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Ann Thorac Surg 2006;82:237-242
© 2006 The Society of Thoracic Surgeons

Original article: General thoracic

Intraoperative, Radio-Guided Sentinel Lymph Node Mapping in 110 Nonsmall Cell Lung Cancer Patients

Witold Rzyman, MD, PhD a , * , Ole M. Hagen, MD f , Rafal Dziadziuszko, MD, PhD b , Grazyna Kobierska-Gulida, MD, PhD c , Andrzej Karmolinski, MD, PhD c , Inger M. Lothe, MD, PhD g , Almira Babovic, MD h , Maciej Murawski, MD a , Waldemar Paleczka, MD a , Tomasz Jastrzebski, MD, PhD d , Andrzej Kopacz, MD, PhD d , Jacek Jassem, MD, PhD b , Piotr Lass, MD, PhD e , Jaroslaw Skokowski, MD, PhD a

a Department of Thoracic Surgery, Medical University of Gdansk, Gdansk, Poland
b Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland
c Department of Pathology, Medical University of Gdansk, Gdansk, Poland
d Department of Surgical Oncology, Medical University of Gdansk, Gdansk, Poland
e Department of Nuclear Medicine, Medical University of Gdansk, Gdansk, Poland
f Department of Thoracic Surgery, Ullevaal University Hospital, Oslo, Norway
g Department of Pathology, Ullevaal University Hospital, Oslo, Norway
h Department of Nuclear Medicine, Ullevaal University Hospital, Oslo, Norway

Accepted for publication January 26, 2006.

* Address correspondence to Dr Rzyman, Department of Thoracic Surgery, Medical University of Gdansk, 7 Debinki St, Gdansk, 80-211 Poland (Email: wrzyman{at}amg.gda.pl).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: Sentinel lymph node identification has been tested in lung cancer patients with conflicting results. The present study was designed to assess the sensitivity, negative predictive value, and accuracy of intraoperative sentinel lymph node mapping by means of a radio-guided method in patients with nonsmall cell lung cancer to find the most appropriate definition of sentinel lymph node and to evaluate the usefulness of different particle sizes of radiocolloid.

METHODS: One hundred ten patients with clinically N0 nonsmall cell lung cancer were enrolled in the pilot study of intraoperative sentinel node identification. Four quadrants of the peritumoral tissue were injected with 2 mL of 0.5 mCi technetium-99m suspension. Four radiocolloids of different particle size were used. After complete lymphadenectomy, all resected lymph nodes were examined with hematoxylin-eosin staining. All sentinel nodes negative for metastases by routine staining were searched further for metastatic deposits with both serial sections and immunohistochemistry for cytokeratins.

RESULTS: The radio-guided method had a high identification rate, a high sensitivity, and a high negative predictive value (100%, 87%, and 93%, respectively) when immunohistochemistry was considered. When standard hematoxylin and eosin staining was applied, sensitivity and negative predictive value of sentinel lymph node labeling was lower (74% and 89%, respectively). No significant differences were found in either the sensitivity or negative predictive value among the colloid solutions of different particle size used in radio labeling, although smaller particles have shown a tendency to produce better results.

CONCLUSIONS: The radio-guided technique provides efficient sentinel lymph node identification in lung cancer. Further studies are warranted to confirm the clinical utility of this strategy.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
Almost fifty percent of patients operated on for early stage nonsmall cell lung cancer (NSCLC) die within 5 years after the pulmonary resection [1]. Although the cause of recurrence is multifactorial, statistics suggest that conventional methods of lymph node assessment fail to detect metastatic tumor deposits in a substantial proportion of patients.

