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Eur J Cardiothorac Surg 2003;23:214-220
© 2003 Elsevier Science NL

Intraoperative radioguided sentinel lymph node biopsy in non-small cell lung cancer

^a Division of Thoracic Surgery, Cardiac and Thoracic Department, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy
^b Division of Nuclear Medicine, University of Pisa, Pisa, Italy
^c Division of Radiology, Department of Oncology, University of Pisa, Pisa, Italy

Received 2 September 2002; received in revised form 25 October 2002; accepted 4 November 2002.

* Corresponding author. Tel.: +39-50-995211; fax: +39-50-9957239
e-mail: f.melfi{at}med.unipi.it

	Abstract

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Appendix A. Conference... References

 
Objectives: The aim of this study was to determine the accuracy and the role of the sentinel lymph node (SLN) technique in patients with early non-small cell lung cancer (NSCLC). Methods: This study was carried out on 29 consecutive patients (M/F=24:5, mean age 65.9±7.1 years) with resectable NSCLC (Stage IA–IB). Intraoperative injection with a ^99mTc-nanocolloid suspension was performed in the first ten patients; the following patients were injected under computed tomography scan guidance. A total dose of 37 MBq (1 ml) was administered in two to four divided aliquots (depending on the size), injected in the periphery of the tumour. Intraoperative radioactivity counting started a mean of 1 h (range 50–70 min) after the injection. The SLN was defined as the node with the highest count rate using a handheld gamma probe counter. Resection with mediastinal node dissection was performed and findings were correlated with histologic and immunohistochemistry (IHC) examination. Results: Three of the 29 patients did not have NSCLC (two benign lesions, and one metastatic breast tumour) and were excluded. The SLN was identified in 25/26 (96.1%) patients (a total of 31 SLNs); 7/31 (22.5%) of the SLNs were positive for metastatic involvement after histologic and IHC examination. One inaccurately identified SLN was encountered (3.8%). Conclusions: These preliminary results demonstrate the feasibility of this procedure in identifying the first site of potential nodal metastases of NSCLC. The actual clinical impact of this procedure remains to be elucidated by further investigation in larger groups of patients.

Key Words: Lung cancer • Sentinel lymph node • Skip metastases • Radioguided biopsy

	1. Introduction

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Appendix A. Conference... References

 
The prognosis of operable non-small cell lung cancer (NSCLC) is set by the extent of lymph node involvement according to the TNM classification. However, clinical staging is not reliable inasmuch as enlarged nodes may be benign in more than 40% of cases and normal nodes may be diseased in almost 25% of cases. Furthermore, it is quite common that node stations be skipped. As a consequence, the standard surgical operation practice is to perform a complete lymphadenectomy for resection of the primary tumour [1–3] although this procedure is not without morbidity [4]. However, up to 40% of the patients with early stage lung cancer have a recurrence of the tumour and die despite complete surgical resection [5,6]. This suggests that the occult micrometastatic tumour cells, which are not detected by current clinical staging examinations and conventional histopathological methods (such as haematoxylin and eosin staining), have already spread to the regional lymph nodes (lymphatic loco-regional metastasis) at the time of surgery.

Identification of sentinel lymph nodes (SLNs) with radioisotope tracer has been used for years on patients with a variety of solid tumours. Experience with melanoma [7] and breast cancer [8] demonstrated that selective dissection of the lymph node stained first was accurate with respect to prediction of the status of more distant lymph node stations. This early-staining node (defined as the first drainage from the primary tumour) has been referred to as SLN. The accuracy of this technique has been studied in patients with NSCLC. In those patients at an early stage, complete lymphadenectomy could be reduced by an intraoperative pathologic diagnosis of SLN.

Recently M.J. Liptay and associates used a technetium-99m (^99mTc) colloid and reported that the identification rate for SLN was 82% with an accuracy of 95% [9,10]. We used a similar radioisotope to detect the SLN but only in Stage I NSCLC patients. We applied a modified protocol in which the radiopharmaceutical ^99mTc-nanocolloid was injected under computed tomography (CT) guidance just before the operation. Our intent was to determine the accuracy and the usefulness of the SLN technique. We also hypothesized that SLN histology would accurately predict distal lymphatic histology in these patients.

The preliminary results have demonstrated the feasibility to identify the first site of potential nodal metastases of NSCLC. Furthermore, accurate sentinel node identification allowed pathologists to focus on examinations with sensitive techniques (immunohistochemistry, IHC) to validate the SLN and to identify the presence of ‘skip metastases’ [11–14].

