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SENTINEL LYMPH NODE MAPPING IN LUNG CANCER

Michael J. Liptay

Evans ton Northwestern Healthcare, Evanston, IL, USA

INTRODUCTION

Lung cancer remains the most common cause of cancer-related mortality in both sexes worldwide. Over 180,000 new cases will be diagnosed this year in the United States alone. Only 25-30% of these patients are considered candidates for potential curative resection. If pathologic lymph node involvement is recognized, the chances of a long- term survival are less than 50%. Improved staging techniques are the cornerstone of advancements in new therapeutic strategies allowing for homogeneous study group selection and balanced assessment of true effects.

Lymph node status is the single most important prognostic factor for localized potentially resectable non-small-cell lung cancer. Nodal involvement decreases the 5-year survival by nearly 40% compared to similar patients without nodal metastases. Nonetheless, up to 40% of completely resected "histologically node negative" patients relapse and die of their original cancers often recurring within 2 years. This is at least in part due to inaccurately staged nodal disease. Recent studies suggest that the presence of nodal micrometastatic disease in lung cancer may garner the same poor prognosis as metastases evident by conventional techniques. A powerful application of the sentinel node technique in lung cancer is the identification of specific nodes for further ultrastaging pathologic and molecular examination.

Sentinel node mapping has become the standard of care in both breast cancer and melanoma. The primary utility of these tumors is avoidance of nontherapeutic axillary or groin lymph node dissections and their incumbent morbidities. The morbidity of a complete mediastinal node

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dissection for lung cancer is not excessive and the procedure may be therapeutic.

Another important role is directing pathologic examination to specific sentinel nodes and applying more sensitive techniques on a limited amount of tissue to detect occult micrometastatic disease.

Sentinel node mapping in lung cancer is in the evaluation phase.

Several techniques have been proposed as valid ways to identify the first site of nodal drainage. Radioisotopes injected both intraoperatively and preoperatively have been reported most frequently. This chapter will focus on our technique of intraoperative sentinel node mapping with technetium sulfur colloid.

TECHNIQUE

We have performed intraoperative sentinel node mapping in over 200 patients using the injection of technetium -99m suspensions directly into lung masses at the time of thoracotomy. Our original methods have been described in a previous publication detailing our experience with our first 52 patients.1 Modification to the technique has included most importantly a decrease in the amount of radioactivity injected into the tumors from an original total dose of 2 mCi to our current dose of 0.25 mCi. This has allowed a significant decrease in background radiation from the tumor allowing improved identification of sentinel node stations in vivo.2

The tumor mass itself is injected in a four-outer-quadrant fashion with technetium sulfur colloid filtered once through a 20-micron filter.

The filtering of the particles assures rapid passage of radioisotope through the lymphatics to allow for sentinel node identification without prolonging the planned resection.

The Radiation Safety regulations in Illinois require a licensed physician to dispense the radioisotope. Our protocol has a nuclear medicine physician prepare four tuberculin syringes under sterile technique with the 0.25 mCi dose divided. These are then passed on to the sterile operating field. The surgeon injects the radioisotope in a four- quadrant fashion directly into the tumor. The syringes are collected by the nuclear medicine personnel and the area surveyed with a Geiger counter to detect spillage and contamination. No other precautions are necessary such as special decontamination after the case or additional protection of OR personnel.

A standard dissection is then performed to complete an anatomic resection of the tumor. Readings are taken with the hand-held gamma probe counter (Navigator® system, United States Surgical Corporation) after calibration. The minimum necessary migration time from injection of the tumor with the technetium-99m sulfur colloid solution to the detection of radioactivity in the lymph nodes has been found to be 10 minutes.

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During the time of migration, care is taken to avoid dissection of the bronchial structures and peribronchial tissues where the majority of lymphatics are located. The bronchial dissection and division are performed last in the majority of cases if the operation permits.

Successful studies utilizing preoperative injection of various radioisotopes within 24 hours of the planned surgery have been reported.

Our technique is based on the intraoperative injection of the radioisotope with attention paid to: preparation, injection of the radioisotope into the tumor, anatomic dissection, in vivo and ex vivo readings, and re- surveillance for residual radioactivity.

PREPARATION

After the preoperative evaluation and informed consent, patients are taken to the operating room and the standard preparations made for mediastinoscopy (if indicated), thoracotomy, and resection. After thoracotomy, patients are injected with technetium-99 sulfur colloid (0.25 mCi) divided into four equal doses. The radioisotope is prepared according to the manufacturer's instructions and drawn through a 200-nm sterile filter once. For the injection preparation, the radioisotope is drawn into four tuberculin syringes (1 ml) and injected using 27 gauge needles.

Preparation of the radioisotope is performed under the direction of a nuclear medicine physician. After injection of the technetium the syringes are given back to nuclear medicine, the area is surveyed for residual radioactivity, and the materials are taken back for disposal.

INJECTION

Moist lap pads are positioned around the tumor in the chest to avoid spillage of radioisotope during injection into the tumor. The isotope is injected into the periphery of the lung tumor in a four-quadrant pattern.

The injections are made into the tumor and not in the lung parenchyma surrounding the tumor to avoid the confounding incidence of aerosolization of the radioactivity into the parenchyma and airways. After injection the chest is irrigated with sterile water solution to wash out any stray radioisotope (Figure 1).

