Seminars in Oncology
Volume 32, Issue 3 , Pages 269-278, June 2005

Mediastinal Staging 2005: Pictures, Scopes, and Scalpels

  • Harvey I. Pass

      Affiliations

    • Corresponding Author InformationAddress reprint requests to Harvey I. Pass, MD, Harper University Hospital, 3990 John R, Suite 2102, Detroit, MI 48201

Thoracic Oncology Section, Multidisciplinary Lung Team, Karmanos Cancer Institute, Detroit, MI

Article Outline

Staging of the mediastinum for lung cancer has matured dramatically with the advent of newer technologies in imaging and endoscopic surveillance. Some of these technologies such as positron emission tomography (PET) scanning are becoming mainstream in the evaluation of patients with clinically suspicious mediastinal disease as seen on computed tomography (CT), while others such as endobronchial ultrasound are reserved for specialty expertise and await validation. While much improvement has been made in the accurate preoperative staging of patients having surgery as the primary modality in lung cancer, controversy exists regarding the restaging of locally advanced cases after induction chemotherapy or chemoradiotherapy. A major concentration on these restaging issues is warranted since it is now generally agreed that sterilization of the mediastinum after induction therapy has an impact on the prognosis of patients with stage IIIA disease, and accurate staging after therapy may rationally guide diverse therapeutic interventions in these patients.

 

Staging of the mediastinum either by invasive or noninvasive techniques should efficiently and accurately determine whether patients are candidates for a potentially curative surgical resection, or for protocols involving multimodality approaches prior to or instead of attempted surgical resection. Newer techniques to stage the mediastinum are rapidly evolving, and older techniques, instead of being replaced by newer technologies, are being supplemented with information that hopefully stratifies patients into categories for the most appropriate therapy based on their prognosis (Table 1). The most confounding aspect of the surgical staging of lung cancer involves accurate assessment of the mediastinum, which ideally should define (1) mediastinal lymph node status and (2) mediastinal invasion.

Table 1. Options for Staging of the Mediastinum
Noninvasive/radiographic
Chest x-ray
Computed tomography
Magnetic resonance imaging
Positron emission tomography
Minimally invasive
Bronchoscopy with transbronchial/transcarinal biopsy (± endobronchial ultrasound)
Endo-esophgeal ultrasound/fine-needle aspiration biopsy
Invasive staging
Mediastinoscopy
Mediastinotomy
Extended cervical mediastinoscopy
Video-assisted thoracoscopic biopsy
Thoracotomy with intraoperative frozen section mediastinal sampling or dissection
Mediastinal sentinel lymph node mapping

Back to Article Outline

Mediastinal Involvement 

Lymph Nodes 

Approximately 26% to 44% of patients with newly diagnosed lung cancer will have mediastinal lymph node involvement.1, 2 The prognostic implications of mediastinal lymph node involvement have been extensively detailed in numerous publications, and reflect a heterogeneous spectrum of disease that could influence protocol development as well as patient selection. Adverse prognostic factors associated with positive mediastinal nodes include extracapsular spread of tumor, multiple levels of involved lymph nodes, bulky enlarged nodes, and the size of the primary tumor.3, 4, 5, 6 There is controversy regarding whether involvement of the higher, superior mediastinal nodes (nodes found positive that are generally available for biopsy at mediastinoscopy) portends a worse prognosis than a negative mediastinoscopy result in patients who are found to have positive nodes at thoracotomy.7 Multiple studies have found that metastatic disease to the subcarinal lymph nodes adversely affected prognosis compared to other lymph nodes.8, 9, 10, 11, 12, 13, 14, 15, 16 It is generally believed that multistation nodal disease has a somewhat worse prognosis than single-station disease, but the location of metastatic disease to a single nodal station probably has no significant effect.

