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Originally published as Ann Surg Oncol Early Release 10.1245/ASO.2004.03.054 on November 15, 2004

Annals of Surgical Oncology 11:1085-1092 (2004)
© 2004 Society of Surgical Oncology
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ORIGINAL ARTICLES

In Vivo Optical Imaging of Pleural Space Drainage to Lymph Nodes of Prognostic Significance

Cherie P. Parungo, MD, Shunsuke Ohnishi, MD, PhD, Alec M. De Grand, BS, Rita G. Laurence, BS, Edward G. Soltesz, MD, Yolonda L. Colson, MD, PhD, Peter M. Kang, MD, Tomislav Mihaljevic, MD, Lawrence H. Cohn, MD and John V. Frangioni, MD, PhD

From the Department of Surgery (CPP, RL, EGS, YLC, TM, LHC), Brigham & Women’s Hospital; and Division of Hematology/Oncology and Department of Radiology (SO, AMD, JVF) and Department of Cardiology (PK), Beth Israel Deaconess Medical Center, Boston, Massachusetts.

Correspondence: Address correspondence and reprint requests to: John V. Frangioni, M.D., Ph.D., Division of Hematology/Oncology and Department of Radiology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Room SL-B05, Boston, MA 02215; Fax: 617-667-0981; e-mail: jfrangio{at}bidmc.harvard.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Understanding the spatial and temporal drainage patterns of the pleural space could have profound impact on the treatment of lung cancer and mesothelioma. The purpose of this study was to identify the in vivo pattern of drainage from the pleural space to prognostic lymph node stations.

Methods: Fifty-six rats underwent pleural space injection of a novel lymph tracer composed of recombinant human serum albumin (HSA) covalently conjugated to the near-infrared (NIR) fluorophore IRDye78 via an amide bond (HSA-78). Nodal uptake was imaged at 10, 20, 30, and 60 minutes and 4, 12, and 24 hours after injection with a custom system that simultaneously acquires color video, NIR fluorescence of HSA-78, and a merged picture of the two. Six pigs underwent the same procedure with imaging at 30 minutes, 1 hour, and 24 hours.

Results: In both the rat model and the pig model, HSA-78 drained from the pleural space to superior mediastinal lymph nodes first, followed by other intrathoracic and then extrathoracic lymph nodes over the course of 24 hours.

Conclusion: NIR fluorescence imaging in two species shows that the superior mediastinal lymph nodes are the first to drain the pleural space. Over the course of 24 hours, the pleural space also communicates with other intrathoracic and then extrathoracic lymph nodes. This study also demonstrates an intraoperative method for identifying nodes communicating with the pleural space, with potential utility in the staging and/or resection of lung cancer and mesothelioma.

Key Words: Lymph node • Lymphatic drainage • Mesothelioma • Near-infrared fluorescence • Pleural space • Visceral pleural invasion


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Knowledge of pleural space lymphatic drainage is critical to accurate staging and treatment in the setting of malignant pleural mesothelioma and lung cancer with visceral pleural invasion (VPI). In mesothelioma, nodal involvement is a significant negative prognostic factor.1,2 In lung cancer, VPI is correlated with lymph node involvement and distant metastasis.3,4,5 In both mesothelioma and VPI, staging is dependent on assessment of lymph nodes draining the pleural space, and in both diseases locoregional control has positive prognostic value. Thus, a systematic method of sampling and resecting involved lymph nodes based on anatomic patterns of pleural drainage is necessary.

The current understanding of pleural lymph node drainage is based on dissection in animals and cadavers. Different studies have suggested an anatomic connection of the pleural space with intercostal, superior mediastinal, or tracheobronchial nodes.6,7 In a study by Pereira et al., tungsten powder was used as a lymph tracer of the pleural space. The dogs were killed and only thoracic lymph node groups were imaged at 1 to 7 days.8 These previous studies did not demonstrate the functional pattern of pleural lymph drainage throughout the body.

