Intraoperative Radioisotope Sentinel Lymph Node Mapping in Non Small Cell Lung Cancer

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1 Intraoperative Radioisotope Sentinel Lymph Node Mapping in Non Small Cell Lung Cancer Michael J. Liptay, MD, Gregory A. Masters, MD, David J. Winchester, MD, Brian L. Edelman, MD, Ben J. Garrido, BA, Todd R. Hirschtritt, BA, Reid M. Perlman, MD, and Willard A. Fry, MD Departments of Surgery, Radiation Medicine, Division of Medical Oncology and Department of Pathology, Evanston Northwestern Healthcare, Northwestern University Medical School, Evanston, Illinois Background. Lymph node metastases are the most significant prognostic factor in localized non small cell lung cancer (NSCLC). Nodal micrometastases may not be detected. Identification of the first nodal drainage site (sentinel node) may improve detection of metastatic nodes. We performed intraoperative Technetium 99m sentinel lymph node (SN) mapping in patients with resectable NSCLC. Methods. Fifty-two patients (31 men, 21 women) with resectable suspected NSCLC were enrolled. At thoracotomy, the primary tumor was injected with 2 mci Tc-99. After dissection, scintographic readings of both the primary tumor and lymph nodes were obtained with a handheld gamma counter. Resection with mediastinal node dissection was performed and findings were correlated with histologic examination. Results. Seven of the 52 patients did not have NSCLC (5 benign lesions, and 2 metastatic tumors) and were excluded. Forty-five patients had NSCLC completely resected. Mean time from injection of the radionucleide to identification of sentinel nodes was 63 minutes (range 23 to 170). Thirty-seven patients (82%) had a SN identified; 12 (32%) had metastatic disease. 35 of the 37 SNs (94%) were classified as true positive with no metastases found in other intrathoracic lymph nodes without concurrent SN involvement. Two inaccurately identified SNs were encountered (5%). SNs were mediastinal (N2) in 8 patients (22%). Conclusions. Intraoperative SN mapping with Tc-99 is an accurate way to identify the first site of potential nodal metastases of NSCLC. This method may improve the precision of pathologic staging and limit the need for mediastinal node dissection in selected patients. (Ann Thorac Surg 2000;70:384 90) 2000 by The Society of Thoracic Surgeons Lung cancer is the number one cause of cancer-related mortality in the United States in both men and women. In 1999 more than 180,000 people in the US were diagnosed with lung cancer [1]. Surgical resection of localized tumors remains the principal therapy with curative potential. Nonetheless, up to 40% of patients will relapse and die of their disease after complete resection [2]. In localized tumors, intrathoracic lymph node metastases are the most powerful predictors of survival and curability [2]. A prognostically verified staging system based on the TNM classification and a regional lymph node classification were recently revised [3]. The current regional lymph node classification system breaks down the nodal stations into N1 (intralobar and hilar nodes confined to the pleural envelope), N2 (ipsilateral mediastinal lymph nodes including the subcarinal station), and N3 (contralateral mediastinal nodes and supraclavicular or scalene nodes). Nevertheless, few improvements in lymph node staging have occurred since the technique of Presented at the Thirty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 31 Feb 2, Address reprint requests to Dr Liptay, Section of Thoracic Surgery, Evanston Northwestern Healthcare, Burch 100, 2650 Ridge Ave, Evanston, IL 60201; m-liptay@nwu.edu. cervical mediastinoscopy was described by Carlens in 1959 [4]. Sentinel lymph node identification has been well studied in both melanoma and breast cancer [5 7]. Using technetium 99m sulfur colloid injection, accuracy of the technique has been reported to exceed 90% [6, 8]. In these malignancies sentinel node identification has allowed limiting formal nodal basin dissections to those patients with positive sentinel nodes. The selective application of potentially morbid axillary or inguinal dissections may benefit patients. An additional benefit in sentinel node detection has been the application of more sensitive pathologic detection techniques to the specified sentinel nodes. Immunohistochemistry (IHC) and reverse transcription-polymerase chain reaction techniques have increased the accuracy of the detection of micrometastases [9, 10]. The utility of these findings remains to be determined. The presence of metastatic disease in the mediastinal lymph nodes has been shown to be the most important predictor of a poor survival after resection of non small cell lung cancer (NSCLC) [2, 11]. Clinical radiologic staging of intrathoracic lymph nodes with computed tomography (CT) scanning underestimates lymph node involvement in approximately 25% of cases [12, 13]. A 2000 by The Society of Thoracic Surgeons /00/$20.00 Published by Elsevier Science Inc PII S (00)01643-X

