Early in the nineteenth century, Virchow implicated lymph nodes in the process of the local spread of solid tumors to a more widespread systemic disease. The node identified by Virchow is specifically located in the left supraclavicular region. In the modern vernacular, the term sentinel lymph node (SLN) describes the first lymph node to receive drainage from any solid tumor in any anatomic region. It was not until 1989 that the concept of SLN biopsy, as it is currently known, was first made popular based on studies by Morton et al.¹ A feasibility study using blue dye was translated into a successful clinical trial in patients with melanoma. Their results indicated that biopsy and analysis of SLNs accurately reflected the tumor status of the lymph node basin. SLN biopsy was introduced in breast cancer patients shortly thereafter.² Further studies supported SLN biopsy as a way to identify patients at highest risk for locoregional recurrence and metastatic spread, and, therefore, most likely to benefit from adjuvant therapy. SLN mapping aids in the identification of lymph nodes at highest risk of metastasis and allows for more detailed analysis to detect early metastatic disease thus identifying patients who may benefit from adjuvant therapy. While SLN biopsy is standard in both breast cancer and melanoma patients, a number of factors have led to slower adoption in patients with non-small cell lung cancer (NSCLC).

Lung cancer is the leading cause of cancer deaths among both men and women in the US, with an estimated 170,000 new cases and 160,000 deaths reported each year.³ Even in patients with stage I disease thought to have undergone curative resection, recurrence rates remain high at nearly 40%.⁴ This high incidence of recurrent disease in stage I lung cancer patients suggests that these patients are currently understaged and undertreated. In fact, retrospective analysis has demonstrated that nearly 15% to 20% of N0 patients harbor “occult” metastatic disease when nodes are histologically scrutinized in the manner done for breast cancer and melanoma.⁵ Not surprisingly, patients with occult nodal disease exhibit poorer survival and increased rates of recurrence. Despite all the recent clinical advances in lung cancer therapy, the best predictor of patient outcome following surgical resection remains the presence or absence of metastatic disease to lymph nodes. To improve survival of patients with surgically resectable lung cancer, detailed intraoperative lymph node evaluation is needed to more accurately stage patients and identify candidates for early adjuvant therapy.

SLN mapping seeks to identify the first lymph node to harbor metastatic disease from a nearby tumor and has become an integral part of patient selection for adjuvant treatment in solid malignancies such as breast cancer and melanoma. The two primary benefits of SLN mapping in breast cancer and melanoma have been (1) limiting the extent of lymph node dissection in the axilla or groin and (2) focused pathologic assessment of specific “at risk” nodes. In lung cancer surgery, the morbidity of mediastinal node dissection or sampling is low; however, lymph node drainage patterns are complex and variable, and thus the primary utility of SLN mapping is to identify those nodes at highest risk for metastatic disease and to facilitate the focused assessment of such nodes. The ability to conduct more detailed histologic and molecular analysis on the identified SLN would allow for better patient selection for subsequent adjuvant therapy in hopes of improving survival and decreasing locoregional recurrence. Although the goal of detecting micrometastatic disease prospectively via SLN mapping in lung cancer is sound, conventional SLN mapping techniques using radioisotopes or blue dye have not been successfully translated to the thorax, and currently this important therapeutic intervention is not clinically available for the care of lung cancer patients.

Several factors unique to the lung, including the presence of intrapulmonary and anthracotic (black) lymph nodes, have made identification of SLN with blue dye more difficult in lung cancer patients. Furthermore, “shine through” of radioactivity from the tumor injection site to nearby nodes in the mediastinum and hilum has hampered reliable SLN identification using radioisotopes in the thorax. In this chapter, we review prior attempts at SLN identification in non-small cell lung cancer and discuss recent research findings using indocyanine green (ICG) dye and near-infrared (NIR) fluorescence imaging to improve SLN mapping in patients with early-stage lung cancer.

SLN biopsy is currently the standard of care in both melanoma and breast cancer patients, but these methods have not been successfully translated to NSCLC. Unfortunately, only approximately 45% of surgeons completely remove lymph nodes from the hilum and mediastinum at the time of surgical resection.⁶ In addition, lymphatic drainage patterns are highly variable in the lung, making it difficult to predict the draining lymph node basin that should be sampled, and it is unknown whether the specific SLN for a patient is even included in the conventional surgical lymphadenectomy specimens. Furthermore, skip metastases to the N2 nodal station have been shown to bypass the nearby N1 stations and are present in an estimated 20% of cases.⁷ By removing only the nodes included with the resection specimen and failing to sample hilar and mediastinal nodes, surgeons are missing these skip metastases.

In addition to potentially missing nodal disease during surgical resection, current conventional histologic analysis may also miss micrometastatic disease in removed nodes. This prospect is particularly worrisome as nearly 16% of patients with histologically node-negative lung cancer and up to 27.5% of patients with subcentimeter adenocarcinomas are found to harbor evidence of occult micrometastatic disease or disseminated tumor cells within sampled nodes when these nodes are analyzed retrospectively with more time-intensive “SLN” histologic analysis techniques. Furthermore, Liptay et al. recently demonstrated in an analysis of 104 patients with lung cancer, and Takizawa in a series of 157 lobectomies, that the SLN was the only positive node present in 36% to 37% of node-positive patients.^7,8 This is important information, since failure to remove this node or to identify metastatic disease histologically leaves the patient with untreated occult micrometastatic disease which has been shown to correlate with a threefold increase in recurrence and a significant decrease in patient survival.⁸ To impose more focused histologic analysis on all lymph nodes removed during a lung resection is impractical. However, if SLN mapping could identify a small subset of nodes for the pathologists to scrutinize, focused histological and molecular examination could be performed on these nodes to better identify micrometastasis.

Conventional means of SLN mapping using blue dye and radioactive have been attempted in NSCLC but have remained unreliable secondary to physical properties of both the tracer and the lung. The initial attempt at SLN biopsy in lung cancer was performed in 1999 by Little et al.⁹ Thirty-six patients underwent intraoperative injection of blue dye with a SLN identified in only 47% of patients. Low success rates were attributed to the learning curve associated with the injection technique in presence of anthracotic nodes. The authors acknowledged an unacceptably low rate of SLN identification, but advocated for the addition of radiolabeled tracers to improve sensitivity and specificity. Unfortunately, however, this combination proved unsuccessful.