Interact CardioVasc Thorac Surg 2007;6:214-218. doi:10.1510/icvts.2006.141911
© 2007 European Association of Cardio-Thoracic Surgery
Institutional report - Thoracic general |
Successful migration of three tracers without identification of sentinel nodes during intraoperative lymphatic mapping for non-small cell lung cancer
Antoine Meyera,
Cai Chenga,
Christian Antonescub,
Edgardo Pezzettaa,
Angelika Bischof-Delaloyeb and
Hans-Beat Risa,*
a Division of Thoracic Surgery, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland
b Department of Nuclear Medecine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
Received 9 August 2006;
received in revised form 21 November 2006;
accepted 22 November 2006
 Presented at the joint 18th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 12th Annual Meeting of the European Society of Thoracic Surgeons, Leipzing, Germany, September 12–15, 2004.
*Corresponding author. Tel.: +41 21 314 24 08; fax: +41 21 314 23 58.
E-mail address: hans-beat.ris{at}chuv.ch (H.-B. Ris).
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Abstract
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Prospective comparative evaluation of patent V blue, fluorescein and 99mTC-nanocolloids for intraoperative sentinel lymph node (SLN) mapping during surgery for non-small cell lung cancer (NSCLC). Ten patients with peripherally localised clinical stage I NSCLC underwent thoracotomy and peritumoral subpleural injection of 2 ml of patent V blue dye, 1 ml of 10% fluorescein and 1ml of 99mTc-nanocolloids (0.4 mCi). The migration and spatial distribution pattern of the tracers was assessed by direct visualisation (patent V blue), visualisation of fluorescence signalling by a lamp of Wood (fluorescein) and radioactivity counting with a hand held gamma-probe (99mTc-nanocolloids). Lymph nodes at interlobar (ATS 11), hilar (ATS 10) and mediastinal (right ATS 2,4,7; left ATS 5,6,7) levels were systematically assessed every 10 min up to 60 min after injection, followed by lobectomy and formal lymph node dissection. Successful migration from the peritumoral area to the mediastinum was observed for all three tracers up to 60 min after injection. The interlobar lympho-fatty tissue (station ATS 11) revealed an early and preferential accumulation of all three tracers for all tumours assessed and irrespective of the tumour localisation. However, no preferential accumulation in one or two distinct lymph nodes was observed up to 60 min after injection for all three tracers assessed. Intraoperative SLN mapping revealed successful migration of the tracers from the site of peritumoral injection to the mediastinum, but in a diffuse pattern without preferential accumulation in sentinel lymph nodes.
Key Words: Lung cancer; Diagnosis and staging; Lung cancer surgery; Lymph nodes; Imaging
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1. Introduction
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Sentinel lymph node (SLN) mapping was advocated by Morton et al. in patients with melanoma of the lower extremities [1]. This elegant technique allowed accurate identification of loco-regional disease while avoiding unnecessary formal groin dissections. Peritumoral intradermal injection of a lymphotropic dye enabled the identification and excision of one or two SLN (‘blue node’) after having performed a small inguinal skin incision (Fig. 1). The SLNs were localised within the first station draining the lymphatic basin of a specific anatomical region containing the tumour. Formal groin dissection was then performed as a staged procedure selectively in patients with loco-regional disease after immunohistochemical examination of the SLN. The procedure was refined by preoperative lymphoscintigraphy in order to centre the skin incision over the SLN [1]. As a consequence, the concept of SLN mapping and dissection was explored for other primary tumours such as breast, colon and lung cancer [2–11].
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Fig. 1. Identification of blue-stained afferent lymphatics draining into a single sentinel inguinal lymph node (‘blue node’) in a patient with lower extremity melanoma after intradermal peritumoral injection of patent blue, according to the technique described by Morton et al. [1].
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SLN mapping has emerged as an attractive concept in situations where (a) routine dissection of lymphatics is associated with a specific and inherent morbidity (e.g. lymph oedema of the lower limb after groin dissection), (b) formal lymph dissection can be performed as a staged procedure after immunohistochemical examination of the SLN and (c) the lymphatics drain into one specific lymph node station without parallel drainage pathways and inter-individual variability.