With the development of chemotherapeutic agents possessing significant activity against lung cancer and sophistication of modern radiotherapy techniques, studies have suggested that combining chemotherapy and/or radiotherapy followed by surgery in selected stage IIIA patients may offer therapeutic benefit.17, 18, 19 The poor survival rates with surgery alone in N2 disease, without significant benefit for adjuvant postoperative chemotherapy or radiotherapy,20, 21, 22 have led to protocols designed to use nonsurgical (radiotherapy and/or chemotherapy) therapy first, often to convert the “unresectable” tumor to resectable, in order to improve long-term survival.17 In general, patients with lymph nodes greater than 2 cm in short-axis diameter measured by computed tomography (CT), who have extranodal involvement and multistation disease along with groups of multiple involved smaller lymph nodes are considered to have bulky, unresectable disease. These patients are referred for protocols involving chemoradiation if they are functionally fit to tolerate the therapy. The heterogeneity of N2 prognostic categories can certainly confound ongoing prospective trials attempting to define good-risk candidates for multimodality therapy. The heterogeneity phenomenon of mediastinal lymph node involvement was reviewed by Andre et al in 702 consecutive patients having surgical resection of N2 non-small cell lung cancer (NSCLC).23 A multivariable analysis using Cox regression identified four negative prognostic factors: clinically apparent N2 disease, involvement of multiple lymph node stations, either pathologic stage T3 or T4 status, or no preoperative chemotherapy. For patients having primary surgery, the 5-year survivals varied according to N2 characteristics: one level node involvement with microscopic disease (34%), multiple level lymph nodes with microscopic disease (11%), single level clinically apparent disease (8%), and multilevel clinically apparent disease (3%). For patients with single level microsopic disease, there was no difference in survival between different lymph node stations. These data reinforce the importance of knowing not only whether mediastinal lymph nodes are involved in NSCLC, but also the extent to which they may be involved.

Invasion 

It is just as important to have accurate information on the T status of the tumor and its relation to the mediastinum and, in order to do so, one must be familiar with the structures that are contained within the mediastinum that may abut or be invaded either by tumor on the visceral pleural envelope or by potentially involved bulky lymph nodes, or both. An awareness of this anatomy helps in the staging workup to determine whether the extent of mediastinal involvement is T3 (nontransmural involvement of the pericardium, involvement of the phrenic nerve focally, or extrapericardial involvement of the pulmonary artery or veins) or T4 (involvement of the superior vena cava, aorta, main pulmonary artery, esophagus).1, 2 Extension of tumor into these structures radically alters the T status of the tumor and influences surgical decision making towards primary resection or protocol-directed induction therapy with later surgical consideration. The limited studies that deal with T3 involvement of the mediastinum report a 5-year survival approaching 25% if the mediastinal lymph nodes are not involved.24 However, with T4 involvement of the superior vena cava, main pulmonary artery, or aorta, the 5-year survival in very limited series is approximately 15%, with the best survival rates (30%) reported in patients with localized superior vena caval involvement.24

Back to Article Outline

Methodology of Mediastinal Staging 

Noninvasive Staging Modalities 

Computed Tomography 

(Table 2) It is generally agreed that a patient who presents with a known or suspected treatable lung cancer should have a chest CT.25 Although many criteria have been used to define metastases to mediastinal lymph nodes, the standard adapted by most radiologists is a short axis lymph node diameter of ≥1 cm on a transverse CT scan to maximize sensitivity at the expense of specificity, thus minimizing false negative examinations. A recent review of 20 studies published since 1993 with a cohort of 3,438 patients evaluated the accuracy of CT scanning for the mediastinal staging of lung cancer.2 There was marked heterogeneity for the sensitivity (pooled value = 0.57) and specificity (pooled value = 0.82), with a positive predictive value of 0.56 and a negative predictive value of 0.83. These data reinforce that findings on CT scan cannot be used solely to determine mediastinal lymph node status, and reveal that the accuracy of CT scanning of the mediastinum has not changed despite improvements in technology. Obstructive pnemonitis with resulting enlarged lymph nodes can account for the fact that 40% of lymph nodes thought on CT scan to be malignant were actually benign, and microscopic involvement of lymph nodes is encountered in up to 15% of patients who undergo complete mediastinal lymph node dissection for presumed stage I disease.