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Figure 1. Radio-isotope injection. 0.25mCi of filtered Tc-99m was injected in four quadrants directly into tumor 10 minutes before fissural or peribronchial dissection.

ANATOMIC DISSECTION

Our preliminary work has found the minimum time required for successful migration of radioisotope is 10 minutes. During the time allowed for migration of the radioactivity, usual preparative dissection for resection is performed with a few considerations.

The fissure structures and peribronchial tissues known to be rich in lymphatics are to be left undisturbed until a minimum of 10 minutes after injection time. Dissection is generally commenced at the anteromedial hilum overlying the pulmonary vein and truncus branches of the pulmonary artery. The inferior pulmonary ligament and posterior mediastinal pleura are left intact until 10 minutes has elapsed.

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SENTINEL NODE MAPPING

In Vivo Readings

The tumor specimen and nodal stations are initially surveyed in the thorax with the hand-held gamma probe (Navigator®), and background levels are recorded within the chest, distant from the primary tumor. The initial intrathoracic readings may be unreliable if there is high residual radioactivity in the primary tumor in close proximity to nodes within the chest (shine-through effect). To minimize this, the probe is angled away from the tumor if possible as it is generally exponentially more radioactive than the nodes (Figure 2).

Figure 2. Intrathoracic SN reading for measurement of radioactivity background in chest. Hand-held gamma counter measures nodal stations.

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&

^ Figure 3. Ex vivo reading of dissected nodes. Nodes are separated from tumor on field. Highest CPS & 3x background = SN. The hemithorax is resurveyed postresection for residual CPS/nodes.

Ex Vivo Readings

Visible mediastinal, peribronchial, and hilar lymph nodes are dissected from the primary tumor and are also measured separately from the tumor specimen after removal from the chest (ex vivo). The time from injection of the tumor with the technetium-99m to the first ex vivo measurement of radioactivity is recorded.

The migration of the technetium sulfur colloid solution is considered successful if a specific nodal station registered counts per second (CPS) greater than 3 times background values. The most accurate reading of

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nodal radioactivity appears to be the ex vivo readings taken after separating the nodes from the tumor/lobar specimen. All lymph nodes with the requisite radioactivity 3-fold greater than intrathoracic background are classified as sentinel nodes. Our average number of sentinel nodes has been 1.5 (range \-A) (Figure 3).

RESURVEY FOR RESIDUAL RADIOACTIVITY

After the initial scintigraphic readings and standard anatomic resection with ipsilateral mediastinal node dissection is completed, a repeat examination with the gamma probe is performed to assess for residual radioactivity and potentially overlooked lymph nodes. The remaining radioactivity levels are recorded and re-resections of nodal stations performed if indicated by the handheld gamma counter readings and visual inspection.

GAMMA PROBE

The Navigator GPS® gamma probe is used and set up according to the manufacturer's recommendations. The isotope selector switch is set to Tc99m. The Navigator Top Gun® external collimator is used to facilitate identification of hot nodes in close proximity to the injection site. The Count button initiates the required 10-second timed counts on the nodes and background. A sterile plastic sheath is used to cover the probe.

SPECIAL CONSIDERATIONS

Our experience to date suggests that sentinel node mapping in potentially resectable lung tumors may have its most important role in the staging and treatment of clinically early stage I tumors. 3'4 Large tumors with central necrosis or those patients with clinically positive lymph nodes had less accurately detected sentinel nodes and whatever information is gained in these advanced tumors, the detection of micrometastases appears less important to their treatment plans.

We have been successful less than 60% of the time in predicting a sentinel node station based solely on the intrathoracic in vivo readings in the thorax. This is due to the shine-through effect from the radioactivity of the tumor and in addition the aerosolization of technetium into the airways causing inaccurate readings.

This has led some to question the utility of this technique where limitation of node dissection is not possible with the methods described.3'5

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While we await advances in the field to aid in limiting thoracic lymphadenectomy, the ability to select a few sentinel nodes for further study in search of micrometastatic disease from an average of 20-30 nodes allows pathologists to focus their efforts on the most promising tissues.

A multicentered trial is opening in the Cancer and Leukemia Group B to test the applicability of this promising technique in patients with potentially resectable clinical stage I lung cancers.

REFERENCES

1. Liptay MJ, Masters G, Winchester DJ, et al. Intraoperative radioisotope sentinel lymph node mapping in non-small cell lung cancer (NSCLC). Ann Thorac Surg (2000 Aug) 70:384-390.

2. 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 (April 15, 2002) 20:1984-1988.

3. Ueda K, Suga K, Kaneda Y, et al. Radioisotope lymph node mapping in non small cell lung cancer: can it be applicable for sentinel node biopsy? Ann Thorac Surg (2004 Feb) 77(2): 426-430.

4. Sugi K, Kaneda Y, Sudoh M, et al. Effect of radioisotope sentinel node mapping in patients with eTINOMO lung cancer. J Thorac Cardiovasc Surg (2003 Aug) 126(2): 568-573.

5. Liptay MJ. Sentinel node mapping in lung cancer. Ann Surg Oncol: (2004 Mar) ll(3suppl):271S-274S.

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