The use of SLN mapping for patients with operable lung cancer has been shown to be feasible and safe [2–11]. However, some inherent conceptual problems have been identified which require a critical approach of SLN mapping in this context. First, formal lymph node dissection which has been identified as an integral part of lung cancer surgery by most institutions does not necessarily lead to a specific and inherent morbidity per se [12]. Complications which have been described in this respect are usually related to technical difficulties and may be avoidable [3]. Second, several studies have demonstrated the complexity and inter-individual variability of the lymphatics of the lungs containing a multitude of lymphatic pathways with different drainage patterns to the mediastinum [13, 14]. It seems therefore unlikely that the lymphatics of the lung are governed by a SLN system such as found in the upper and lower extremities. Third, intraoperative SLN mapping during lung surgery may prolong the operation time without having a direct impact on the surgical procedure. SLN examination by immunohistochemistry cannot be obtained by frozen section at the time of surgery in most institutions. Moreover, up to 64% of the patients undergoing lung resection and intraoperative SLN mapping revealed that the tumour spread to additional lymph node stations in the case of SLN involvement [5]. Most protagonists of intraoperative SLN mapping advocate therefore formal lymph node dissection at the time of lung resection, even after successful SLN identification, in order to obtain optimal intraoperative staging and local tumour control [12].
This study was designed to assess the migration pattern after intraoperative peritumoral injection of three commonly used tracers for SLN mapping in patients with clinical stage I NSCLC. The distribution pattern of the tracers from the peritumoral area to the mediastinum were observed in regular time intervals up to 60 min after injection in order to assess their potential to accumulate in specific SLN during the migration process.
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2. Patients and methods
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2.1. Patient enrolment
Ten consecutive patients with clinical stage I NSCLC were enrolled between January 2004 and September 2004. All patients had a histologically proven and peripherally localised NSCLC and were eligible for surgery according to pulmonary function testing. Staging included CT of the chest, FDG-PET scan and brain MRI. CT scan revealed absent enlargement (<1 cm diameter) and calcifications of mediastinal or hilar lymph nodes in all patients and there was no focal uptake of 18F-FDG in the mediastinum on PET scan. The study was approved by the Local Ethical Committee of the University of Lausanne and signed informed consent was obtained from all patients.
2.2. Technique
Surgery was performed under thoracic epidural anaesthesia and double lumen intubation. A standard postero-lateral thoracotomy was performed. The chest cavity was inspected and the tumour and nodal stations were surveyed initially. The tumour was exposed by two Duval forceps (Fig. 2). Peritumoral subpleural injection of 2 ml patent V blue dye, 1 ml of 10% fluorescein and 0.8 ml of 99mTc-nanocolloid (0.4 mCi) was performed by use of a tuberculin syringe in a four-quadrant injection pattern. The lung parenchyma of the involved lobe as well as all extralobar lymph node stations such as interlobar (ATS 11), hilar (ATS 10) and mediastinal (right sided tumours: ATS 2,4,7; left sided tumours: ATS 5,6,7) were systematically assessed every 10 min up to 60 min after injection. No attempt of interlobar, hilar or mediastinal dissection was performed during SLN mapping in order to avoid disruption of lymphatics leading to interruption of tracer migration.
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Fig. 2. Technique of intraoperative peritumoral subpleural tracer injection by use of a tuberculin syringe in a four-quadrant injection pattern after exposure of the peripherally situated tumour by two Duval forceps.
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The pattern of patent V blue and fluorescein distribution at any time point and lymph node station was assessed independently by two surgeons equipped with magnification glasses by direct visualisation of the dye, and fluorescence signalling by use of a lamp of Wood, respectively. Sentinel lymph node mapping was considered successful if one or two clearly identifiable lymph nodes within one lymph node station demonstrated an early and preferential accumulation of patent V blue or fluorescein dye.
Radioactivity was recorded at any time point and lymph node station with the handheld gamma probe counter after calibration (Scinti probe MR 100, Pol.hi.tech srl, Corsoli, Italy). Migration of 99mTc-nanocolloids was considered successful if a specific nodal station registered counts per second greater than three times intrathoracic background values. Radio-guided SLN identification was considered successful if one or two clearly identifiable lymph nodes within one lymph node station registered counts per second greater than three times background values of the surrounding lympho-fatty tissue of that station.
SLN mapping was followed by lobectomy and excision of the interlobar and hilar lymph nodes and mediastinal lymph node dissection [12]. All resected lympho-fatty tissue of each lymph node station specimen was separately labelled and histologically assessed. Throughout the study the lymph node mapping schema according to the revised international staging system has been applied for perioperative lymph node classification [15].
