Ann Thorac Surg 2008;85:S778-S779. doi:10.1016/j.athoracsur.2007.10.103
© 2008 The Society of Thoracic Surgeons
Supplement: The Minimally Invasive Thoracic Surgery Summit
Sentinel Node Mapping in Lung Cancer: The Holy Grail?
Michael J. Liptay, MD*
Division of Thoracic Surgery, Rush University Medical Center, Chicago, Illinois
* Address correspondence to Dr Liptay, Rush University Medical Center, Division of Thoracic Surgery, 1725 W. Harrison, Ste 774, Chicago, IL 60612-3824 (Email: michael_liptay{at}rush.edu).
Presented at the Minimally Invasive Thoracic Surgery Summit, New York, NY, June 8–9, 2007.
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Introduction
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Sentinel node identification has become standard of surgical care for melanoma and breast cancer. The idea of a first nodal station draining a tumor theoretically would allow the assessment of that node(s) to represent the state of the remaining regional nodes. The sentinel node is used to limit potentially morbid lymph node dissections. Another benefit of the technique is directing applications of more focused pathologic or molecular staging techniques such as serial sections, immunohistochemistry, and reverse transcription-polymerase chain reaction. This ability to direct a more focused search for metastatic disease in the sentinel node rather than all of the nodes removed is a primary benefit of the technique in lung cancer.
Most reported clinical trials and experience with the sentinel node technique in lung cancer were conceived before the current data supporting adjuvant chemotherapy for all node-positive patients. With current indications for adjuvant chemotherapy in resected lung cancer largely determined by the status of the locoregional lymph nodes, the accurate identification of positive nodes has gained therapeutic importance. Sentinel node identification may aid identification of more patients who could benefit from postoperative chemotherapy. Patients with only micrometastatic nodal disease in theory should benefit as well, but the data are less clear.
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Intraoperative Tracer Injection
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The application of the sentinel node technique to lung cancer began with Little and colleagues [1] in 1999. The use of isosulfan blue dye resulted in an identification rate of slightly less than 50%. The primary drawback of the blue dye was the frequent black anthracosis encountered in thoracic nodes that made dye detection difficult.
Our group first reported the use of intraoperative radioactive tracer in 2000 [2, 3]. The technique used sulfur colloid labeled with technetium 99m (Tc 99m) filtered through a 20-µg filter. Before the multicenter phase II Cancer and Leukemia Group B (CALGB) trial, intraoperative sentinel lymph node mapping was performed on 165 consecutive patients presenting as candidates for anatomic resection of a suspected primary lung cancer [4]. Of these, 148 consecutive patients had completely resected non-small cell lung cancers and were included in this study group.
Successful migration of the radioisotope through lymphatics was seen in 120 of 148 patients (81%). A sentinal node was identified in 104 of 120 patients (87%) with successful migration of radioisotope, or 70% (104 of all 148 attempted mapping procedures). Our initial experience included all patients undergoing resection for suspected lung cancers, regardless of the presence of hilar or mediastinal adenopathy or large necrotic tumors.
We failed to demonstrate migration of the radioisotope through the lymphatics in 28 of the 148 patients (19%). Hilar or mediastinal adenopathy, or both, was present in 8 patients, whereas 9 patients had tumors greater than 5 cm. Two patients underwent preoperative chemoradiation. No explanation was found for the technical failure in 11 patients.
In our series, the sentinel node was positive for metastatic disease in 33 of 104 patients (32%); the sentinel node was the only metastatic node in 12 of 33 patients (36%). We detected micrometastatic disease in the sentinel node with immunohistochemistry or serial sectioning in 8 of 33 patients (24%). Thus, in our first experience with the sentinel node procedure, lung cancers were upstaged in 8 of 148 patients (5.5%).
Mediastinal lymph node involvement without concurrent spread to the intraparenchymal and hilar nodal basins has been termed "skip metastasis." The incidence of this phenomenon in patients with positive N2 mediastinal nodes is between 20% and 30% in most series [5]. In our study, 25 of 104 sentinel nodes (24%) were mediastinal.
Since our initial reports, other groups reported sentinel node identification rates of 74% with Tc 99m alone [6], and 81% used a combination of Tc 99m and blue dye [7].
The phase II multicenter CALGB 140203 trial opened for accrual in September 2004. The technique was based on our intraoperative mapping with Tc 99m–labeled sulfur colloid. The inclusion criteria were clinical stage 1 patients with suspected non-small cell lung cancer. After 2 years, 46 of the planned 150 patients were accrued. A recent review of the data showed a disappointing 47% sentinel node identification rate. Factors affecting accrual and accuracy rates included necessary cooperation between nuclear medicine, surgery, and pathology for intraoperative use of radioactivity; various state regulations for radioactivity handling; and a learning curve potentially not overcome by the time of the study was terminated. Whatever the explanation, it became clear a simpler and more effective technique was needed.