	2. Methods

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Appendix A. Conference... References

 
2.1. Patients and eligibility
Between May 2001 and June 2002, 29 patients with peripheral lung cancer were enrolled in this study. It is a pilot study which includes 24 men and five females with a mean age of 65.9±7.1 years (range 52–74 years). Before the operation each patient underwent a physical examination, blood chemistry analysis, plain chest roentgenography, thoracic CT scanning, abdominal ultrasonography and bronchoscopy to determine the staging. Furthermore, bone scintigraphy and brain CT scan were performed in patients with suspected distant metastases. The tumour stage was classified according to the Revisions in the International System for Staging Lung Cancer (1997). Patients with pulmonary metastasis were excluded. All patients enrolled were at an early stage (clinical Stage I) and had a small size tumour (3.1±1.4 cm; range 1.0–6.5 cm).

Selection criteria were: (a) peripherally sited; (b) clinical Stage I NSCLC; and (c) absence of clinical intrathoracic adenopathy. Mediastinal lymph nodes less than or equal to 10 mm along the short axes (except for subcarinal lymph node) were defined by CT scan as not being metastatic lymph nodes. For the subcarinal lymph nodes, nodes less than or equal to 15 mm along the short axes were defined as not being metastatic lymph nodes. Mediastinoscopy was not performed.

Informed consent was obtained from all patients for the use of this technique.

2.2. Methods
We sought to determine the intrathoracic SLN by using radiolabeled colloids. The sentinel node was classified as the node(s) with the highest count rate.

Standard protocol was applied in our study. It includes two different stages with two different surgical approaches:

1st intraoperative radioguided SLN technique performed in open surgery;

2nd intraoperative radioguided SLN technique by the video assisted thoracic Surgery (VAT) procedure.

So far we have tested the first stage of our protocol with all the operations performed by open surgery (postero-lateral thoracotomy). At the beginning of this study (the first ten patients (Group I)), we injected the radioisotope suspension directly in the lung tumour, at the time of the thoracotomy. Afterwards (Group II), we performed the intra-tumoral injection, under CT guidance, just before the operation (30–60 min). We used the ^99mTc-nanocolloids of human albumin (particle size: over 95% <80 nm). A total dose of 37 MBq in a maximum volume of 1 ml was administered in two to four divided aliquots (depending on the size of the tumour), injected at the periphery of the tumour. Readings were taken with the gamma ray detector (Scinti Probe MR100-Pol.hi.tech., Aquila, Italy).

2.3. Technical details
2.3.1. Group I (patients injected at the time of the thoracotomy) (Fig. 1)
Intraoperative radioactivity counting at the nodal stations started a mean of 1 h (range 50–70 min) after the injection with the radioisotope suspension. During this interval we waited for the radioisotope migration without performing any procedure. In order to avoid heat loss, the thoracotomy was approximated by means of two Polysorb sutures held together with two Criles, and covered with a sterile drap.

View larger version (145K): [in this window] [in a new window]   Fig. 1. Radio-injection with 99mTc-nanocolloid® at the time of the thoracotomy.

At the end of the operation (after the lobectomy and excision of the SLN) the mediastinal stations were also examined before performing a complete lymph node dissection. On completion of the procedure a repeated examination with gamma probe was performed to check the residual activity. If indicated by the gamma counter, we completed the re-resections of the nodal stations.

2.3.2. Group II (patients injected under CT guidance) (Fig. 2)
The tumours were localized by means of 5 mm thick high resolution axial CT sections. Local anaesthesia of the thoracic wall was performed; under CT guidance three 22 G needles were introduced at the peripheral margins of the tumour. The interval between the injection under CT guidance and moving the patients from the CT room to the operating room was sufficient for the radio-migration (30–60 min); then the operation started immediately. The procedure which followed was similar to that in Group I. Mediastinal nodal dissection was performed in all eligible patients. Mediastinal metastasis was considered ‘skipping’ if any one of the mediastinal lymph nodes was involved by the tumour, without hilar or intrapulmonary node metastases. Reassessment of the mediastinum with gamma probe after dissection was routinely performed.

View larger version (78K): [in this window] [in a new window]   Fig. 2. Radio-injection with 99mTc-nanocolloid® under CT guidance.

	3. Results

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Appendix A. Conference... References

 
This study was carried out in a group of 29 consecutive patients who underwent open surgery. Three patients with benign lesions (two patients) and a metastatic breast cancer (one patient) were excluded from further analysis. Twenty-five patients underwent a lobectomy procedure, and one patient underwent sleeve lobectomy. Fifteen of these had tumours of 3 cm or less in diameter; one patient (the first case of this series) had a tumour size of 6.5 cm, and the remaining others had tumours greater than 3 cm. The mean tumour size was 3.1±1.47 cm (range 1–6.5 cm). The histologic types included ten squamous cell carcinomas, seven adenocarcinoma, seven bronchoalveolar cell cancer and two typical carcinoids. According to TNM classification, pathologic staging was as follows: (a) 18 patients (69.3%) had Stage I disease, T1N0M0 in nine and T2N0M0 in the remaining nine patients; (b) four patients (15.3%) had Stage II disease, T1N1M0 in two patients and T3N0M0 in the other two patients; (c) four patients (15.3%) had Stage IIIA disease, T1N2M0 in two patients and T2N2M0 in the remaining two patients (Table 1).