In 1951, Cahan [2] proposed radical lobectomy, consisting of anatomical lobe resection and lymphadenectomy instead of pneumonectomy (a gold standard at that time) for the surgical treatment of NSCLC. Mediastinal lymph node dissection has become an integral part of NSCLC surgery ever since then, enabling accurate disease staging. However, the degree to which the mediastinal lymph nodes should be inspected and the extent of their removal remain controversial. Current surgical practice varies from lymph node sampling to radical lymphadenectomy. Sentinel lymph node (SLN) labeling is one of the most promising developments in this area, potentially allowing for sparing mediastinal node dissection in patients without lymph node involvement. Such strategy may shorten the duration of surgery, decrease complication rate, and avoid potential immunologic effects of extensive lymphatic ablation. The concept of the SLN is based on the assumption that identification of the lymph node that first drains the lymph from the tumor predicts the status of the entire regional lymphatic system. Sentinel lymph node mapping has become a standard surgical procedure in early breast cancer and melanoma and has been investigated in many other solid tumors with promising results. Apart from avoiding extensive surgery, SLN mapping may enhance the prognostic and diagnostic accuracy of histologic examination by its focus on the lymph nodes with the highest likelihood of metastatic involvement. This technique may also allow the application of sophisticated molecular methods to further explore biological behavior of metastases in the future.

In 1999, Naruke and colleagues [3] retrospectively determined SLN for the different lung lobes based on an analysis of 1,815 patients operated on for NSCLC. Since then only a few pilot studies have addressed intraoperative SLN identification in NSCLC patients undergoing pulmonary resection [4–9]. These studies included a relatively small number of patients. The aim of our study was to assess the clinical relevance of SLN mapping by means of radioisotope techniques in a large series of NSCLC patients. The present pilot study was designed to determine the sensitivity, negative predictive value (NPV), and diagnostic accuracy of SLN identification in patients with clinically node-negative NSCLCs. Different criteria for the definition of SLN and different radiocolloids were analyzed to propose the best methods for further clinical development.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 Acknowledgments
 References
 
Patients
One hundred twenty-five NSCLC patients with clinically negative hilar and mediastinal lymph nodes (a diameter of less than 1.5 cm along the longest axis on a computed tomographic scan) were enrolled in a pilot study of radiocolloid lymphatic mapping with SLN biopsy. Neither mediastinoscopy nor positron emission tomographic scan was used to assess mediastinal involvement preoperatively. These patients underwent pulmonary resection between July 2002 and March 2004 at two institutions (ie, the Department of Thoracic Surgery, Medical University of Gdansk, Gdansk, Poland and the Heart-Lung Center, Ullevaal University Hospital in Oslo, Oslo, Norway) (Table 1). In both institutions the study was approved by the institutional review boards dealing with research on human subjects (Gdansk, NKEBN/421/2002 No. 19.092002 and Oslo, RKMF No. 435-03166/2002). Written informed consent was obtained from all patients.


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  		Table 1. Patient Characteristics: 110 Clinically Lymph Node-Negative Patients
 
One hundred ten patients were eligible for the final analysis, after excluding a total of 15 cases due to the benign character of the tumor (11 patients), small cell lung cancer (1 patient), and technical issues (3 patients) (ie, radioactive contamination of operation field after inappropriate injection of radioisotope in 2 patients and technical problems with gamma camera in 1).

Radioisothope Tracers
Four tracers were used for SLN labeling applied as random series: (1) Nanocoll (Nycomed, Denmark), human albumin, particle size < 80 nm; (2) Nanocis (CIS bio Schering SA, France), sulfur colloid, particle size 32 to 178 nm (median, 100 nm); (3) filtered Nanocis particle size < 50 nm, filtered with 100 nm filter (Whatmann, Great Britain); and (4) MTcK-2 (Obri [Polatom, Poland]), tin colloid, particle size 100 to 3,000 nm.

Intraoperative Technique
A total of 2 mL of colloid including 0.5 mCi of the appropriate radioactive tracer were injected in four quadrants of the peritumoral tissue after entering thoracic cavity by posterolateral thoracotomy. Originally we planned to use the two most popular tracers of different particle size (human albumine and sulfur colloid), but after subsequent publications of Liptay and colleagues [4] and Nomori and colleagues [10] we decided to additionally test two other radiocolloids. The standard operative technique described in detail by Liptay and colleagues [11] was used. This delicate approach avoids dissection in the proximity of bronchial structures and the lymph nodes; all lymphatic pathways from the lung tissue run along the bronchial system. Intraoperative SLN identification and postoperative ex vivo measurements of radioactivity were performed immediately prior to bronchus resection at 15 to 100 minutes (median, 50 minutes) and then out of the operation filed, 25 to 220 minutes (median, 70 minutes) after radiocolloid injection. The ex vivo measurements were done to estimate the effect of shine through (ie, the readings of radiation from the injected area around the tumor, despite the collimator placed on the top of the probe). Only intraoperative measurements were considered to identify SLN. The gamma probe counter (Neoprobe [Johnson & Johnson]) was placed over the appropriate lymph node and backwards to the injected area. Whenever possible, the probe was held parallel to the bronchus to prevent calculation of airway activity. After completion of the measurements, intraoperative SLN labeling, and bronchial resection, complete lymphadenectomy was performed on the operated side. Lymph node numbers 1 to 4 and 7 to 12 on the right side and numbers 4 to 12 on the left side were harvested and then precisely marked and described using a current Union Internacional Contre Cancer classification [12].