The purpose of our study was to identify the in vivo, in situ, and temporal pattern of drainage from the pleural space to prognostic lymph node stations throughout the body. Using two different animal species, we identified the temporal order of flow from the pleural space to superior mediastinal lymph nodes first and then to intrathoracic and lastly to extrathoracic nodes. Our studies lay the foundation for the use of NIR fluorescence technology for intraoperative imaging of pleural space drainage.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Intraoperative NIR Fluorescence Imaging System
The imaging system has been described in detail previously.9 Briefly, it is composed of two wavelength-isolated excitation sources, one generating 0.5 mW/cm2 of 400 to 700 nm "white light," and the other simultaneously generating 5 mW/cm2 of 725 to 775 nm light over a 15-cm diameter field of view. Photon collection is achieved with custom-designed optics that maintain separation of the white light and near-infrared fluorescence (>795 nm) channels. After computer-controlled camera acquisition, anatomic (white light) and functional (near-infrared fluorescent light) images can be displayed separately and merged. All images are refreshed 15 times per second. The entire apparatus is suspended on an articulated arm over the surgical field, thus permitting noninvasive and nonintrusive imaging. Real-time video images assisted in the location and dissection of HSA-78-positive tissue. Depending on the application, fluorescence can be detected through up to 1 cm of tissue.10

NIR Fluorescent Lymph Tracer
The chemical and optical properties of HSA-78 will be described in detail elsewhere (Ohnishi et al., manuscript in preparation). In brief, human serum albumin (HSA) was covalently conjugated to the tetra-sulfonated, heptamethine indocyanine IRDye78 (LI-COR, Lincoln, NE) via an amide bond (HSA-78). The ratio of IRDye78 to albumin was 3.4 to 1, and its net charge at pH 7.4 was –27, facilitating lymph node retention. Peak absorbance and emission of HSA-78 were 778 nm and 795 nm, respectively, in phosphate buffered saline (PBS) at a pH of 7.4. The hydrodynamic diameter of HSA-78 is approximately 7 nm. A stock solution of 0.8 mg/ml of HSA-78 in PBS was used for all studies.

Small-Animal Studies
Animal protocols were in accordance with Institutional Animal Care and Use Committee Guidelines, including the Guide for the Care and Use of Laboratory Animals published by the National Institute of Health (NIH publication 5–23, revised 1985). Adult male Sprague-Dawley rats of 200 g were anesthetized with xylazine (10 mg/kg) and ketamine (100 mg/kg) intraperitoneally. Rats were shaved, prepped, and draped in the usual sterile fashion. A 2-cm midline laparotomy was made from the xyphoid to the mid abdomen for visualization of the diaphragm. Accurate administration of HSA-78 (0.5 mg/kg body weight) into the pleural space through a percutaneous, transthoracic injection with a 25-gauge needle could be monitored in real time by imaging the diaphragm through the laparotomy incision. Injection of HSA-78 was monitored in real time with the NIR fluorescence imaging system to confirm injection into the pleural space and not into lung. Though HSA-78 tracking to lymph nodes is visible in real time, observation of HSA-78 migration from the pleural space to lymph nodes would require a thoracotomy, which in turn would alter the lymph flow. So, after HSA-78 injection into the right pleural space, cohorts of six rats each were imaged at 10 minutes, 20 minutes, 30 minutes, 1 hour, 4 hours, 12 hours, or 24 hours. Animals underwent redosing of anesthesia as necessary. At the time of imaging, animals underwent intubation with a 16-gauge catheter and were ventilated appropriately. Thorough exposure and in vivo investigation of all lymph node groups of the thorax, chest wall, neck, axilla, and intra-abdominal compartment were performed. This protocol was repeated, except HSA-78 was injected into the left pleural space with monitoring of the administration through the left diaphragm. Two rats each were imaged at 10 minutes, 20 minutes, 30 minutes, 1 hour, 4 hours, 12 hours, or 24 hours after injection into the left pleural space.