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Preoperative Tracer Injection
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As a result the restrictions in the use and handling of radioactive substances in Japan, Japanese surgeons have been pioneers in the extension of sentinel node techniques to include the preoperative injection of radioactive tracer. Technetium 99m–labeled tin colloid has emerged as the most reported. With its higher mass, the migration time is prolonged enough so that the computed tomography (CT)–guided injection can be done the day before the surgical procedure. Nomori and colleagues [8] have reported the largest series. Most recently, they report an 83% sentinel node identification rate in 53 patients with small clinical T1 N0 tumors considered for segmentectomy. Their sentinel node guided segmentectomy resulted in positive sentinel nodes on frozen section leading to completion lobectomies in 3 patients [8].
The preoperative injection has some logistical benefits allowing the injection in nuclear medicine and avoiding the intraoperative handling of the radioisotope. Conversely, the risks of significant pneumothorax, bleeding, and seeding of tumor along needle tracts are all at least theoretic concerns.
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Intraoperative F18-Fluorodeoxyglucose Positron Emission Tomography
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In a pilot study, Nwogu and colleagues [9] injected 10 patients with 10 mCi of F18-fluorodeoxyglucose (FDG) on the day of operation. Using a handheld device during the procedure, they discovered 3 patients (30%) who had FDG-positive nodes with micrometastases present. This technique differs from a standard sentinel node mapping because the FDG is selectively taken up by tumor cells rather than by tracking the lymphatic drainage. Further study on this form of ultrastaging is needed [9]. This was the first study that examined a technique to actually identify metastases and not the sentinel node that may harbor disease.
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Nonradioactive Tracers
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Several groups have moved on to study new techniques to nodal mapping that do not rely on radioactive materials and have had promising results.
Soltecz and colleagues [10] reported on the use of quantum dots that fluoresce in the near-infrared spectrum. They used a camera system that simultaneously acquires color video, the near-infrared fluorescence, and a merged picture to guide dissection. In pigs this technique was able to reliably identify nodal drainage and sentinel nodes. Lymphatics and nodes could be seen through 1 cm of solid tissue and 5 cm of lung parenchyma [10]. A clinical trial using this technology in humans with lung cancer is nearing accrual at the Brigham & Womens Hospital under the direction of Yolanda Colson.
Adusumilli and colleagues [11] have recently reported success with herpes simplex virus containing a green fluorescent protein transgene. In a murine model, this oncolytic herpes strain was shown to easily infect cancer cells and track lymphatic metastases within 2 to 4 hours of injection. Fluorescent thoracoscopy could detect these nodal metastases aiding in resection, and owing to the oncolytic effect of the virus, a therapeutic potential was also cited [11].
In summary, the role of lymph node status in operable lung cancer remains critical. The investigation of sentinel node techniques has progressed. With the aid of new technologies and innovation, the surgeon will continue to lead the diagnosis and treatment of early stage lung cancer.
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References
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- 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;117:220-224.[Abstract/Free Full Text]
- Liptay MJ, Masters GA, Winchester DJ, et al. Intraoperative radioisotope sentinel lymph node mapping in non-small cell lung cancer Ann Thorac Surg 2000;70:384-389.[Abstract/Free Full Text]
- Liptay MJ, Grondin SC, Fry WA, et al. Intraoperative sentinel lymph node mapping in non–small-cell lung cancer improves detection of micrometastases J Clin Oncol 2002;20:1984-1988.[Abstract/Free Full Text]
- Liptay M. Sentinel node mapping in lung cancer Ann Surg Oncol 2004;11:271S-274S.[Abstract/Free Full Text]
- Andre F, Grunenwald D, Pignon JP, et al. Survival of patients with resected N2 non-small-cell lung cancer: evidence for a subclassification and implications J Clin Oncol 2000;18:2981-2989.[Abstract/Free Full Text]
- Rzyman W, Hagen OM, Dziadziuszko R, et al. Intraoperative, radio-guided sentinel lymph node mapping in 110 nonsmall cell lung cancer patients Ann Thorac Surg 2006;82:237-242.[Abstract/Free Full Text]
- Schmidt FE, Woltering EA, Webb WR, et al. Sentinel nodal assessment in patients with carcinoma of the lung Ann Thorac Surg 2002;74:870-874.[Abstract/Free Full Text]
- Nomori H, Ikeda K, Mori T, et al. Sentinel node navigation segmentectomy for clinical stage IA non-small cell lung cancer J Thorac Cardiovasc Surg 2007;133:780-785.[Abstract/Free Full Text]
- Nwogu C, Fischer G, Tan D, Glinianski M, Lamonica D, Demmy T. Radioguided detection of lymph node metastasis in non-small cell lung cancer Ann Thorac Surg 2006;82:1815-1820.[Abstract/Free Full Text]
- Soltesz EG, Kim S, Laurence RG, et al. Intraoperative sentinel lymph node mapping of the lung using near-infrared fluorescent quantum dots Ann Thorac Surg 2005;79:269-277.[Abstract/Free Full Text]
- Adusumilli PS, Eisenberg DP, Stiles BM, et al. Intraoperative localization of lymph node metastases with a replication-competent herpes simplex virus J Thorac Cardiovasc Surg 2006;132:1179-1188.[Abstract/Free Full Text]
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Introduction
Intraoperative Tracer Injection