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© 2002 American Society for Clinical Oncology Intraoperative Sentinel Lymph Node Mapping in Non–Small-Cell Lung Cancer Improves Detection of MicrometastasesByFrom the Division of Thoracic Oncology, Radiation Medicine, and the Department of Pathology, Evanston Northwestern Healthcare, Northwestern University Medical School, Evanston, IL. Address reprint requests to Michael J. Liptay, MD, Section of Thoracic Surgery, Evanston Northwestern Healthcare, 2650 Ridge Ave, Burch 100, Evanston, IL 60201; email: m-liptay{at}nwu.edu
PURPOSE: Lymph node metastases are the most significant prognostic factor in localized non–small-cell lung cancer (NSCLC). Nodal micrometastases may not be detected with current standard histologic methods. We performed intraoperative technetium-99m (99mTc) sentinel lymph node (SN) mapping in patients with resectable NSCLC. This study aimed to identify the first station of nodal drainage of operable lung cancers. Serial section histology and immunohistochemistry were used to validate the SN and to identify the presence of micrometastatic disease. PATIENTS AND METHODS: One hundred patients with potentially resectable suspected NSCLC were enrolled. At thoracotomy, the primary tumor was injected with 0.25 to 2 mCi 99mTc. Intraoperative scintigraphic readings of both the primary tumor and lymph nodes were obtained with a hand-held gamma counter. Anatomic resection with a mediastinal node dissection was then performed. RESULTS: Nine of the 100 patients did not have NSCLC (seven benign lesions and two metastatic tumors) and were excluded. Seventy-eight (86%) of 91 patients had a SN identified and a complete resection. Sixty-nine (88.5%) out of the 78 SNs were classified as true-positive with no metastases found in other intrathoracic lymph nodes without concurrent SN involvement. In nine patients, the SN was the only positive node. In seven of these nine patients, the SN was found to harbor only micrometastatic disease. CONCLUSION: Intraoperative SN mapping with 99mTc is an accurate way to identify the first site of lymphatic tumor drainage in NSCLC. This method may also improve the precision of pathologic staging.
SENTINEL NODE (SN) mapping techniques have been applied to most solid tumors. Introduced first by Cabanas1 in 1977 and more widely applied for melanoma and breast cancers in the past decade, they have become accepted procedures to limit potentially morbid nodal basin dissections in both the axilla and groin. Our initial series on intraoperative SN mapping with radionuclide in lung cancer established the feasibility of the technique and formed the basis of this progress report on the evolving utility of SN mapping in lung tumors.2 Although SN mapping has become a standard of care in both breast cancer and melanoma, it remains investigational in most other solid tumors. The primary use of the SN procedure in both breast cancer and melanoma is to limit potentially morbid axillary and groin nodal basin resections. The morbidity of a complete mediastinal node dissection for lung cancer is not excessive, and the procedure may be therapeutic.3,4 In our experience, the most promising potential benefit of SN mapping in resectable lung cancer is its ability to more accurately direct the pathologic examination to the most likely site of nodal metastases. By concentrating on the SN station rather than all of the resected nodes, the routine application of more sensitive pathologic techniques (immunohistochemistry [IHC], serial sectioning, reverse transcriptase polymerase chain reaction) and the identification of micrometastatic disease in lymph nodes becomes more feasible. The ability of serial sectioning and IHC techniques to enhance the detection of cancer cells within the lymphatics has been frequently described in lung and other solid tumors.5-8 Lymph node metastasis is the most important prognostic factor in localized and resectable non–small-cell lung cancer (NSCLC).9 The presence of nodal micrometastatic disease in lung cancer may garner the same poor prognosis as metastases evident by conventional techniques.10,11 Currently, conflicting data exist to support the administration of chemotherapy for localized completely resected lung cancer, although clinical trials continue to investigate this intervention. If improvements in systemic therapy are forthcoming, more accurate or ultra-staging techniques may assist in selecting patients at highest risk for recurrence and perhaps most likely to benefit from additional therapies. Mediastinal lymph node involvement without spread to the intraparenchymal and hilar nodal basins has been termed skip metastases. The incidence of this phenomenon in patients with positive N2 mediastinal nodes has been reported to be between 20% and 30% in most series.12 Recent studies have attempted to distinguish between skip N2 metastases and traditional N1- and N2-positive patients by arguing that the skip pattern patients have a prognosis similar to stage II patients (N1) rather than stage III patients (N2).12 New data suggest that the nearly 40,000 patients with stage III locoregionally advanced disease have a wide variation of prognoses within the same stage.13 The SN technique may allow better understanding of common drainage patterns of different tumor locations. This may lead to improved prognostic separation of patients based on the number and degree (gross/micrometastatic) of nodes involved. The impact on overall prognosis, therapeutic decision-making, and new staging systems remains to be determined. This prospective study sought to examine the feasibility of intraoperative SN mapping with radioisotope in potentially resectable NSCLC. Specific measurements of accurate SN identification and the influence of pathologic staging with detection of micrometastases will be assessed.
