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Ann Thorac Surg 2006;82:1815-1820
© 2006 The Society of Thoracic Surgeons

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Original Articles: General Thoracic

Radioguided Detection of Lymph Node Metastasis in Non-Small Cell Lung Cancer

^a Department of Thoracic Surgery, Roswell Park Cancer Institute, State University of New York at Buffalo, Buffalo, New York
^b Department of Pathology, Roswell Park Cancer Institute, State University of New York at Buffalo, Buffalo, New York
^c Department of Nuclear Medicine, Roswell Park Cancer Institute, State University of New York at Buffalo, Buffalo, New York

Accepted for publication May 31, 2006.

^_* Address correspondence to Dr Nwogu, Department of Thoracic Surgery, Roswell Park Cancer Institute, Elm and Carlton Sts, Buffalo, NY 14263 (Email: chumy.nwogu{at}roswellpark.org).

Presented at the Fifty-second Annual Meeting of the Southern Thoracic Surgical Association, Orlando, FL, Nov 10–12, 2005.

	Abstract

Top Abstract Introduction Patients and Methods Results Comment Discussion References

 
BACKGROUND: The detection of micrometastases in thoracic lymph nodes may improve the staging of non-small cell lung cancer patients.

METHODS: Ten patients with resectable lung cancers were enrolled in this pilot study. Every patient had preoperative positron emission tomography (PET) imaging and mediastinoscopy. Patients were injected with 10 mCi of F18-fluorodeoxyglucose (FDG) on the day of surgery, within 4 hours of the planned surgical procedure. A handheld device detected increased FDG uptake (gamma emission) within thoracic lymph nodes during pulmonary resection procedures. The lymph nodes that demonstrated increased FDG uptake, but were nonmalignant by conventional hematoxylin and eosin staining, underwent further serial sectioning and immunohistochemical staining.

RESULTS: The handheld probe detected all FDG-avid lesions on PET imaging. In 3 patients (30%), the probe led to the detection of FDG-avid lymph nodes harboring micrometastases missed by conventional pathologic analysis. A fourth patient had aortopulmonary nodes that were FDG-avid on PET and showed metastases by hematoxylin and eosin staining, but the probe detected adjacent nodes in the same station with micrometastases. Three nodes were false-positive by gamma probe.

CONCLUSIONS: It is feasible to detect occult metastases in lymph nodes by using an FDG-sensitive intraoperative gamma probe, resulting in upstaging of patients. A larger study is indicated to evaluate the sensitivity, specificity, and clinical utility of such a device.

	Introduction

Top Abstract Introduction Patients and Methods Results Comment Discussion References

 
Lung cancer is the most frequent cause of cancer death in both men and women in the United States [1]. Lymph node staging provides the most important prognostic information in patients with locoregional non-small cell lung cancer (NSCLC). This information is critical in the stratification of patients into appropriate therapeutic categories, including their enrollment into clinical trials. Standard methods of evaluating thoracic lymph nodes such as by hematoxylin and eosin staining (H&E) can miss micrometastases [2–5]. Detailed pathologic techniques such as serial sectioning and immunohistochemistry are more sensitive in detecting these micrometastases [6, 7]; however, a pathologist can practically apply these techniques to only a limited number of lymph nodes in each patient.

We decided to investigate the use of a radioguided intraoperative technique to select the specific lymph nodes that should be studied intensely. It is known that intravenously injected 18F-fluorodeoxyglucose (FDG) accumulates in thoracic lymph nodes when they harbor metastatic carcinoma cells, and this underlies the utility of positron emission tomography (PET) imaging in clinical staging of lung cancer patients [8]. We hypothesized that local detection of gamma radiation using an intraoperative handheld gamma probe after intravenous FDG injection would identify lymph nodes containing metastases in a much more sensitive manner. Detailed pathologic analysis (multiple step sections and immunohistochemistry) of these lymph nodes would then result in more accurate staging than that provided by conventional (H&E) staining.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Comment Discussion References

 
Our Institutional Review Board approved this pilot study in January 2004, and individual patient consent was obtained.

Patient Selection
We enrolled 10 patients with resectable NSCLC into this study. We selected patients likely to have micrometastatic disease in some of their thoracic lymph nodes. This was based upon the identification of lung masses larger than 3 cm in size or the presence of enlarged thoracic lymph nodes on computed tomography (CT) scans. These features prompted a mediastinoscopy in all patients. All patients had identical preoperative staging by CT and PET imaging.