Large-Animal Studies
Large-animal protocols were in accordance with Institutional Animal Care and Use Committee Guidelines, including the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH publication 5–23, revised 1985). Three male Yorkshire pigs of 35 kg were anesthetized with intramuscular Telazol (Fort Dodge Laboratories) and xylazine (4.4 mg/kg and 2.2 mg/kg, respectively) for induction of anesthesia. Once sedated, the animals received oxygen and isoflurane (0.5%–5%) to effect. Once the animals were under full anesthesia, the trachea was intubated with a 7-mm cuffed endotracheal tube. The animals were prepped and draped in the usual sterile fashion. Pigs underwent a right subcostal incision to visualize the diaphragm. Accurate administration of HSA-78 (0.5 mg/kg body weight) into the right pleural space through a percutaneous, transthoracic injection with an 18-gauge needle could be monitored in real time by imaging the diaphragm through the laparotomy incision. Animals were recovered and then imaged at 30 minutes, 1 hour, or 24 hours. At the time of imaging, animals underwent anesthesia and intubation as described above. Thorough exposure and in vivo investigation of all lymph node groups of the thorax, chest wall, neck, axilla, and intra-abdominal compartment was performed. This protocol was repeated in three pigs, except HSA-78 was injected into the left pleural space with monitoring of the administration through the diaphragm through a left subcostal incision and imaging at 30 minutes, 1 hour, and 24 hours.

Histology
Histology was performed on fluorescing tissue of the rat and pig to confirm presence of lymph nodes and to confirm the presence of HSA-78 within each specimen. Nonfluorescing tissues were also sent for histology for comparison. Lymph nodes were placed in histology cassettes, embedded with Tissue-Tek O.C.T. compound, and frozen in liquid nitrogen. The nodes were sectioned, and alternate cuts were examined by hematoxylin and eosin (H&E) staining and NIR fluorescence imaging. The NIR fluorescence was visualized by means of a modified microscope with custom-designed optics, as described previously.11


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Rats underwent injection of HSA-78 into the pleural space through a transthoracic injection. Real-time imaging ensured accurate injection of HSA-78 into the right pleural space (Fig. 1A).



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  		FIG. 1. In vivo imaging of pleural space drainage to lymph nodes of the rat. (A) HSA-78 injected into the right pleural space of a rat as visualized with color video (left), NIR fluorescence (middle), and color-NIR merge imaging (right). (B) NIR fluorescence imaging of HSA-78 uptake by ipsilateral superior mediastinal and chest wall lymph nodes (arrows) and contralateral superior mediastinal lymph nodes (arrowheads), both 30 minutes after injection.

 
Lymph Nodes Involved in Pleural Space Drainage of the Rat
HSA-78 injected into the pleural space drained to the superior mediastinal (Fig. 1B), intercostal (Fig. 1B), paraesophageal, and extrathoracic lymph node groups in the neck, axilla, and abdomen (data not shown). HSA-78 was clearly present in some lymph nodes and absent in others (Fig. 2A), suggesting that the pleural space communicated with a particular population of lymph nodes. It is important to note the pleural space communicated with ipsilateral, contralateral, or sometimes bilateral superior mediastinal and paraesophageal lymph nodes.



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  		FIG. 2. HSA-78 migrates from the pleural space to specific lymph nodes within the abdomen of the rat. (A) Top row shows the in vivo abdominal compartment of the rat visualized with color video (left), NIR fluorescence (middle), and color-NIR merge images (right). Shown are lymph nodes positive (arrows) and negative (arrowheads) for HSA-78 uptake. Bottom row shows the same lymph nodes after resection. (B) Top row shows an HSA-78-positive lymph node of the rat with hematoxylin and eosin (H&E) staining (left) and a consecutive unstained section of the same node imaged for NIR fluorescence (right). Bottom row shows an HSA-78-negative lymph node of the rat with H&E staining and a consecutive unstained section imaged for NIR fluorescence. NIR fluorescence images have identical exposure times and normalizations.

 
HSA-78-positive tissue was sectioned and adjacent cuts either were stained with H&E or prepared for imaging with a custom microscope capable of detecting NIR fluorescence. Light microscopy of the H&E-stained sections confirmed that the HSA-78-positive tissue was lymph node tissue. The NIR fluorescence imaging of this same tissue was able to identify HSA-78 fluorescence within the lymph node, with its distinction predominantly at the periphery, but also extending into the cortex (Fig. 2B).