Defining Sentinel Lymph Node Using a Radio-Guided Method
Intentionally, no arbitrary definition of SLN was taken. After analyzing the whole study material, definitions as those assuming SLN to be the lymph node with an activity exceeding 2, 4, and 5 times the background value were excluded due to the high number of sentinel nodes (mean, 4) in the first, and low identification rate in the two latter instances (56% and 40%, respectively). In order to choose the most adequate definition of SLN in the radio-guided method, identification rate, false-negative rate, NPV, and sensitivity were calculated for three various definitions in which SLN could be assumed to be a lymph node:

Definition 1: with the highest activity
Definition 2: with an activity 3 times the background value
Definition 3: either with an activity 3 times the background value or if that fails, then with the highest activity.

Pathologic Examination
All harvested lymph nodes were fixed in 4% buffered formalin and examined histologically after hematoxylin and eosin (HE) staining of paraffin embedded sections (one section of each lymph node). If no tumor was identified in the sentinel nodes using HE staining, cytokeratin immunohistochemical staining (CK-IHC) was performed. All sentinel nodes smaller than 10 mm were cut longitudinally in two halves. Lymph nodes larger than 10 mm were cut into 2 to 3 mm slices. Paraffin blocks were serially sectioned at 4 µm intervals, and consecutive pairs of slides were stained (ie, one was routinely stained with HE and another with cytokeratin [AE1/AE3 antibody Dako No. M3515]). Two pathologists independently examined all the specimens for the presence of cancer metastases.

Statistical Analysis
Identification rate was defined as a percentage of the patients with detected SLN among the whole analyzed group. Sensitivity, NPV, and accuracy were calculated according to commonly accepted definitions [13] (Table 2).


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  		Table 2. Definitions
 
The previously indicated measurements were calculated with 95% confidence intervals to indicate precision of their estimation. The {chi}2 test or Fisher's exact test were used to compare groups in contingency tables. Two groups of continuous variables were compared with the Mann–Whitney U test. Type one error of 0.05 was used for hypothesis testing with no adjustment for multiple comparisons.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 Acknowledgments
 References
 
One thousand, eight hundred twenty-four lymph nodes from 110 patients were harvested and examined with routine HE staining (median, 15 nodes). Pathology examination revealed lymph node metastases in 66 lymph node groups of 35 patients (32%). In this group, 21 patients (60%) had metastases in one lymph node group, 7 (20%) in two, and 7 (20%) in multiple levels. Two of the 13 patients (15%) with mediastinal involvement had skip mestastases (levels 6 and 7) in a solitary mediastinal lymph node group. The distribution of detected SLNs and lymph node metastases in SLNs is shown in Table 3.


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  		Table 3. Number of Sentinel Lymph Nodes and Metastatic Lymph Nodes in Sentinel Lymph Nodes According to Lymph Node Group (Union Internacional Contre Cancer Classification, 1997)
 
One hundred ninety-eight lymph nodes were labeled as SLNs. Of those, 54 SLNs (27%) were found in the mediastinum. In 36 SLNs, metastases were found and 12 of those (33%) were the only site of metastases.

In 162 SLNs considered tumor free in routine HE staining, immunohistochemical staining with CK-IHC was performed. Micrometastases were found in 16 SLNs from 11 patients (10%), and five patients had micrometastasis in two SLNs. Six of those patients had no lymph node involvement in routine pathologic examination with HE staining. According to this finding, 2 patients were upstaged from stage IA to IIA, 3 from stage IB to IIB, and 1 from stage IIB to IIIA. Retrospectively, in all 16 SLNs with micrometastases found by immunohistochemical staining, serial section had already revealed the presence of metastatic foci. In all cases there was interobserver agreement between two pathologists concerning immunohistochemical staining evaluation.