Operative Procedure
On the day of surgery (within 4 hours of the planned surgical procedure), each patient was injected intravenously with 10 mCi of FDG by our nuclear medicine technicians (standard PET protocol). Measurement of the FDG uptake in the primary tumor and in each of the thoracic nodal basins was performed during video-assisted or open thoracic procedures by using the Gammed VI handheld surgical gamma probe (Capintec, Ramsey NJ). Standard lung resection, as appropriate for the individual patient's tumor, was followed by complete thoracic lymphadenectomy. The lymph nodes were labeled using the American Thoracic Society/Naruke lymph node map [9].

All harvested lymph nodes were scanned with the gamma probe outside the thoracic cavity to measure the gamma radiation resulting from any accumulated FDG in individual nodes. The resected tumor was similarly scanned outside the thorax.

The ex vivo radioactivity of healthy lung tissue was used as the reference point for assessment of increased radioactivity in the primary tumor. A primary tumor that had more than three times the radioactivity of healthy lung tissue was classified as FDG-avid (hot). We compared the radioactive signals from the lymph nodes. The FDG-avid (hot) nodes had more than twice the signal intensity of the coldest lymph node in the entire thoracic field for that particular patient. These gamma probe–positive lymph nodes were labeled for the pathologist and subjected to ultrastaging.

Lymph Node Ultrastaging
All surgically removed lymph nodes were bisected and examined by routine H&E. The gamma probe–detected FDG-avid lymph nodes that were malignant on H&E staining required no further pathologic analysis. However, the FDG-avid lymph nodes that were not malignant on H&E staining were subjected to ultrastaging with multiple step sections and immunohistochemistry.

These nodes were processed according to a standard protocol. After formalin fixation and embedding in paraffin, step sections of each lymph node were taken at 30-µm to 40-µm intervals. The sections were stained with H&E, and an average of 10 serial sections were evaluated. Immunohistochemistry was performed with a standard cytokeratin cocktail (AE1/AE3) and was considered positive if it demonstrated positive cell clusters or individual cells with the appropriate tumor cell morphology.

	Results

Top Abstract Introduction Patients and Methods Results Comment Discussion References

 
We screened 12 patients (7 men) for the protocol. Two were ineligible owing to the diagnosis of a pulmonary granuloma in 1 patient and bulky mediastinal nodal disease in the other. The characteristics of the 10 eligible patients are summarized in Table 1. All of the patients had FDG-avid primary lung tumors on the preoperative PET scan, but 3 of 10 patients were staged as lymph node–negative by this preoperative scan (Table 2).

The handheld probe detected all of the lesions identified on the preoperative PET scan, although one patient's specimen was inserted in formalin before gamma probe readings could be done. This occurred early in our experience.

The in-vivo probe readings were universally high owing to intense cardiac radioactivity despite shielding of the probe with a collimator; however, the ex-vivo readings reflected the true FDG accumulation in the lymph nodes. We recorded the radioactive counts of the harvested lymph nodes in each patient (Table 3) and selected the most FDG-avid nodes for ultrastaging.

	Comment

Top Abstract Introduction Patients and Methods Results Comment Discussion References

 
It is estimated that there will be 174,470 new cases and 162,460 deaths from lung cancer in the United States in 2006 [1]. This accounts for more deaths than the estimates for prostate, breast, and colon cancer combined. Thus, the human and economic impact of lung cancer is enormous.

The staging of lung cancer plays a critical role in efforts to combat this disease, but progress in the ability to accurately identify all lymph node disease in patients has been limited. This is reflected in the modest 5-year survival (67%) reported in stage IA, the earliest stage of NSCLC [9]. Nearly 40% of node-negative patients will develop recurrent disease and die within 2 years [10]. This is believed to be due to understaging of lung cancer patients by under-recognition of micrometastases by standard H&E staining of lymph nodes. Better staging methods are thus necessary to better stratify patients, make therapeutic choices, and evaluate effectiveness of various treatment modalities.

PET has emerged as an extremely valuable tool in staging thoracic malignancies [8, 11, 12]. This technology is now available intraoperatively in the form of a handheld gamma probe for use after intravenous radioisotope injection to detect metastases in lymph nodes [13]. The use of such radioguided techniques to identify lymph nodes likely to harbor micrometastases has the potential to markedly improve the accuracy of lymph node staging [7].

The sentinel lymph node mapping technique evaluates the first echelon of lymph nodes that would drain a primary lung cancer [3, 7, 14]. These selected lymph nodes may be studied with detailed pathologic techniques, such as serial sectioning and immunohistochemistry (ultrastaging) [15]. However, accurate staging of NSCLC requires evaluation of all the sites of potential thoracic lymph node metastasis. This requires assessment of more than the first echelon of draining lymph nodes. Detection of lymph node involvement beyond the first echelon can increase the patient's tumor stage from II to III. This has major prognostic implications [10].