Node group specimens that did not exhibit HSA-78 uptake were similarly harvested and analyzed. H&E staining confirmed that the HSA-78-negative tissues were lymph node tissue, and NIR fluorescence imaging showed no autofluorescence and no fluorescence from HSA-78 uptake (Fig. 2B).

Kinetics of Drainage from the Pleural Space to Lymph Node Groups of the Rat
HSA-78 drained from the pleural space to lymph node groups in a specific temporal pattern (Fig. 3). The pleural space drains first to the superior mediastinal lymph nodes. HSA-78 was detected in superior mediastinal lymph nodes in 3 of 8 rats by 20 minutes and in 8 of 8 rats by 30 minutes and remained in all rats imaged at later time points. By 1 hour, HSA-78 migrated to intercostal lymph nodes in 6 of 8 rats and paraesophageal lymph nodes in 5 of 8 rats. By 24 hours after injection into the right pleural space, HSA-78 had migrated to specific extrathoracic lymph node groups in the neck (7 of 8 rats), axilla (7 of 8 rats), and abdomen (6 of 8 rats). At 24 hours, HSA-78 was not equally distributed to all lymph nodes but was clearly present in some nodes and absent in others.



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  		FIG. 3. Kinetics of HSA-78 drainage from the pleural space to different lymph node groups. HSA-78 drains from the pleural space to the superior mediastinal lymph node groups first. Although HSA-78 remains in the superior mediastinal lymph nodes, it also migrates to other lymph nodes of the thorax by 30 minutes and to extrathoracic lymph nodes by 24 hours.

 
Confirmation of Results in the Pig Model
The small-animal data encouraged further investigation of pleural space lymph node mapping in a larger model, approaching the size of humans. Three pigs received a transthoracic injection of HSA-78 into the right pleural space, and three received injection into the left pleural space. Pigs each were imaged at 30 minutes, 1 hour, and 24 hours after injection of HSA-78. At 30 minutes after injection, no HSA-78 could be detected in lymph nodes. At 1 hour after injection, HSA-78 drained to only the superior mediastinal lymph node group in both pigs (Fig. 4A). At 24 hours after injection, HSA-78 was detected in the superior mediastinal, paratracheal, and intraabdominal lymph node groups (Fig. 4B). Regardless of whether HSA-78 was injected into the right or left pleural space, contralateral lymph node groups were sometimes positive, even though some ipsilateral nodal stations were not.



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  		FIG. 4. Drainage of the pleural space to lymph nodes of the pig. (A) HSA-78 injected into the right pleural space of the pig drains to a superior mediastinal lymph node (arrow) after 1 hour. Shown is the in vivo thorax visualized with color video (left), NIR fluorescence (middle), and color-NIR merge images (right). (B) In vivo image of the pig 24 hours after injection into the right pleural space. Top row shows HSA-78 remaining in the superior mediastinal lymph node (thick arrow) but also migrating to a paratracheal lymph node (thin arrow). Bottom row shows HSA-78 migration to a specific lymph node within the abdomen (arrow). Also shown is an adjacent HSA-78-negative lymph node (arrowhead). (C) The same positive and negative lymph nodes pictured in Figure 4B with H&E staining (left) and a consecutive unstained section of the same node imaged with NIR fluorescence (right). NIR fluorescence images have identical exposure times and normalizations.

 
HSA-78-positive tissues in the lymph node basins were excised and sectioned for staining with H&E or frozen-sectioned for NIR fluorescence imaging (Fig. 4C). The H&E images confirmed that the brightly fluorescent specimens were lymph nodes. The NIR images confirmed that HSA-78 could be detected within the substructure of the lymph node. As a control, tissues within lymph node basins that were not fluorescent and presumably not communicating with the right pleural space were also harvested and prepared for histology. H&E staining confirmed that the specimens were lymph nodes. As expected, the NIR images showed no fluorescence within these nodes.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
There are several advantages to using NIR fluorescence imaging to study the spatial and temporal pattern of pleural space lymphatic drainage. First, HSA-78 is an excellent tracer for mapping lymph nodes. It fluoresces brightly against a low background. In contrast to carbon and tungsten suspensions used in previous mapping studies, HSA-78 is uniform in size, thus giving a reliable pattern of flow through lymphatics. HSA-78 also mimics normal pleural proteins. Tungsten particles, on the other hand, may introduce a confounding immune reaction, especially after the 3 days required to migrate from the pleura to communicating lymph nodes.8 With the NIR fluorescence imaging system, accurate administration of the lymph tracer to the right pleural space could be confirmed by simply imaging the external chest wall. Additionally, HSA-78 fluorescence can be detected through up to 1 cm of tissue, depending on the application. The entire animal could be scanned for in situ HSA-78-positive nodes, thus minimizing sampling error. Finally, the NIR fluorescence imaging system assists in the excision of lymph nodes for the purpose of histologic confirmation. Because the HSA-78 withstands histologic processing, we had another degree of certainty in the detection of HSA-78 in lymph nodes.