2 Ann Thorac Surg LIPTAY ET AL 2000;70: SENTINEL NODE MAPPING IN NSCLC 385 significant proportion of patients with normal mediastinal lymph nodes on CT scan may harbor lymph node metastases. Thoracic nodal dissection including mediastinal stations has been advocated as the most accurate method of staging patients and defining prognosis. Nevertheless, this procedure is not without morbidity. Recurrent laryngeal nerve injury, chylothorax, bronchial devascularization, and excess blood loss have all been reported [12]. The potential benefits of sentinel node mapping in lung cancers include enhancing prognostic and diagnostic accuracy. Accurate sentinel node identification allows pathologists to focus examinations, while intraoperative scintigraphy can assist the surgeon in performing a complete nodal dissection and give real-time feedback to the adequacy of resection. The potential role of sentinel node evaluation in limiting mediastinal node dissection in lung cancer remains to be determined. Patients with mediastinal nodal metastases (N2 disease) without hilar or intralobar nodal involvement are described as having skip metastases. The incidence of skip metastases is poorly understood. Skip metastases to mediastinal lymph nodes account for between 25% to 40% of resected N2 disease [14 17]. Likewise there are data supporting an improved survival in these patients with isolated N2 station disease relative to those with both positive N1 and N2 disease [18]. The true prognostic significance of isolated N2 skip metastases is unknown as to whether the tumors of these patients behave more like stage II (T1 2, N1) or stage IIIA (T1 3, N2) tumors. The identification of sentinel nodes occurring in the mediastinum may improve understanding of the mechanisms involved in so-called skip metastases. The goal of this pilot study was to evaluate the safety and feasibility of intraoperative sentinel thoracic lymph node mapping with technetium-99 (Tc-99)-labeled colloid. The issues to be examined included: (a) would the radionucleide migrate to the lymphatics without significantly prolonging the operative time; (b) would the intraoperative scintographic scanning accurately detect unique sentinel node stations; (c) if so, what is the incidence of skip metastases or N2 level sentinel nodes in these patients; and lastly (d) what are the potential adverse effects or complications associated with the technique. Material and Methods Eligibility This study was approved by the Evanston Northwestern Healthcare Investigational Review Board for protocols dealing with human subjects. Fifty-two consecutive patients were enrolled in this pilot study after giving signed, informed consent. The patients were considered for surgical resection of suspected locoregionally confined lung cancers. Routine preoperative assessment of operability included pathologically negative mediastinoscopy for enlarged mediastinal lymph nodes (more than 1.0 cm in short axis diameter) or if the primary lesion was larger than a 3-cm (T1) lesion. After the preoperative evaluation, patients were taken to the operating room and the standard preparations were made for a thoracotomy and resection. Intraoperative Technique Intraoperative injection of technetium 99m sulfur colloid suspension was performed directly into lung masses at the time of thoracotomy. A total dosage of 2 mci was administered in a four-quadrant injection pattern. Divided doses of 0.5 mci suspended in 0.5 ml were injected at the outer margins of the tumor. The standard dissection was performed to complete an anatomic resection of the tumor. Readings were taken with the handheld gamma probe counter after calibration. The value of counts per second of the primary tumor and intrathoracic nodal stations were documented. The time from injection of the tumor with the technetium 99m sulfur colloid solution to the detection of migration throughout the lymphatics was recorded. The tumor specimen and nodal stations were surveyed initially in the thorax. Radiolabeled nodes were also examined off the operative field and separately from the tumor specimen. The migration of the technetium sulfur colloid solution was considered successful if a specific nodal station registered counts per second greater than three times background values. 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 that station was classified as a sentinel node and reported as such to the surgical pathology department. Pathologic Evaluation After identification of the sentinel nodal station, these nodes were examined according to a standard protocol. After formalin fixation and embedding in paraffin, step sections were taken at 30- to 40- m intervals, the sections were stained with hematoxylin and eosin, and 10 sections were evaluated. Additional resected nodes were examined using conventional bivalving techniques on each node creating one slide stained with hematoxylin and eosin for each node. Sentinel and nonsentinel lymph nodes were then examined by IHC. Immunohistochemistry was performed using AE1/AE3/PCK26 (Ventana Medical Systems, Tucson, AZ) cytokeratin antibody using a standard protocol. A single section of both the sentinel and nonsentinel lymph nodes were examined. The IHC result was considered positive if the procedure demonstrated positive cell clusters or individual cells with the appropriate tumor cell morphology. Rescanning of the Hemithorax After the initial scintigraphic readings and standard anatomic resection with ipsilateral mediastinal node dissection were completed, a repeat examination with the gamma probe was performed to assess for residual radioactivity and potentially overlooked lymph nodes. The remaining radioactivity levels were recorded and