This study was approved by the Evanston Northwestern Healthcare Investigational Review Board for protocols dealing with human subjects. One hundred consecutive patients were enrolled onto this study after giving signed, informed consent between July 15, 1998, and March 1, 2001. The patients were considered for surgical resection of suspected locoregionally confined lung cancers. This report includes 52 patients from our initial report of the technique.2 Only patients able to tolerate anatomic resection of their tumors and a complete mediastinal node dissection were included in the study. Patients were not excluded based on size of tumor or clinical intrathoracic adenopathy. A preoperative cervical mediastinoscopy was performed if enlarged mediastinal lymph nodes (> 1.0 cm in short axis diameter) were present on computed tomography scan or the primary lesion was larger than 3 cm in size (T1). After the preoperative evaluation, patients were taken to the operating room, and the standard preparations were made for a thoracotomy and resection.
Intraoperative Technique
Radionuclide Migration Time The time from injection of the tumor with the 99mTc sulfur colloid solution to the detection of migration throughout the lymphatics was recorded. In our previous publication, we stated a minimal migration time of 30 minutes was required for nodal radioactivity to appear. As our experience with the intraoperative SN mapping technique has increased, we have noted detectable 99mTc migration within 10 to 15 minutes after initial injection into the tumor. During the time of migration, care is taken to avoid dissection of the bronchial structures and peribronchial tissues where the majority of lymphatics are located.14 The bronchial dissection and division are performed last in the majority of cases if the operative dissection permits. The tumor specimen and nodal stations were initially surveyed in the thorax. Radiolabeled nodes were also examined off the operative field and separately from the tumor specimen. The migration of the 99mTc sulfur colloid solution was considered successful if a specific nodal station registered counts per second greater than three times background values. In our initial report, if a lymph node station was found to have the highest counts per second and the ex vivo measurements were greater than three times the intrathoracic background then it was classified as an SN and reported as such to surgical pathology. In addition to resecting the SN, a complete hilar and mediastinal node dissection was performed in all patients. This included routine complete removal of mediastinal nodal stations 4, 7, and 10 on the right side and 5, 6, 7, and 10 on the left. As have others,15 we have since recognized that there may be more than one unique SN station in a given tumor; therefore, if any node measures greater than three times background, it is categorized as an SN.
Pathologic Evaluation Sentinel and nonsentinel lymph nodes were subsequently examined by IHC. IHC was performed with AE1/AE3/PCK26 (Ventana Medical Systems, Inc, Tucson, AZ) cytokeratin antibody using a standard protocol. A single section of both the sentinel and nonsentinel lymph nodes were examined. IHC was considered positive if it demonstrated positive cell clusters or individual cells with the appropriate tumor cell morphology.
One hundred consecutive patients with potentially resectable suspected NSCLC were included in this prospective analysis of the intraoperative SN technique. The cohort consisted of 54 men and 46 women, with a mean age of 70 years (range, 39 to 89 years). Nine of the 100 patients did not have NSCLC (seven benign lesions and two metastatic tumors) and were excluded from further study. The remaining ninety-one patients with resectable lung cancer underwent the intraoperative SN procedure along with an anatomic resection including a formal complete mediastinal node dissection. The demographic distribution of patients, pathologic cell types, tumor staging data, and the resections performed are listed in Table 1.
Accuracy of Technique Successful migration of the 99mTc sulfur colloid through the pulmonary lymphatics was observed in 78 (86%) of the 91 patients. In all of these 78 patients, a unique SN station was identified. In four patients, two separate stations were classified as SN, with significant radioactivity in each level. In 69 (89%) of the 78 patients, the identified SNs were classified as true-positive, with no metastases found in other intrathoracic lymph nodes without concurrent SN involvement (Table 2).
SN Accuracy/Localization Initial studies began with the injection of 2 mCi of the 99mTc sulfur colloid. The background from the radioactive tumor within the chest often hindered accurate in-vivo SN detection. This made the ex-vivo separation of the nodes from the tumor specimen necessary. Over the last 25 cases, we have decreased the radioactivity injected to 0.25 mCi. This has successfully decreased the tumor radioactivity background without decreasing the ability to detect and identify sentinel lymph nodes. Although the correlation between in-vivo and ex-vivo SN identification has been improved with the injection of less radioactivity, the final arbitrator for accurate readings remains the ex-vivo radioactivity measured off the field with the individual nodal stations dissected free from the tumor.
Detection of Micrometastases (Ultrastaging)
Incidence of Skip Metastases SNs were found to reside in the mediastinum (N2) in 16 (20.5%) of the 78 patients with identified SNs. These nodes were subcarinal (level 7) in six patients, paratracheal (level 4) in five patients, and aortopulmonary window (level 5) in five patients (Table 4).