In this study we identified the pattern of pleural space lymph node drainage in both small and large animal models. The superior mediastinal lymph node group was the first to receive drainage of the pleural space, as evidenced by HSA-78 uptake at the earliest time points. This group corresponds to lymph node station 1, according the Regional Lymph Node Classification for Lung by the American Joint Committee on Cancer (AJCC). The superior mediastinal lymph node group was the only lymph node group in which 100% of animals showed uptake of HSA-78, an effect lasting from 30 minutes to 24 hours without diminution. This suggests that the superior mediastinal lymph node group is not simply a conduit of lymph flow but a primary site of pleural space lymph drainage. The incidence of contralateral drainage may be one reason why survival rates for lung cancer patients with evidence of pleural disease, even by cytology alone, are similar to those for patients with IIIb node disease.

Though cadaveric dissections demonstrated a connection between the pleural space and thoracic lymph nodes, we demonstrated a functional communication of the pleural space with paraesophageal and chest wall lymph nodes by 30 minutes. Within 24 hours, HSA-78 migrated to selected cervical, axillary, and intraabdominal lymph nodes as well. A previous anatomic study showing large lymph channels throughout the diaphragm suggested a communication between the pleura and abdomen,12 but this is the first report of in vivo communication of the pleural space to intraabdominal lymph nodes.

Our results regarding the drainage patterns of the pleural space may be useful for the staging and treatment of malignant pleural mesothelioma. Most patients with mesothelioma die of locoregional disease within 1 year of diagnosis.13 The involvement of extrapleural lymph nodes (stage III) is a major prognostic factor for mesothelioma.14 Given the recent evidence of response rates for pemetrexed-based chemotherapy, it is appropriate to reassess current surgical practice and to consider preresectional lymph node staging. Furthermore, resection of involved nodes could aid in local control and could assist in the selection of patients more likely to benefit from neoadjuvant therapy. Previous to this study, sampling lymph nodes by open biopsy, mediastinoscopy, or positron emission tomography (PET) scanning had not suggested preferential nodal stations for pleural drainage. The known communication with the pleural space to chest wall, paraesophageal, cervical, axillary, and intra-abdominal lymph nodes justifies extra scrutiny of these locations for a directed preresectional lymph node staging.

Pleural space drainage patterns help in the understanding of poor prognosis of lung cancer with VPI. Involvement of ipsilateral superior mediastinal, chest wall, and paraesophageal lymph nodes in lung cancer is defined as nodal stage N2, and involvement of contralateral nodes is defined as N3 by the American Joint Committee on Cancer (AJCC) classification of lung cancer nodes.3 Observed communication between the pleural space and these nodal groups provides an anatomic basis for the clinical observation of advanced nodal disease and poor prognosis in the setting of VPI. Consistent drainage of the pleural space to superior mediastinal nodes suggests a role for preoperative nodal biopsy in experimental protocols involving surgical resection of pleural-based disease. Observed communication from the pleural space to extrathoracic lymph nodes provides an anatomic explanation for the clinical observation of metastatic disease and poor survival in the setting of VPI. It is not practical to biopsy all communicating node groups. In the staging and treatment of mesothelioma and lung cancer with VPI, an ideal solution would be the development of an intraoperative system to map the sentinel lymph node (SLN) of the pleural space.