SLN Definition
To arrive at the definition of SLN in a radio-guided technique, identification rate, sensitivity, NPV, and accuracy were calculated for three definitions of SLN as previously stated. Definition number 3 (lymph node with an activity 3 times the background value or, if that fails, then the one with the highest activity) had the highest accuracy, sensitivity, NPV, and 100% identification rate. Based on these results, definition number 3 was subsequently applied in further analysis (Table 4).


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  		Table 4. Results of Sentinel Lymph Node Mapping With a Radio-Guided Technique Including Immunohistochemical Staining
 
Radiocolloid Particle Size
The results of SLN radio labeling by radiocolloids of different particle size are shown in Table 5. No false negatives were found with the use of filtered sulfur colloid when CK-IHC was applied. There were no differences in sensitivity, NPV, and false negative rate among the four applied tracers as indicated by their overlapping 95% confidence intervals; therefore we included different tracers in one analysis for the whole study group.


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  		Table 5. Results of Radio-Guided Sentinel Lymph Node Mapping With Radiocolloids of Different Particle Size
 
Nine false negatives were found in routine HE staining examination of SLN; however in four of them subsequent CK-IHC examination revealed micrometastases. Therefore, the application of CK-IHC resulted in a change of false negative rate from 26% to 13%, sensitivity from 74% to 87%, and NPV from 89% to 93%.

In 4 of 5 patients (80%) with false negative results, solitary lymph node metastasis was found in the segmental lymph node (No. 13) of which radioactivity was not measured intraoperatively. Intraoperative and postoperative SLN measurements of SLN radioactivity were concordant in 101 patients (92%). Sensitivity, false negative rate and NPV of ex vivo measurements were 94%, 6%, and 98%, respectively.


   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
Acknowledgments
 References
 
In our study, a radio-guided technique of intraoperative SLN identification and conventional HE staining showed sensitivity of 74% and NPV of 89%. Cytokeratin immunohistochemical staining enhanced both sensitivity and NPV of the approach to 87% and 93%, respectively, which was close to the level of 90% and 95%, respectively, the value considered appropriate for standard clinical use in malignant melanoma and breast cancer.

The relatively low experience with SLN technique in lung cancer reflects limited interest of thoracic surgeons in this approach. Preoperative injection of radioisotope, which is currently considered the most reliable sentinel marker, is logistically difficult due to the necessity of computed tomographic-guided injection. Perioperative injection leads to short migration time and a shine-through effect, making results questionable. The regional lymphatic system of the lung is complex and tends to drain in different directions, even to the inaccessible, contralateral mediastinal lymph nodes. Nevertheless, the results achieved in pilot studies of NSCLC provide a promising basis for further investigations.

In the present study the definition of a SLN was determined post-hoc after exploratory data analysis of all data collected. This type of analysis is prone to a type I error and the results of an exploratory analysis should be interpreted with caution.There was no difference between definitions 2 and 3 regarding sensitivity as indicated by overlapping 95% confidence intervals. However, the high identification rate of definition 3 (100%) compared favorably with the lower identification rate of definition 2 (84%). The selection of definition 3 in this study is based on the assumption that there should always be at least one identifiable SLN; however, such attitude is debatable. The definition of SLN varies widely not only in lung cancer studies [4, 6, 10, 14, 18], and it is the most important and questionable issue in intraoperative SLN identification.

The size of radiocolloids used in this study was chosen arbitrarily regarding the conflicting data reported by several authors in smaller series of lung cancer patients. Although we did not find differences in either sensitivity or NPV among the four applied radiocolloids, those with a particle size less than 100 nm showed slightly better results. Sensitivity and NPV were 100% when a filtered radiocolloid was used, but small study subgroup precludes meaningful interpretation of this observation. Our finding corresponds to the observation by Liptay and colleagues [4, 11] who showed a low false negative rate with a filtered sulfur colloid, thus indicating the usefulness of such particle size for intraoperative SLN labeling in NSCLC. Similarly to Hung and colleagues [15], we used a 100 nm filter to obtain a radiocolloid with a particle size of less than 50 nm. According to the study of Nomori and colleagues [10], tin colloid would seem to be inappropriate to intraoperative SLN identification due to its big particle size and slow migration in lung lymphatics. Our study did not confirm this assumption. Currently a small particle sized (ie, 7 nm) molecular tracer accumulating in the lymphatic tissue is being evaluated and preliminary data suggest its usefulness [16].