3 386 LIPTAY ET AL Ann Thorac Surg SENTINEL NODE MAPPING IN NSCLC 2000;70: Table 1. Sentinel Node (SN) Identification Identification N Migration Time (min) SN localized (successful migration of radionucleide) 37 of 45 (82.2%) 63.4 (range, ) Accurately identified SN 35 of 37 (94.6%) Inaccurately identified SN (false-negative nodal 2 of 37 (5.4%) histology) SN positive for metastases 12 of 37 (32.4%) SN not identified No migration of radionucleide 8 of 45 (17.8%) 47.2 (range, 10 86) reresections of nodal stations performed if indicated by the handheld gamma counter readings and visual inspection. Results Patients/Procedures Performed Fifty-two patients (31 men and 21 women) with resectable suspected lung cancers were enrolled consecutively in this pilot study. The mean age of the patients was 70 years old (range 47 to 89 years). Forty-five of the patients had a pathologic diagnosis of NSCLC. Seven patients did not have a primary lung cancer. Five had a benign diagnosis and 2 patients had metastatic tumors (1 melanoma, 1 transitional cell carcinoma). These patients were not included in the analysis of sentinel node stations despite 4 of 7 having evidence of radionucleide lymphatic migration. Of the 45 patients who underwent resection for lung cancer, 28 had upper lobe tumors, 15 had lower lobe lesions, and 2 patients had right middle lobe tumors. The mean tumor size was 4.3 cm (range 0.3 to 10.5 cm). Lobectomy was performed in 29 patients, with 5 pneumonectomies, 4 bilobectomies, 3 enbloc lobectomies with chest wall resections, 3 segmental resections, and 1 sleeve lobectomy performed on the remainder of the cohort. The stages of disease ranged from IA to IIIB (see Table 2). Eleven patients had stage IA and 9 had IB tumors. Nineteen patients had stage II lesions and 6 were diagnosed with stage III lung cancers. Adenocarcinoma was the most prevalent cell type, present in 26 patients. Squamous cell tumors were diagnosed in 11 patients, with 3 large cell, 3 bronchoalveolar cell carcinoma, and 2 mixed adenosquamous cell types. No complications related to the intraoperative sentinel node procedure occurred in the 52 patients who underwent the intraoperative injection of technetium and subsequent scintographic mapping. Seven patients were excluded from the analysis of sentinel node identification because the final pathology results were not primary lung cancers. Radionucleide Migration Time The average migration time for the 37 successfully identified sentinel nodes was 63 minutes (range 23 to 170 minutes). The average migration time for the 8 cases in which a sentinel nodal station was not found was only 47 minutes (range 10 to 86 minutes). Three of these patients were early in our series prior to our knowledge of minimal migration times required. In this early experience we noted no migration of radionucleide before 30 minutes. Subsequently, we did not perform scintographic surveillance until at least 30 minutes had elapsed after initial injection. Likewise in 4 of the 8 patients with a diagnosis of lung cancer who failed to demonstrate migration of the radionuclide into the lymphatic system, the tumors were large (5, 8, 9.6 and 10.5 cm, respectively) and had a significant amount of central necrosis within the primary lesions. Sentinel Node Accuracy/Localization Successful radionucleide migration occurred in 37 of the 45 patients with primary lung cancer (82.2%) (Table 1). Histopathologic serial sectioning detected metastatic disease in 12 of the 37 sentinel nodes examined (32.4%). Nodal metastatic disease was present in 4 of the 8 patients in whom the radionucleide did not migrate (1 patient had N2 mediastinal disease and 3 patients had N1 bronchopulmonary nodal metastases). The accuracy of the sentinel node identification was assessed by the presence of cancer-bearing metastatic lymph nodes not identified as sentinel nodes while the labeled sentinel nodes appeared histologically uninvolved. False-negative sentinel nodes occurred in 2 of the 37 patients. The first patient had a 6.5-cm left upper lobe Table 2. Sentinel Node Stations Level N No. Positive for Metastases N1 (n 29 patients) 10 9 a N2 (n 8 patients) b a Three patients had positive intraparenchymal nodes by direct extension. b 21.6% (8 of 37 patients) had a skip metastasis drainage pattern.