The SLN was detected in 25 out of 26 patients (identification rate 96.1%). Only in one patient with a large tumour size (6.5 cm) was the SLN not identified for poor migration of the radiocolloid tracer. In this case no SLN was detected whereas the histopathologic analysis revealed positive nodes located in level 12.

Each mediastinal lymph node was lobe specific: the lymphatic flow from the right upper lobe proceeds to tracheobronchial lymph nodes, the left upper lobe to para-aortic lymph nodes and the lower lobe to pulmonary ligament (Table 2). A total of 31 SLNs were detected (Table 3). A single SLN was identified in 19/25 patients (76%) and double labelled lymph nodes were found in the remaining six patients (24%). Seven out of 31 SLNs (22.5%) were positive for metastatic involvement after full histopathologic evaluation, including IHC. In five of these positive SLNs (71%) the intraoperative lymph node detected with gamma probe was the only metastatic station involved. In the remaining two patients (28.5%) with positive SLN in level 10, serial sectioning with IHC revealed an additional positive N2 station. Two positive SLNs (28.5%) were skipping metastases in which the first station was detected at level 9 (pulmonary ligament) and level 7 (subcarinal), respectively. Step sections and IHC examination revealed micrometastases in five (20%) out of 25 patients without metastasis in the routine haematoxylin and eosin-stained sections (Table 4).

	4. Discussion

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Appendix A. Conference... References

Recently, it has been shown that in some NSCLC patients an early micrometastatic spread of tumour cells to the regional lymph nodes occurs [18,19]. Even in patients with small primary tumours such as tumour cell dissemination, micrometastases can be detected in about 20% of the patients by using immunohistochemical methods [18]. This suggests that occult micrometastases may exist at the time of surgery.

A plausible explanation of this occult spread may be an inadequate nodal dissection or an inadequate pathological analysis of dissected lymph nodes, which are underestimated by current clinical staging examinations and by conventional histopathological methods.

The detection and the identification of the SLN with radiolabeled colloids has been studied in melanoma and breast cancer with an upward staging which allowed selective applications of sensitive pathologic techniques to assess occult micrometastases.

In lung cancer surgery, Little and colleagues [20] demonstrated that the identification rate of SLNs with Isosulfan Blue dye occurs in fewer than 50% of patients because lymph node colour is usually grey or black, which made the blue dye method inaccurate. Recently Liptay and colleagues used a ^99mTc-sulphur colloid and the accuracy was 95% [10,11]. We used a similar pattern with the first ten patients of our series (for our learning curve) who were injected in open surgery, at the time of thoracotomy. At the beginning of this study the detection (with gamma probe) started 15 min after the radio-injection. This waiting time was insufficient for the migration of the radioisotope through the lymphatic flow, therefore it was progressively increased until we found the optimal mean time of 1 h (range 50–70 min) in Group I. The following patients (Group II) were injected under CT guidance. In these cases the interval (between the injection and moving the patients from the CT room to the operating room) was sufficient for the radio-migration (30–60 min).

We chose to use ^99mTc-albumin nanocolloids (particle size: over 95% <80 nm) because the small size of the particles allows a fast lymphatic migration of the tracer into the SLN. This radiopharmaceutical (registered in Europe) for the radioguided SLN technique both in melanoma and breast cancer and the size of the particles are similar to the particles of filtered ^99mTc-sulphur albumin colloid (used in the USA for the SLN technique). With larger size particles the uptake in the sentinel node is delayed and the identification rate of the SLN is very low in the first hours after injection. Thus, if the injection of the radiopharmaceutical is performed during surgery, or up to 2 h before surgery, the use of small radiocolloids is mandatory.

Thanks to our previous experience with the radioguided technique [21], we performed the injection under CT guidance safely. Although pneumothorax, bleeding and the potential pleural seeding of the tumour have been reported when using this technique [22], we have not encounter any complication, even if the number of cases treated is still too small.

In this first phase of our study, which we consider a validation phase, we sought to determine the accuracy and the role of the SLN technique in patients with peripheral early stage NSCLC. Although this was a very brief experience, our preliminary data are encouraging and show a sensitivity up to 96% for this technique.