Sentinel lymph node identification in NSCLC is a demanding method in terms of knowledge of the lymphatic system anatomy and the need for a delicate technique of tissue preparation. Particularly difficult is the preparation of segmental lymph nodes (number 13). In our study four false negatives occurred when the radioactivity was not measured with segmental lymph nodes due to technical problems. There are several factors contributing to this outcome. First, when the lobe or segmental hilus, or both, are fibrotic, the dissection in this area takes a long time to complete. Second, a dissection often induces extravasation of the blood with contamination of the area of measurement by the radiocolloid. Third, the measurements may be difficult to perform when the central tumor is close to the lymph nodes and the placing of a probe backward to the injection site is impossible. Although dissection of the lymph nodes in this area prolongs the operation time, it is indispensable due to frequent occurrence of SLN in this group of lymph nodes. On the other hand, in our experience, the SLN mapping procedure itself added only 5 to 8 minutes to the operation time.

The in vivo and ex vivo radioactivity measurements have shown only slight influence of shine through effect on the sensitivity and NPV of the radio-guided method, being concordant in 92% of the cases. In our series subsequent CK-IHC revealed micrometastases in 10% of SLN considered tumor free in routine HE staining. The detection of micrometastases led to upstaging in 6 patients and reduced the false negative rate by detecting micrometastases in the SLN of 4 patients with negative HE staining. Currently, intraoperative immunohistochemical staining is in the early phase of development and thus not yet applicable in clinical practice. Twenty-seven percent of the labeled SLN were in the mediastinum (Table 3), whereas skip metastases were found in 15% of patients with mediastinal involvement, a figure corresponding with the large series by Naruke and colleagues [3] and Asamura and colleagues [17], as well as with other studies addressing SLN identification [4, 9].

The identification of SLN is applicable only in clinically node negative patients. In our view, currently the goals of SLN mapping in NSCLC include a uniform attitude to lymphadenectomy in those cases, reduction of sampling error, an accurate intraoperative examination of SLN, and a possibility of applying sophisticated molecular methods in one instead of several lymph nodes. A uniform attitude to lymphadenectomy is probably the most practical goal given the fact that many surgeons are still reluctant to perform lymph node dissection in NSCLC. The rationale to perform a routine and complete lymphadenectomy, which is a potentially harmful procedure in node-negative patients, is based on weak clinical evidence. On the other hand, omitting this procedure in patients with microscopic nodal involvement have unknown consequences. In this context, SLN mapping and its intraoperative pathologic examination may contribute to the decision of whether to perform or not to perform a lymphadenectomy. It could also have practical impact on the operation strategy when mediastinal SLN is found to contain tumor deposits placing the patient in stage III. In such situations, most surgeons would choose resection provided lobectomy. However, if pneumonectomy is necessary, its performing may be questionable. The strategy of SLN mapping will become even more accurate with the development of real-time reverse transcriptase–polymerase chain reaction, enabling the intraoperative analysis of genetic mutations or real-time immunohistochemistry leading to detection of micrometastases. Postoperative SLN assessment would allow pathologists to focus more intensely on selected tissue sample to perform molecular studies. Although the significance of micrometastases remain unclear, they are likely to increase the risk of relapse. The identification of lymph node micrometastases leads to upstaging, and thus some patients estimated as node negative by standard HE staining may become candidates to adjunctive therapies.

Our results indicate that the radio-guided technique is a useful method of SLN labeling in NSCLC. However, the studies of SLN identification in lung cancer patients do not allow changing the current clinical practice due to several methodological issues and the lack of evidence from prospective phase III studies. This technique definitely needs time to evolve as in breast cancer and melanoma to accomplish a high level of accuracy and sensitivity before being safely introduced into clinical practice.


   Acknowledgments
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
References
 
This study was supported by the Medical University of Gdansk, Gdansk, Poland (grant no. W 909 and no. St 94), and an individual grant of the Head of Heart Lung Center, Oslo, Norway.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 

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