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3. Results
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The patient characteristics are summarised in Table 1. There were six men and four women with a mean age of 63 years ranging from 54–71 years. Five patients had tumours situated in the right upper lobe, three in the left upper lobe and two in the right lower lobe. The peripherally localised tumours were classified as T1 in seven patients and as T2 with involvement of the visceral pleura in three. There were five adenocarcinoma, two squamous cell carcinoma, two broncho-alveolar carcinoma and one undifferentiated carcinoma.
All patients underwent SLN mapping, lobectomy of the involved lobe and mediastinal lymph node dissection without intraoperative complications. There was no 30-day-mortality. Two patients developed postoperative atelectasis and one atrial fibrillation and required bronchoscopy and medical conversion, respectively. The mean operation time was 140 min (range 130–160 min).
Peritumoral injection of patent V blue, fluorescein and 99mTc-nanocolloids resulted in successful migration of the tracers from the peritumoral area to the mediastinum in all patients within the observation period of 60 min. Whereas the patent V blue distribution was difficult to identify in the majority of the patients (60%) due to the presence of anthracotic alterations, the migration process and spatial distribution of fluorescein and 99mTc-nanocolloids over time was easily detectable in all patients at any time point assessed. In all patients there was a concordant spatial distribution pattern of the tracers at any time point assessed with migration of the tracers over time from the peritumoral area across the involved lobe to the interlobar (ATS 11), hilar (ATS 10) and mediastinal (right-sided tumours: ATS 2,4,7; left-sided tumours: ATS 5,6,7) lymph node stations. However, the migration process of the dyes resulted in a progressive and diffuse staining of the interlobar, hilar and mediastinal lympho-fatty tissue, irrespective of the tumour localisation. The interlobar, hilar and mediastinal lympho-fatty tissues were stained at time intervals after injection of 10, 30 and 50 min, respectively. There was an early and preferential staining of the interlobar lympho-fatty tissue (station ATS 11) for all tumours assessed, however, without preferential accumulation of the dyes in one or two SLN within that station. The same holds true for radio-guided detection of 99mTc-nanocolloid migration. We observed a continuous decrease of radioactivity over time at the injection site and a steady increase of radioactivity in the interlobar, hilar and mediastinal lympho-fatty tissues (Fig. 3). The interlobar, hilar and mediastinal stations revealed a significant (3 time background values) increase of counts per second at time intervals after injection of 10, 30 and 50 min, respectively, for all tumours assessed. The interlobar station ATS 11 revealed an early and preferential accumulation of 99mTc-nanocolloids in all patients, however, without preferential staining of one or two clearly identifiable lymph nodes within the lympho-fatty tissue of that station. The increase of radioactivity over time was slower and less pronounced for hilar than for interlobar lymphatics, and for mediastinal than for hilar lymphatics, without difference between subcarinal, paratracheal and aorto-pulmonary levels. There was no clearly identifiable SLN within the hilar or mediastinal lympho-fatty tissues.
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Fig. 3. Intraoperative radioisotope counting (counts/s, mean±S.D.) up to 60 min after injection at the level of (a), the primary tumour and (b), the interlobar (ATS 11), hilar (ATS 10) and mediastinal lympho-fatty tissue (subcarinal ATS 7; upper mediastinal right ATS 2,4; upper mediastinal left ATS 5,6), demonstrating successful tracer migration from the peritumoral site to the mediastinum, with early and preferential accumulation at the interlobar level.
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Histological assessment of the surgical specimens after lobectomy and formal lymph node dissection revealed stage I (N0) disease in seven patients, stage II (N1) in two and stage IIIA (N2) in one, without bulky disease or extracapsular tumor spread in any patient with lymph node involvement.