4 Ann Thorac Surg LIPTAY ET AL 2000;70: SENTINEL NODE MAPPING IN NSCLC 387 tumor. The sentinel node was classified as a level 5 aortopulmonary window station. Histologic examination revealed the only positive nodes to be located in the level 11 interlobar area. In the other patient radioactivity was measured in both the level 11 interlobar and level 10 hilar stations. The level 11 nodes were noted to be most radioactive and classified as sentinel nodes. Serial sectioning revealed no metastases in the level 11 (sentinel nodes) but a single focus of microscopic tumor in the substance of the level 10 hilar nodes. Two of 37 patients thus provide a false-negative rate of 5.4% or an accuracy rate of 94.6%. Immunohistochemistry was performed on all resected nodes in this study. Using antibodies specific for cytokeratin (a marker of epithelial cell origin), both sentinel and nonsentinel nodes were examined to further validate the technique. No further false-negative sentinel nodes were identified using this technique. Two patients were upstaged with IHC identifying metastases in previously described negative nodes. In 1 patient the original sentinel node was classified as negative by serial sectioning and IHC was positive for metastases whereas no other resected nodes showed metastatic spread. A second patient had an N1 sentinel node positive for tumor whereas IHC detected additional positive N2 metastatic foci. Of the 37 sentinel nodal stations identified, 29 were found within the pleural envelope or N1 stations. Three patients in this group had positive metastases in intralobar lymph nodes by direct extension. One of the limiting factors of this technique is the inability to resolve spatially the individual radioactivity readings unless the nodes can be separated from the primary tumor. Intralobar lymph nodes not contiguous with the primary tumor can be separated for individual readings off of the operative field. In 8 patients (21.6%) the first station of lymphatic drainage was noted to be a mediastinal (N2) lymph node. These were three level 4 right paratracheal nodes in right upper lobe tumors, three level 5 aortopulmonary window nodes in left upper lobe tumors, one paraaortic level 6 node in a left upper lobe lesion, and one subcarinal level 7 node in a lower lobe lesion. Comment Nodal Status Is Most Important Prognostic Factor The prognosis of patients diagnosed with NSCLC is poor in general. In the 30% of patients with stage I/II disease, complete surgical resection currently represents their best chance for cure. The most significant prognostic variable in these patients is the presence or absence regional lymph node involvement. Despite the histopathologic diagnosis of negative nodal spread, up to 40% of patients who undergo complete resection without evidence of lymph node metastases relapse within 24 months after surgery [11]. The explanation for this high relapse rate is poorly understood. It is likely that these patients harbor micrometastatic disease in the lymph nodes or at distant sites at the time of resection that go undetected and untreated. This clinically occult spread may relate to inadequate nodal sampling and dissection, thus leaving tumor behind in the chest, or to inadequate sensitivity of histologic detection of nodal micrometastases. Efforts to improve our ability to find and remove lymph nodes harboring occult micrometastatic disease may allow better staging and more appropriate referral for adjuvant therapies. Evolving pathologic techniques to detect fewer metastatic cells may also lead to improved prognostic information. Development of the Sentinel Node Technique The detection and identification of sentinel lymph node drainage stations has been studied and is used in several other solid tumors. The first sentinel node study was reported in 1977 by Cabanas utilizing lymphangiography in penile cancer to demonstrate prognostic importance [19]. Morton and colleagues used vital blue dye to map the lymphatic drainage of melanomas [20]. Since these first reports, sentinel node mapping with radiolabeled technetium colloid solutions has become a standard practice in the management of both breast cancer and melanomas. The safety and efficacy of this technique in these settings has been well documented. In the present study we sought to assess whether intraoperative radiolabeled technetium sentinel node mapping was feasible in the patient with potentially resectable lung cancer. The questions we specifically sought to answer were: (a) would the radionuclide migrate in a sufficient time so as not to excessively prolong the operative time, (b) could the technique reliably identify the first nodal stations of drainage (sentinel nodes), and (c) lastly, could the handheld gamma counter direct completion of nodal dissections by measuring for residual radioactivity in resected tumor and nodal beds. Technical Factors An obstacle to the application of sentinel node technology to lung cancers was the morbidity associated with accessing the tumor preoperatively for injection of the isotope. In our own institution s series with breast cancers we have had best results with injection of the breast tumors the night before resection to allow more time for the migration of the technetium to regional nodes [7]. Performing this procedure in lung cancer patients requires a radiology-guided needle access that would place the patient at significant risk of complications such as pneumothorax, bleeding, and the potential pleural seeding of tumor [21]. The intrapulmonary migration time of the radionuclide was unknown at the onset of this pilot study. Whether the intraoperative dissection period was sufficient for the technetium to traverse the regional lymphatic channels was not clear. Fortunately with the great vascularity and lymphatic supply of the lungs, the average migration time of 63 minutes was well within the time parameters of a standard pulmonary resection and nodal dissection.