This study has demonstrated the advantages of NIR fluorescent imaging of lymph node patterns in the animal model; however, NIR fluorescence imaging shows great promise for SLN mapping in humans as well. The SLN concept states that the first lymph node to receive lymphatic drainage from a tumor site will contain tumor cells in the setting of direct lymphatic spread.15 In breast cancer and melanoma, lymph tracers such as vital blue dyes or technetium-99m (Tc-99m) identify this SLN, which can be biopsied. This procedure provides staging information without the need for an extended lymphadenectomy.

Unfortunately, there is no accepted method for identifying SLNs of the pleural space. Vital blue dyes and/or Tc-99m pose several technical obstacles in mapping lymphatic drainage of the pleural space. The thorax often contains anthracotic lymph nodes that can easily be confused with vital blue dye–positive nodes. Tc-99m can often create a "shine-through" effect whereby the injection site creates a confounding positive signal. If the injection site is the entire plural space, this shine-through effect would be even more troublesome in the identification of SLNs.

HSA-78 is an excellent candidate for a lymph node tracer in sentinel lymph node (SLN) mapping. It is composed of nontoxic components, and light of the near-infrared spectrum used to visualize HSA-78 is also nontoxic. HSA-78 drains to lymph nodes within 30 minutes, a feasible time course for preoperative injection of HSA-78 into the pleural space and intraoperative imaging. The main advantage of NIR fluorescence imaging over vital blue dyes and Tc-99 sentinel lymph node mapping is that lymph nodes can be clearly identified and quantified in situ without need for dissection. The real-time display of color, NIR fluorescence, and merged images can then assist in the accurate and complete excision of lymph nodes.

Advancing this technology to SLN biopsy in humans could have clinical impact on staging of lung cancer. Studies to adapt the NIR technology to a mediastinoscope and a thoracoscope are currently underway. Our findings indicate that the superior mediastinal lymph nodes are the first lymph nodes to receive pleural space drainage. These nodes correspond to level 1 lymph nodes of the AJCC staging system and are within the field of standard staging mediastinoscopy. If future studies show that the SLN of the pleural space in humans is not in the mediastinum but within the thoracic cavity, the thoracoscopic NIR imaging system could still visualize these nodes. In lieu of standard sampling of lymph nodes during staging mediastinoscopy, NIR fluorescent imaging could identify SLNs of the pleural space on a patient-specific basis. Such an advancement of technology could direct biopsies, limit dissection, decrease patient risk and morbidity, and increase accuracy in the staging of lung cancers.

Future studies will also focus on applying NIR fluorescent imaging to an animal model of pleura-based diseases. Tumor burden within the pleura may alter lymphatic flow from the mapping pattern we have demonstrated in this study. However, the strength of NIR fluorescent imaging is the ability to scan an entire field for involved lymph nodes, even to unpredictable locations.

In conclusion, our findings establish NIR fluorescence imaging as a novel means to identify lymph nodes draining the pleura in the in vivo, in situ, intraoperative setting. We have also determined the temporal and spatial pattern of communication of the pleural space to nodal stations of prognostic significance and have shown that these may often be contralateral to the pleural space being studied. Last, this study sets the groundwork for further studies of NIR fluorescence imaging for mapping pleural lymph nodes in humans.


   ACKNOWLEDGMENTS
 
This work was supported in part by National Institutes of Health NRSA grant F32 HL72568–01 (to CPP) and grant R21/R33 EB-00673 (to JVF), the U.S. Department of Energy (Office of Biological and Environmental Research) grant DE-FG02–01ER63188 (to JVF), and two Proof of Principle Awards from the Center for Integration of Medicine and Innovative Technology (CIMIT; to JVF and TM).


   FOOTNOTES
 
The pattern of pleural space drainage to lymph nodes of prognostic significance was determined with use of a novel near-infrared fluorescent imaging system. The pleural space drains to superior mediastinal nodes first and then to other lymph nodes over 24 hours.

Received for publication March 19, 2004. Accepted for publication August 17, 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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M. J. Liptay
In Vivo Sentinel Lymph Node Mapping in Lung Cancer
Ann. Surg. Oncol., February 1, 2005; 12(2): 102 - 103.
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