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4. Comment
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Sentinel lymph node (SLN) mapping in patients with NSCLC has first been advocated by Little et al. by the use of intraoperative peritumoral injection of isosulfan blue dye and successful identification of a SLN was obtained in 47% of the patients [2]. The low SLN identification rate was attributed to the difficulty to distinguish blue-coloured lympatics from adjacent anthracotic tissues. As a consequence, the technique of sentinel lymph node mapping was refined by use of other tracers such as magnetite [9], indocyanine green [7] and 99mTc-colloids [3]. Radio-guided SLN mapping was subsequently assessed in several studies with administration of 99mTc-nanocolloids by intraoperative peritumoral [7, 10] or intratumoral [4, 5] injection, preoperative transthoracic CT-guided intratumoral injection [6–8] or preoperative endobronchial intratumoral injection by use of bronchoscopy [11]. The reported results suggest a successful SLN identification rate varying between 6% and 95% [5]. Liptay et al. reported on their experience with intraoperative radio-guided SLN mapping in 148 patients and observed successful tracer migration and SLN identification in 81% and 70% of the patients, respectively [5]. However, most authors consider radio-guided SLN mapping successful when lymph node stations with higher than background radioactivity are identified rather than single nodes with early and preferential tracer accumulation, in contrast to the initial concept of SLN mapping [1]. Moreover, the ‘hottest node’ does not necessarily correspond to the ‘earliest node’ which should be considered as the first (or sentinel) lymph node draining the lymphatics of a specific anatomical area [1].
This prospective study was designed to assess the migration process and the spatial distribution pattern of patent V blue, fluorescein and 99mTc-nanocolloids over time after intraoperative peritumoral injection. Only patients with small peripherally localised clinical N0 NSCLC were included since obstruction of the lymphatics by hilar or mediastinal adenopathy and large necrotic lesions or centrally localised tumours may interfere with the migration of tracers [3]. Similarly excluded were patients with advanced chronic obstructive lung disease and calcified lymph nodes which has also be shown to interfere with the migration process [6]. No hilar or mediastinal dissection was performed during observation of the migration process in order to avoid disruption of afferent lymphatics. The tracer migration process was systematically observed every 10 min up to 60 min after peritumoral injection, since the minimum and average migration time has been reported to be 10–15 min and 63 min, respectively [3].
Our results indicate a concordant migration and spatial distribution pattern over time for the three tracers. In all patients, continuous migration of fluorescein and 99mTc-nanocolloids was observed without skipping from the peritumoral area to the interlobar, hilar and mediastinal lymphatics. The interlobar lympho-fatty tissue (ATS 11) demonstrated the earliest and most relevant tracer accumulation for all tumours assessed but without preferential staining of one or two lymph nodes. Similar results were obtained in a study which assessed the pattern of lymphatic spread from the lung to the mediastinum by lymphoscintigraphy [13] as well as in two reports of radio-guided SLN mapping [6, 8]. Ueda et al. found tracer accumulation in mediastinal lymph nodes only in combination with the presence of hot nodes at the hilar level after intraoperative radio-guided SLN mapping [8]. Nomori et al. identified mediastinal SLN in 14/40 patients (35%) after preoperative CT-guided radioisotope injection but 13 of these 14 patients had tracer accumulation at the hilar level as well [6]. The same authors identified hilar SLN in 7/40 patients but all of these patients had additional interlobar (12/40) or lobar (34/40) SLN as well, indicating a stepwise migration process of the radioscopic tracers from the site of injection to the mediastinum. Rzyman et al. assessed intraoperative radio-guided SLN mapping in 110 patients with clinical N0 NSCLC [10]. They tested three different SLN definitions (highest activity vs. activity three times background value vs. activity three times background value, or if that fails, highest activity) and found a false negative rate (95% CI) of 27% (16–42%), 15% (6–31%) and 12% (5–26%), respectively [10]. The same group has also assessed colloid solutions with different particle sizes for SLN mapping and has found no significant difference in sensitivity and negative predicted value in this respect [10].
Intraoperative sentinel lymph node mapping has been designed to contribute to the decision of whether or not to perform routine formal lymph node dissection during lung surgery for NSCLC and to omit formal lymph node dissection in patients with tumour-free sentinel lymph nodes. The published results and those from the present study suggest that this procedure is safe and feasible with successful tracer migration from the peritumoral area to the mediastinum in most patients with clinically N0 NSCLC. Targeted immunohistochemical examination of the lympho-fatty tissue of the lymph node station with preferential tracer accumulation during SLN mapping may allow for a more precise pathological staging of patients with resectable NSCLC compared with conventional histological assessment of the surgical specimen [5, 10]. However, our results and those from other reports do not support the view that intraoperative SLN mapping has a practical impact on the operation strategy at the present time and should not replace formal lymph node dissection in patients with resectable NSCLC.
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References
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Abstract
1. Introduction