5 388 LIPTAY ET AL Ann Thorac Surg SENTINEL NODE MAPPING IN NSCLC 2000;70: The sentinel node technique has been examined in lung cancer using isosulfan blue dye. Little and colleagues [22] reported on a pilot series of 37 patients in whom intraoperative blue dye injection of the primary tumor was performed. Their false-positive rate was also 0% but they identified a sentinel node in only 17 (47%) of the patients studied [22]. The authors hypothesized that the addition of the radionuclide tracer may improve sensitivity but might also lead to false-positive results due to increased uptake of tracer in nonsentinel node stations. Our findings did not confirm these concerns. Our sensitivity with the radioisotope was over 80% and we misidentified only 2 of 37 sentinel nodes (5%). The radioisotope method of sentinel node identification appears to be more accurate than the blue dye technique. A possible explanation may include the difficulty of differentiating anthracotic black-appearing nodes from nodes stained with the dark blue dye. Focus Pathologist to Examine Carefully for Micrometastases Occult metastases or micrometastases to regional lymph nodes have been studied extensively in breast cancer with general agreement that between 10% and 15% of patients initially deemed node negative will have occult metastases identified with more precise examination such as serial sectioning, IHC, and reverse transcriptionpolymerase chain reaction techniques [9, 10, 23, 24]. The prognostic significance of these findings remains unclear. In a previous report from our institution, 11 of 86 breast cancer patients with initially reported histologically negative nodes contained occult metastases as confirmed by IHC using a cocktail of antikeratin antibodies. These patients had a significantly increased risk of recurrent disease compared with the node-negative patients [25]. Izbicki and colleagues [26] found that NSCLC patients originally staged with pn 0 or pn 1 disease who were found to have micrometastases to their mediastinal lymph nodes by IHC had an equally poor survival compared with patients diagnosed with pn 2 by original histopathologic techniques. These authors also found a greater than 40% incidence of skip metastases to the mediastinal lymph nodes (negative N1 lymph nodes) in their series. Our present study examined the identified sentinel nodes with 10 serial sections at 30- to 40- m intervals. All nodes were subjected to IHC for cytokeratin markers. This type of exhaustive evaluation is impractical for routine pathologic examination in all lung cancer resections. Accurate identification of the first nodal station draining a lung cancer (a sentinel node) will allow pathologists to selectively apply these more sensitive techniques in their search for micrometastases. Avoidance of Routine Mediastinal Node Dissection Several articles and editorials have been written regarding the role of complete mediastinal node dissection. The therapeutic benefit of complete mediastinal lymph node dissection remains unclear. In many series of resected stage IIIA NSCLC, a complete resection or negative highest mediastinal nodal station have been strong predictors of outcome [15, 27]. Although it is clear that more accurate staging is accomplished with thorough nodal dissection, it is also agreed that additional operative time, along with the potential complications of increased blood loss, recurrent laryngeal nerve injury, chylothorax, and devascularized bronchi are real concerns [12]. The sentinel node technique if validated may allow for accurate intraoperative identification of nodal involvement in the first lymphatic drainage site and potentially segregate those patients who may require complete nodal dissections to remove further disease versus the allowance of a more focused resection in patients with negative sentinel nodes. Another aim of the study was to evaluate the gamma probe to check for residual radioactivity in the resection bed and mediastinal nodal basins after initial complete dissection. In 4 patients re-resection was performed due to residual radioactivity in the mediastinum and on further dissection remaining nodal tissue was discovered and