Table 2. Radiographic Mediastinal Staging
StudyNo. of PatientsSensitivitySpecificityPositive Predictive ValueNegative Predictive Value
CT3,4380.750.820.560.83
MRI201.00.910.961.0
PET1,0450.840.890.790.93

Modified from Toloza et al.2

The obvious conclusion for the standard of care in 2005 is that CT scanning findings of the mediastinum when using the 1-cm cutoff limit, must be supplemented by other noninvasive and invasive techniques to have a higher confidence that abnormally enlarged lymph nodes truly represent IIIA or IIIB disease.

Magnetic Resonance Imaging 

Magnetic resonance imaging (MRI), like CT, is an imaging modality with the theoretical advantage of multiplanar imaging that is based on anatomic rather than biologic features. MRI currently has a limited role in the noninvasive staging of bronchogenic carcinoma but may be used to evaluate for vascular or vertebral body invasion with suspected T4 tumors or to assess the integrity of the brachial plexus in patients with a Pancoast tumor.26 Due to poorer spatial resolution and motion artifact, it is less sensitive in evaluation of the pulmonary parenchyma.

Noninvasive Staging Beyond CT: Positron Emission Tomography 

Until recently, the next step after CT in mediastinal evaluation would be invasive staging of the mediastinum to establish histologic certainty, either by transcarinal needle biopsy, transbronchial biopsy, or mediastinotomy. The increasing use of positron emission tomography (PET) scanning, and the ability to have PET scanning approved for insurance coverage in the evaluation of the solitary pulmonary nodule, have solidified the role of metabolic imaging for lung cancer staging. PET scanning has become an ideal supplement to CT scanning due to its higher sensitivity and specificity for the evaluation of mediastinal lymph nodes. Toloza et al2 evaluated PET scanning for mediastinal staging in 1,111 patients from 29 reports in the literature, and found a pooled sensitivity of 0.85 and a pooled specificity of 0.88. The overall positive predictive value and negative predictive value were superior to CT scanning (0.78 and 0.93, respectively). Other reports have noted that the use of PET scanning can change decision strategies for treatment in 10% to 20% of patients.27 However, PET scanning is limited in its anatomic interpretation and sensitivity when analyzing lesions less than 1.2 cm. Lymph node stations can be accurately identified when PET images and CT images are fused or interpreted simultaneously, but the volume or number of involved lymph nodes cannot be determined with present PET technology. The size limitations for sensitivity may not only have to do with spatial resolution software but with the type of lesion that is being visualized since the PET intensity is known to be lower in bronchoalveolar lung cancer compared to other histologies.28 Moreover, a detailed analysis of the density of glucose transporters in primary lesions and metastatic lung cancer lesions has not been performed, but there are suggestions that low-expression of Glut-1 transporters could contribute to false negative lymph node results.29

Minimally Invasive Techniques for Mediastinal Staging 

The sensitivity, specificity, and predictive values of the various options for minimally invasive staging are shown in Table 3.

Table 3. Minimally Invasive Mediastinal Staging
ProcedureNo. of PatientsSensitivitySpecificityPositive Predictive ValueNegative Predictive Value
Transbronchial needle aspiration biopsy9100.760.961.000.71
Transthoracic needle aspiration biopsy2150.911.01.00.83
Esophageal ultrasound needle aspiration biopsy2150.880.910.980.77