Regarding the role of radical lymphadenectomy for staging at an early stage of NSCLC, it is still a matter of controversy. Randomized trials (Izbicki and colleagues) showed no survival benefit [12,17] whereas other studies stressed the therapeutic value of radical systematic lymphadenectomy [12,23]. However, lymphadenectomy for staging and arguably for therapeutic benefit remains the gold standard for mediastinal staging. Nevertheless, it is also agreed that additional operative time, along with the potential complications of increased blood loss, recurrent laryngeal nerve injury and devascularized bronchus, are the real concerns [9].

With increased experience the SLN mapping technique may become standard practice in the management of NSCLC patients. We predict two potential benefits which may be obtained with this technique:

• Guiding the surgeon in sampling only the most likely nodes involved, without decreasing the accurate staging (a single node or a few nodes analyzed by using specialized techniques (IHC tests) may increase the ability to detect only a few metastatic cells).
  
• Predicting a pathologic N0 staging status when no metastases are present in the SLN.
  

In addition this technique may improve the understanding of mechanisms involved in the so-called skip metastases. This phenomenon (which occurs in between 25% and 40% of resected N2 diseases) has a considerable significance when we weigh the strategies for lymphadenectomy in such small-sized carcinomas. The true prognostic significance of isolated N2 skip metastases is unknown as is the reason why the tumours of these patients behave like SII (T1–2, N1) or SIIIA (T1–3, N2) tumours [24]. In our series, two (28.5%) out of seven positive SLNs occurred in a skipping manner (N2 diseases). This rate is close to those reported previously: 27% by Martini and colleagues [12]; 28.6% by Ishida and colleagues [13]; and 31.5% by Naruke [25]. Two points were of clinical significance: (1) this ‘skipping’ spread occurred almost exclusively in adenocarcinomas; and (2) a special location of the lymph nodes was affected in the skipping involvement and this was determined by the location of the primary tumour (i.e. tumours of the right upper lobe, skipping involvement occurred in the upper mediastinum). By contrast, in our series the skip metastases were found in two patients with lower right lobe tumours and with different histological types (adenocarcinoma and squamous cell carcinoma, respectively).

Although the intraoperative identification of SLN in the mediastinum may allow a more accurate characterization of these unique patterns of lymphatic tumour drainage, the potential role of SLN evaluation in limiting mediastinal node dissection in lung cancer remains to be determined with small tumours and clinically negative lymph nodes. Further experience will optimize the utility of this procedure, thus avoiding complete lymphadenectomy in early stage tumour with SLN negativity.

This radioguided intraoperative technique is an accurate way to improve the precision of the pathologic staging and may assist the surgeon in a more complete nodal dissection. Nevertheless, the actual clinical impact of this procedure remains to be elucidated by further investigation in larger groups of patients. Once the technique has been validated with the current protocol, our plans are to apply this method by using the VAT procedure (the second stage of our protocol) but in carefully selected patients with first stage NSCLC and with a small peripheral tumour size.

This validation phase will end when we have studied 50 patients. After this, we enter into a second part of this study, which is the application phase, with the aim of avoiding complete lymphadenectomy and carefully analyzing the SLN with a more accurate characterization. Moreover, our intention in the near future is to use a specific pathologic technique such as molecular biology, and apply an immunological characterization of this unique pattern of lymphatic tumour drainage.

	Footnotes

 
Presented at the 16th Annual Meeting of the European Association for Cardio-thoracic Surgery, Monte Carlo, Monaco, September 22–25, 2002.

	Appendix A. Conference discussion

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Appendix A. Conference... References

 
Professor K. Moghissi (Goole, UK): Instead of using the ^99mTc, can you not use an ordinary dye such as Evans blue? That is how the mapping of mediastinal lymph nodes was done, if I recall, by Nohl-Ozer.

Dr Melfi: We didn't use the Isosulfan blue dye because we have some problems with the grey colour of the lymph nodes, so it is not easy to detect the sentinel lymph node with this technique. In the experience of Little and coworkers, they observed that this technique had a very low accuracy. So we decided to use a radioisotope as nanocolloid technetium and we applied a protocol that in the first ten patients was similar to the technique of Liptay. The difference from Dr Liptay is that he applies this technique only in open surgery, during the thoracotomy, whereas we inject the radioisotope under CT guidance which allows us to accurately and immediately detect the lymph node without waiting the radioisotope migration.

Dr I. Poliakov (Krasnodar, Russia): You applied this technique to identify during surgery exactly the lymph nodes, but can you tell me, what is performed during surgery? Do you perform systematic lymph node dissection or do you perform just sampling or systematic sampling or something else?

Dr Melfi: Currently we perform a complete lymph node dissection. With this technique in the first stage we just tested the feasibility in order to use it in the future.

Dr Poliakov: In the future for what?

Dr Melfi: To perform the sampling procedure or less but in any case with a highly accurate staging.

	References

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Appendix A. Conference... References

 

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