removed. In our early experience it appears the extent of resection can be influenced by using the gamma probe to assess adequacy of resection. Incidence of Skip Metastases Subpleural lymphatics link directly to mediastinal lymph nodal stations from the lungs in 20% to 25% of patients [28]. This skip metastases pattern of drainage occurs more frequently in upper lobe tumors [28] and adenocarcinomas [14]. The intraoperative identification of a sentinel node in the mediastinum may allow a more accurate characterization of these unique patterns of lymphatic tumor drainage. Several studies have noted a better survival for patients with a single station of N2 metastases, especially in the case of aortopulmonary nodes in left upper lobe tumors [27, 29, 30]. As we continue to investigate the role of multimodality therapies for locoregionally advanced disease, improvements in accuracy of nodal staging will undoubtedly aid in determining those patients who may benefit from more aggressive adjuvant systemic therapies. As our understanding of nodal drainage patterns improves, a new methodology accounting for the number and location of nodes involved in addition to or instead of the common N1, N2, N3 classification may evolve. Intraoperative thoracic sentinel node mapping with Tc-99-labeled colloid is feasible and safe. The average migration time (63 minutes) to allow for scintographic detection of lymphatic flow does not prolong the operative procedure. Sentinel node detection by this method is highly accurate and may assist the surgeon in more complete nodal dissection and allow the pathologist to provide more precise nodal staging. References 1. Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, CA Cancer J Clin 1999;49: Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997;111:

6 Ann Thorac Surg LIPTAY ET AL 2000;70: SENTINEL NODE MAPPING IN NSCLC Mountain CF, Dresler CM. Regional lymph node classification for lung cancer staging. Chest 1997;111: Carlens E. A method for inspection and tissue biopsy in the superior mediastinum. Dis Chest 1959;36: Gershenwald JE, Thompson W, Mansfield PF, et al. Multiinstitutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol 1999;17: Krag DN, Weaver D, Ashikaga T, et al. The sentinel node in breast cancer: a multicenter validation study. N Engl J Med 1998;339: Winchester DJ, Sener SF, Winchester DP, et al. Sentinel lymphadenectomy for breast cancer: experience with 180 consecutive patients: efficacy of filtered technetium 99m sulphur colloid with overnight migration time. J Am Coll Surg 1999;188: Cox CE, Pendas S, Cox JM, et al. Guidelines for sentinel node biopsy and lymphatic mapping of patients with breast cancer. Ann Surg 1998;227: Slade MJ, Smith BM, Sinnett HD, Cross NCP, Coombes RC. Quantitative polymerase chain reaction for the detection of micrometastases in patients with breast cancer. J Clin Oncol 1999;17: Jannink I, Fan M, Nagy S, Rayudu G, Dowlatshahi K. Serial sectioning of sentinel nodes in patients with breast cancer: a pilot study. Ann Surg Onc 1998;5: Naruke T, Goya T, Tsuchiya R, Suemasu K. Prognosis and survival in resected lung cancer based on the new international staging system. J Thorac Cardiovasc Surg 1988;96: Bollen ECM, van Duin CJ, Theunissen PH, Hof-Grootenboer BE, Blijham GH. Mediastinal lymph node dissection in resected lung cancer: morbidity and accuracy of staging. Ann Thorac Surg 1993;55: Fernando HC, Goldstraw P. The accuracy of clinical evaluative intrathoracic staging in lung cancer as assessed by postsurgical pathologic staging. Cancer 1990;65: Okada M, Tsubota N, Yoshimura M, Miyamoto Y. Proposal for reasonable mediastinal lymphadenectomy in bronchogenic carcinomas: role of subcarinal nodes in selective dissection. J Thorac Cardiovasc Surg 1998;116: Martini N, Flehinger BJ, Zaman MB, Beattie EJ Jr. Results of resection in non-oat cell carcinoma of the lung with mediastinal lymph node metastases. Ann Surg 1983;198: Ishida T, Yano T, Maeda K, Kaneko S, Tateishi M, Sugimachi K. Strategy for lymphadenectomy in lung cancer three centimeters or less in diameter. Ann Thorac Surg 1990;50: Graham ANJ, Chan KJ, Pastorino U, and Goldstraw P. Systematic nodal dissection in the