounding the primary lesion or biopsy scar, typically using 18.5-74 MBq divided into four doses of 0.1 mL each. Gentle massage of the injection site promotes lymphatic uptake.

### Imaging Protocol

Dynamic imaging begins immediately after injection, typically at one to five seconds per frame for 30-60 minutes. Static images are obtained at 30-60 minutes, with delayed views as needed up to 2-4 hours. Anterior and lateral planar views are standard, with oblique views added for anatomically complex regions. A transmission source or body outline marking provides anatomic reference. The sentinel node location is marked on the skin with an indelible marker using gamma probe guidance. SPECT/CT is added when planar imaging is equivocal or anatomy is complex, as frequently occurs with head and neck or trunk melanoma.

### Interpretation

The sentinel node is identified as the first focus of uptake appearing along a lymphatic channel from the injection site. The interpreter documents the number, location, and laterality of all sentinel nodes and notes any interval (in-transit) nodes between the primary site and the nodal basin. Drainage to unexpected basins, such as internal mammary or contralateral axillary chains, is specifically reported because it alters the surgical plan.

## Intraoperative Gamma Probe

### Technique

A handheld gamma probe localizes sentinel nodes intraoperatively by detecting gamma emissions from the Tc-99m label. Counts are measured over the sentinel node, compared against background, and confirmed ex vivo after excision. A node is considered sentinel if its count rate exceeds background by a ratio of 10:1 (or 3:1 in some institutional protocols). After removal, the nodal bed is surveyed to confirm adequate excision. Blue dye (isosulfan blue or methylene blue) is commonly used as an adjunct for visual confirmation.

### Timing of Surgery

For same-day surgery, the radiotracer is injected 1-4 hours before the operation. For next-day surgery, injection occurs the afternoon before, with reimaging and re-marking the following morning if needed. When radiotracer and blue dye are used together, sentinel node identification rates exceed 95%.

![Intraoperative photograph showing gamma probe-guided sentinel lymph node identification](images/intraoperative-gamma-probe-sln.png)

## Disease-Specific Applications

### Breast Cancer

Sentinel lymph node biopsy is the standard approach for clinically node-negative (cN0) early breast cancer and has replaced routine axillary lymph node dissection, substantially reducing arm morbidity. Contraindications include clinically positive nodes, unless the patient has undergone neoadjuvant chemotherapy with a clip-marked node available for targeted retrieval. The ACOSOG Z0011 trial demonstrated that axillary dissection may be safely omitted even in patients with one to two positive sentinel nodes under select circumstances.

### Melanoma

Sentinel lymph node biopsy is recommended for melanomas greater than 1 mm in Breslow thickness (or greater than 0.8 mm with adverse features such as ulceration or high mitotic rate). A positive sentinel node upstages the patient to AJCC stage III and influences decisions about adjuvant therapy. Drainage to multiple basins is common in trunk and head/neck melanoma. The MSLT-I and MSLT-II trials established the role of sentinel node biopsy and defined management of positive findings.

### Head and Neck Squamous Cell Carcinoma

Sentinel lymph node biopsy is emerging as a viable alternative to elective neck dissection for early-stage (T1-T2, N0) oral cavity carcinoma. SPECT/CT is particularly valuable in this setting because complex cervical anatomy and multiple nodal levels make planar imaging unreliable.

## Complications and Limitations

Allergic reactions to blue dye occur in 1-2% of patients and are rare with radiotracers. Injection site shine-through can obscure nearby sentinel nodes, a problem mitigated by SPECT/CT and filtered colloid. Non-visualization is more common in obese patients or those with prior surgery or radiation to the nodal basin. Overall false-negative rates are approximately 5-10%, and a learning curve of 20-30 cases is generally recommended for proficiency.

![SPECT/CT showing sentinel lymph node localization in relation to anatomic landmarks](images/sln-spect-ct-localization.png)

## Clinical Pearls

Filtered Tc-99m sulfur colloid migrates more rapidly to sentinel nodes than unfiltered preparations because its smaller particle size (15-100 nm) is better suited to lymphatic capillary uptake, making it the preferred formulation for breast cancer lymphoscintigraphy. Periareolar injection achieves equivalent sentinel node identification rates to peritumoral injection because the subareolar plexus collects lymphatic drainage from all breast quadrants. SPECT/CT is especially valuable for trunk and head/neck melanoma, where lymphatic drainage patterns are unpredictable and may direct flow to unexpected nodal basins. Tc-99m tilmanocept's receptor-targeted binding mechanism provides high sentinel node retention with minimal distal migration, reducing the chance of misidentifying second-echelon nodes as sentinel nodes.

## References

1. Giammarile F, 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(12):1932-1947.
2. Wong SL, et al. "Sentinel Lymph Node Biopsy and Management of Regional Lymph Nodes in Melanoma: ASCO and SSO Clinical Practice Guideline Update." *J Clin Oncol*. 2018;36(4):399-413.
3. Sondak VK, et al. "Tc-99m Tilmanocept for Sentinel Lymph Node Detection in Melanoma." *Ann Surg Oncol*. 2013;20(5):1494-1502.
4. Giuliano AE, et al. "Effect of Axillary Dissection vs No Axillary Dissection on 10-Year Overall Survival Among Women with Invasive Breast Cancer and Sentinel Node Metastasis: The ACOSOG Z0011 Randomized Clinical Trial." *JAMA*. 2017;318(10):918-926.