Because there are no prior reports on intraoperative radioisotope SN mapping in lung cancer, much of this series must be considered as a developmental experience. The technique continues to evolve as we gain experience with different clinical situations. This process will promote the development of improved guidelines for standardizing the technique and the determination of selection criteria, which, in turn, will optimize the procedure’s utility and potential for success. Clearly, lymph node metastases are the most powerful predictive factor of long-term survival in localized NSCLC.17,18 Despite the initial pathologic diagnosis of node-negative status, up to 40% of traditionally staged stage I patients will recur within 2 years.19 Our study aimed to determine the first lymph node stations to drain specific resected tumors, thereby allowing for the selective application of more sensitive pathologic techniques to assess for occult lymphatic metastases. With smaller sized tumors increasingly identified with computed tomography scan screening techniques, debate has arisen regarding the need for either complete mediastinal node dissections or anatomic resections. Several recent sobering reports have noted a not insignificant incidence of nodal metastases in T1 tumors less than 2 cm in diameter.8,20-22 With increased experience, the SN mapping technique may allow us to sample only the most likely nodes to be involved, thereby limiting the scope of the operation without decreasing the actual staging information gathered with a resection. We noted four patients with more than one SN station identified. The most plausible explanation for this involves two lymphatic channels originating in the region of the primary tumor and running to two separate and distinct lymph nodes. Rather than defining the SN as the hottest node and ignoring other potential efferent lymphatics, we maintain the definition of SN to include all nodes with radioactivity measured greater than three times background in the chest. The term skip metastasis refers to the situation of metastatic foci found in mediastinal lymph nodes (N2) without evidence of metastasis to the parenchymal or hilar nodes (N1).23 The assumption is that the tumor cells have skipped over the usual first site of nodal involvement. The skip metastasis theory has no place in the SN paradigm because the SN (wherever it is found) is by definition the first site of nodal drainage for that particular solid tumor. Yoshino et al24 reported on 110 patients with stage IIIa mediastinal node-positive (N2) resected NSCLC. Thirty-three patients had no metastases to the intraparenchymal or hilar nodes and had a skip metastatic pattern of spread. Seventy-seven patients had the classical pattern of positive N1 and N2 nodal involvement. The 5-year survival was significantly better for the skip metastases group compared with the classical pattern (35% v 12.7%, respectively, P < .05).24 Our detection rate of 20.5% mediastinal (N2) SNs is similar to other skip metastases patterns reported. The ability to define the first echelon of lymphatic drainage for specific tumors to be mediastinal has important staging and prognostic implications. Perhaps the difference between isolated N2 station disease and N1 disease will become less important as our knowledge of lung cancer lymphatic drainage patterns increases with wider application of SN mapping techniques.25 As our selection criteria for the intraoperative SN mapping evolves, our accuracy rate is expected to increase. We included all patients in our study who were candidates for complete resection regardless of tumor size or the presence of clinical hilar adenopathy. Of the 13 patients with unsuccessful migration of radioisotope, eight had tumors more than 4.5 cm in diameter (4.5 to 10 cm). This may be a function of the altered blood supply and lymphatics in larger centrally necrotic tumors. Likewise, of the nine patients with inaccurate SN identification, five had grossly enlarged hilar lymphadenopathy at the time of surgery. As was initially the case in breast cancer, patients with clinically positive nodes were included for study in the SN technique. Theoretical and practical issues, however, would argue against continuing this practice. The presence of gross metastatic disease within a node would likely inhibit the ingress of radionuclide by clogging the lymphatic inflow. Likewise, grossly enlarged lymph nodes that are clinically positive should be routinely removed for accurate staging purposes, assuring a complete resection. The group of patients that has the most potential to benefit from the application of SN technology is the group with small tumors and clinically negative lymph nodes. The incidence of nodal metastatic disease in these patients has been reported to be between 15% and 20%.20 Furthermore, the presence of micrometastatic disease in lymph nodes initially classified as negative by standard histologic examination seems to be of high prognostic relevance. Kubushak et al10 retrospectively identified 125 patients with completely resected NSCLC, all of whom had node-negative tumors by conventional histologic techniques. IHC was performed with an epithelial marker on all resected lymph nodes. Twenty-two percent of the patients had positive tumor cells in nodes originally staged as free of tumor by conventional histology. More importantly, the patients were observed for a mean of 64 months, and the survival curves were significantly worse for those with only micrometastatic disease compared with those with negative IHC examinations.10 The patients with only micrometastatic disease found in SN from our series constituted seven of the 91 patients with resectable NSCLC. Thus, in nearly one of 10 patients who underwent the full procedure, staging was directly affected. The procedure also had potential benefit for patients with negative SNs after the additional pathologic examination by providing more comprehensive staging. Because effective adjuvant therapies are currently lacking, little current practical data is gained. However, to most effectively analyze promising therapies, accurate staging information is paramount, and the ultrastaging ability of the SN technique in lung cancer helps accomplish this goal.26 New initiatives related to this technique include a multicentered trial involving several centers interested in validating this single institutional series. As selection criteria are further defined and more experience is gained with the technique, thoracic surgeons may become more confident in withholding or proceeding with more radical nodal dissections based on intraoperative SN data. The SN technique may also play a role in a new modified staging system, which considers number and degree of involved lymph nodes rather than strictly location (eg, hilar, mediastinal, and so on). Our initial experience with this technique has yielded promising results that await wider application and validation.
Presented in part at the Thirty-Seventh Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