A clinical technique to screen all the thoracic lymph nodes for micrometastases is not currently available. Improvement in the staging of lung cancer will facilitate the selection of patients for novel therapeutic approaches in either the neoadjuvant or adjuvant setting. For instance, the ultrastaging of lymph nodes harvested during mediastinoscopy could identify micrometastases in mediastinal lymph nodes before definitive surgical resections. These patients could then undergo neoadjuvant chemotherapy, followed by complete resection, with expected improvement in survival [16, 17]. Such an evaluation would have to be done after the nodes are biopsied (ex vivo), because the currently available probes are too large to pass down the mediastinoscope. Any gamma probe–positive nodes could be sent for multiple frozen sections, but standard immunohistochemistry would not be immediately available. This form of mediastinal nodal evaluation would probably be most appropriate if it was done on a different day from the primary tumor resection, thus allowing the results to influence the use of neoadjuvant therapy. However, the use of this FDG lymph node mapping technique for a subsequent primary tumor resection would multiply costs. Thus, in our pilot study, we elected to perform the mediastinoscopy immediately before the primary resection in most cases.

We used conventional frozen section techniques to assess the mediastinal nodes intraoperatively, but subjected all the lymph nodes (including those harvested by mediastinoscopy) to the gamma probe assessment. Rapid immunohistochemical staining, reverse transcriptase-polymerase chain reaction assays, and flow cytometry to guide intraoperative decision-making have been reported [18–20]. We plan to assess the FDG-avid lymph nodes harvested during mediastinoscopy using rapid immunohistochemical staining in our follow-up study, thus facilitating the selection of patients for neoadjuvant therapy.

The choice of a threshold for the designation of a lymph node as FDG-avid or gamma probe–positive is somewhat arbitrary. We chose a definition of an FDG-avid (hot) node as one with more than twice the signal intensity of the coldest lymph node in the entire thoracic field for that particular patient. This was based on previously published studies [3, 7, 14]. In the pulmonary sentinel lymph node mapping study of Faries and colleagues [3], they chose "the lymph nodes with the highest radioactivity" as their sentinel nodes. In a similar study, Liptay and colleagues [7] defined their sentinel nodes as those with radioactivity three times the background levels. Essner and colleagues [13], in a study using an FDG gamma probe to detect intraabdominal tumor deposits, used a radioactivity ratio of 1.5:1 to distinguish malignant from healthy tissue. Thus, there is currently no standard radioactivity threshold to define "hot" nodes. We intend to investigate the scientifically appropriate threshold in our follow-up study.

Our use of the gamma probe to detect FDG uptake in thoracic lymph nodes had some limitations. It was difficult to differentiate FDG activity signals in the primary tumor from those in peritumoral lymph nodes. This led to false-negative N1 nodes in 2 patients (Table 3). False-negative nodes can lead to understaging of a patient's tumor and may prevent the patient from receiving adjuvant therapy. This may occur in a patient classified as N0 by standard pathologic techniques who may harbor micrometastases in lymph nodes adjacent to the primary tumor. We can rectify this problem in future patients by dissecting all lymph nodes away from the tumor on a back table after lung resection. We would then measure FDG uptake in these nodes before their delivery to the pathologist.

Immunohistochemical analysis of FDG-avid nodes may detect micrometastases and upstage some patients from stage IA to stage IIA. Such patients would then potentially benefit from adjuvant therapy. Our follow-up study will perform ultrastaging on an equal number of probe-positive and probe-negative nodes. This will provide a better estimate of the incidence of false-negative nodes when this technique is used.

The occurrence of gamma probe–detected FDG activity in lymph nodes that are cancer-free, even by immunohistochemistry, is undesirable. This probably results from inflammation within the lymph node, a well-known source of false-positive results on FDG-PET scans [8]. The occurrence of false-positive nodes increases the cost of the procedure because these nodes are then subjected to ultrastaging (multiple sections and immunohistochemistry). This may be unavoidable with the current technology.

Despite the occurrence of false-positive nodes in 3 of 8 patients (Table 3), the handheld probe permitted the selective application of expensive and labor-intensive pathologic techniques (ultrastaging) to a limited number of lymph nodes. Of 55 lymph nodes harvested during thoracic lymphadenectomy in 10 patients, only nine nodes (16 %) required ultrastaging. Thus, the pathologists were able to focus their attention on the lymph nodes with the highest potential to harbor micrometastases. The development of lymph node mapping agents that are not concentrated in inflamed lymph nodes may minimize the occurrence of false-positive results.

Pathologic ultrastaging after resection can stratify patients in the current TNM (tumor- node-metastasis) stage groups into high-risk and low-risk categories for development of recurrent disease. Most patients with the earliest stage of NSCLC (stage IA) are currently not offered adjuvant chemotherapy [21–23]. However, radioguided lymph node mapping and ultrastaging may identify patients at higher risk for recurrence. These patients may then be offered adjuvant chemotherapy or other molecularly targeted therapy as part of a well-designed, randomized, controlled prospective trial.