intrathoracic staging of patients with non-small cell lung cancer. J Thorac Cardiovasc Surg 1999;117: Yoshino I, Yokoyama H, Yano T, et al. Skip metastases to the mediastinal lymph nodes in non-small cell lung cancer. Ann Thorac Surg 1996;62: Cabanas R. An approach for the treatment of penile carcinoma. Cancer 1977;39: Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992;127: Fry WA, Siddiqui A, Pensler JM, Mostafavi H. Thoracoscopic implantation of cancer with a fatal outcome. Ann Thorac Surg 1995;59: Little AG, DeHoyos A, Kirgan DM, Arcomano TR, Murray KD. Intraoperative lymphatic mapping for non-small cell lung cancer: the sentinel node technique. J Thorac Cardiovasc Surg 1999;117: Rubio IT, Korourian S, Cowan C, Krag DN, Colvert M, Klimberg VS. Use of touch preps for intraoperative diagnosis of sentinel lymph node metastases in breast cancer. Ann Surg Oncol 1998;5: Schreiber RH, Pendas S, Ku NN, et al. Microstaging of breast cancer patients using cytokeratin staining of the sentinel lymph node. Ann Surg Oncol 1999;6: Clare SE, Sener SF, Wilkens W, Goldschmidt RA, Merkel D, Winchester DJ. Prognostic significance of occult lymph node metastases in node negative breast cancer. Ann Surg Oncol 1997;4: Izbicki JR, Passlick B, Hosch SB, et al. Mode of spread in the early phase of lymphatic metastasis in non-small-cell lung cancer: significance of nodal micrometasis. J Thorac Cardiovasc Surg 1996;112: Patterson GA, Piazza D, Pearson FG, et al. Significance of metastatic disease in subaortic lymph nodes. Ann Thorac Surg 1987;43: Riquet M, Hidden G, Debesse B. Direct lymphatic drainage of lung segments to the mediastinal lymph nodes. J Thorac Cardiovasc Surg 1989;97: Thomas PA, Piantadosi S, Mountain CF. Should subcarinal lymph nodes be routinely examined in patients with nonsmall cell lung cancer? J Thorac Cardiovasc Surg 1988;95: Okada M, Tsubota M, Yoshimura M, Miyamoto Y, Matsuoka H. Prognosis of completely resected pn2 non-small cell lung carcinomas: what is the significant node that affects survival? J Thorac Cardiovasc Surg 1999;118: DISCUSSION DR CLAUDE DESCHAMPS (Rochester, MN): I would like to thank Dr Liptay for sending me his manuscript in advance and congratulate him and his group for this very innovative and excellent presentation. Just as some of us were thinking that nothing really new was happening in lung cancer surgery, at least in the operating room, Dr Liptay and his colleagues bring us a new gadget and radioisotope and potentially more insight into the staging of non small cell lung cancer. The true sentinel lymph node is the lymph node most likely to harbor metastatic disease if regional nodal metastasis is present. Doctor Liptay and his colleagues have demonstrated elegantly that the lymph node they identify as the sentinel node was metastatic roughly one third of the time with an accuracy of 95%. The success of sentinel node technique depends on identifying the first lymph node draining the primary tumor. The sentinel node should be the first draining node and the only hot node if the mapping procedure is performed timely after injection. In the case of breast cancer, as time goes on, the isotope material flows further up the chain of nodes and additional nodes become hot; not only that, the hottest node is not always the sentinel node. Potential benefits of this modality include clarification of the concept of skip metastasis and the decrease in morbidity of the lymphadenectomy, although in our database in Rochester, lymphadenectomy accounts for only less than 3% of significant morbidity after thoracotomy for lung cancer. Perhaps the greatest benefit of the sentinel node technique is to allow for a more thorough pathologic examination of the sentinel node, because the false-negative rate of frozen section can be as high as 10% in some institutions. A final benefit is the potential to improve staging and survival. Potential disadvantages include radiation safety regulation, of course; the learning curve; the use of gamma detection instrumentation; and the possible allergic reaction to the colloid used. The technique is an interdisciplinary process, including the pathologist and the radiation doctor. The procedure is compli-