Conversely, NSCLC patients who have low risk of recurrence can be spared the morbidity and expense of adjuvant chemotherapy. For instance, T2N0M0 (stage IB) patients are currently being offered adjuvant chemotherapy routinely, based on recent prospective studies [21–23]. However, the patients in this group who harbor micrometastases may be the particular ones that derive benefit from adjuvant therapy. If so, the patients in this stage without micrometastases may be able to avoid chemotherapy. This hypothesis will need to be investigated prospectively in a randomized trial.

In conclusion, this pilot study showed that it is feasible to detect occult metastases in lymph nodes by using an FDG-sensitive intraoperative gamma probe, resulting in upstaging of patients (Table 4). Evaluation of the sensitivity and specificity of such a device will require a larger study. Such a study may also assess the proportion of patients with micrometastases detected during mediastinoscopy and define the appropriate radioactivity threshold for gamma probe positive lymph nodes.

	Discussion

Top Abstract Introduction Patients and Methods Results Comment Discussion References

 
DR MARK I. BLOCK (Hollywood, FL): Chumy, very nice work. I am sure it is an immense amount of work to get this done in the operating room. I am going to play the devil's advocate and ask you: what is the point? The reason I ask is that with all of the data coming out now about adjuvant chemotherapy, we resect a patient with stage 1B lung cancer and they get adjuvant chemotherapy, we resect somebody who turns out to have 3A disease with N2 disease and they get adjuvant chemotherapy. We are starting to see homogenization of the postoperative management of these patients almost regardless of their stage rather than the opposite, which is what we were expecting. So, yes, I agree with you this is a potentially powerful method to improve the staging of these cancers, but then when I step back and look at the clinical implications of it, I wonder whether it's going to make any difference at all. I am interested to hear your thoughts.

DR NWOGU: Thank you very much. That is an excellent question, Dr Block. The clinical utility of ultrastaging of our patients is that it could guide therapeutic decisions. For instance, we might be able to stratify stage 1B patients, who currently are being offered adjuvant chemotherapy, into high and low "risk of recurrence" groups. There are some patients who might be getting chemotherapy unnecessarily. There are morbidity and costs associated with adjuvant chemotherapy. If we can stratify the patients into those that have micro metastases and those that don't, it would be interesting to study whether those that don't have micro metastases might be spared the adjuvant chemotherapy.

Conversely, there are stage 1A patients who are currently not getting adjuvant chemotherapy that might benefit from it. Thus, better staging of our patients might allow us to appropriately select candidates for adjuvant therapy.

DR THOMAS M. EGAN (Chapel Hill, NC): That was a nice presentation. I have a question that is in a similar vein. If you discovered N2 disease, did it change your therapy or did you go ahead and operate on them anyway? And if you were going to operate on them anyway, why did you do a "mead" in the first place?

DR NWOGU: There was one patient that had extra nodal disease on mediastinoscopy that was not part of this cohort; the patient was not eligible for this study. In one of our patients, we detected positive mediastinal nodes preoperatively by mediastinoscopy. The patient had neoadjuvant chemoradiotherapy and subsequently had surgical resection. That patient was downstaged. So there is the potential to detect micrometastases on mediastinoscopy and then offer those patients neoadjuvant chemotherapy or chemoradiotherapy.

DR SETH D. FORCE (Atlanta, GA): That was an excellent presentation. My question is a little bit more as to the methods. We know that from a lot of the sentinel lymph node studies that are attempted in lung cancer there are various tracers that have been evaluated. Can you tell us why you picked FDG, what the half-life of that is, and how that might have affected the outcomes in your study?

DR NWOGU: Thank you. I think that is an excellent question. We chose FDG because we were interested in evaluating disease beyond the first echelon of lymph nodes. The sentinel node studies have all focused on evaluating the first echelon of draining lymph nodes from a primary tumor. But we felt it was important to assess all the thoracic lymph nodes for potential micro metastases. FDG was the most viable agent, in our minds, to do that. That was the reason we chose it.

The half-life is relatively prolonged [110 minutes]. In discussions with our nuclear medicine physicians, they felt confident that we had hours to be able to distinguish the activity in the affected lymph nodes compared to the normal lymph nodes. Actually, there is radioactive decay of FDG to background levels in about 14 hours.

	References

Top Abstract Introduction Patients and Methods Results Comment Discussion References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Chumy Nwogu Todd Demmy Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nwogu, C. Articles by Demmy, T. Search for Related Content PubMed PubMed Citation Articles by Nwogu, C. Articles by Demmy, T. Related Collections Lung - cancer