Modified from Toloza et al.1

Bronchoscopic Techniques Including Transbronchial Needle Aspiration Biopsy 

Bronchoscopy, besides visualizing obvious endobronchial tumor or airway distortion, can play a key role in the staging of lung cancer. Carinal biopsy alone in the presence of an endobronchial tumor, especially if it is central, can have a yield as high as 5%.30 Bronchoscopy may also detect other unsuspected lesions in the airway, and fluorescence bronchoscopy is being evaluated not only for finding occult lesions but also to define margins of resection of the bronchus that could influence stage, ie, proximity to the carina.31 Transbronchial needle aspiration (TBNA) can be used to assess mediastinal adenopathy, including paratracheal, subcarinal, hilar, and aorticopulmonary window nodes. A variety of needles can be used for transbronchial, transtracheal, or transcarinal aspiration; needles are usually 1.3 cm in length, and the best results are achieved with larger-gauge needles (18 or 19 gauge).32, 33 Inadequate insertion of the needle in the tissue of interest is the most common problem with transbronchial needle mediastinal aspiration and can lead to false negative biopsies without securing lymph nodal tissue. Aspiration of paratracheal lesions is difficult due to the angle of penetration as well as the needle length, and the needle must be anchored between tracheal rings before attempting to advance it. The yield for TBNA varies widely in the literature (20% to 89%) and seems to be related to the size and location of the lesion as well as operator experience.1 In a recent review of the literature regarding the accuracy of TBNA of the mediastinum in patients with lung cancer, the sensitivity was determined to be 76% with a specificity of 96%1 (Table 3). The problem with TBNA is that the false negative rate can be as high as 30% and the yield is reported to improve with at least seven passes with the TBNA needle. To further improve accuracy, a cytopathologist should assess the adequacy of cellularity at the time of the procedure.34 False positives can be decreased by avoiding the primary tumor before sampling the mediastinal nodes to prevent contamination of the bronchoscope channel by tumor cells. The accuracy of TBNA may be improved in the future with the addition of endobronchial ultrasound.

Endobronchial Ultrasound Biopsy 

Endobronchial ultrasound (EBUS) allows visualization of the tracheobronchial and peribronchial lesions, mediastinal lymph nodes, and adjacent vascular structures, as well as peripheral pulmonary tumors, but there have been few studies of its efficacy because its use is primarily limited to specialty centers. Current technology allows for visualization of airway wall structures and, with ultrasound penetration of up to 5 cm, permits easy identification of lymph nodes and vessels while only adding a few minutes to the procedure in experienced hands.35 Through a bronchoscope with 2.8-mm working channel, a flexible ultrasound probe with a 20-MHz transducer is introduced. When the balloon on the probe tip is inflated to achieve coupling with the airway, a 360-degree image of the airway wall and adjacent tissue results. The exact locations of the target lymph nodes and their relation to the tracheobronchial tree are noted, after which the probe is removed from the working channel and TBNA performed. In 207 of 242 patients investigated using EBUS, the lymph nodes were successfully sampled (86%) and a diagnosis or cancer stage could be obtained in 172 patients (72%).36

Endo-esophageal Ultrasound-Guided Fine-Needle Aspiration Biopsy 

The advent of endoscopic ultrasonography of the esophagus also has allowed excellent visualization of the mediastinum, particularly the left-sided mediastinal lymph nodes and the subcarinal space.37, 38, 39 Endo-esophageal ultrasound-guided fine-needle aspiration (EUS-FNA) is usually performed in the outpatient setting with conscious sedation. Because the esophagus lies posteriorly and to the left of the trachea and is in proximity to the lymph nodes between these two structures, lymph node levels 5, 7, 8, and possibly 9 are accessible. Right-sided levels 2 and 4 and the pretracheal space are not accessible with EUS-FNA. Wiersema et al40 recently reported that EUS-FNA was superior to TBNA in the diagnosis of mediastinal metastases in NSCLC. The needle is guided by real-time ultrasonography, and the adequacy of the cytologic aspirate should be confirmed on site. When performed in patients with enlarged lymph nodes, EUS-FNA has a high sensitivity and specificity (0.88 and 0.91, respectively), with an overall positive predictive value of 98% and negative predictive value of 77%1 (Table 3). EUS-FNA can also detect malignancy in normal-sized lymph nodes, and when successful has altered the staging in from 18% to 42% of patients with normal-sized lymph nodes. However, the sensitivity and specificity are low with normal-sized lymph nodes due to the necessity to perform many aspirations of different sites to increase the yield.41

Transbronchial and transesophageal needle biopsy techniques are most useful for patients who have documented enlarged, nondiscrete lymph nodes with extensive mediastinal infiltration (clinical/radiographic evidence of N2/N3 disease). In this situation, TBNA and EUS-FNA provide the best chance for obtaining a diagnosis with the least morbidity. Multiple aspirates should be performed to avoid sampling error.

Invasive Surgical Staging of the Mediastinum 

Overview of Invasive Surgical Staging 

The method by which the mediastinum is explored will depend on the site of the lesion. Cervical mediastinoscopy involves an initial digital exploration palpating suspicious nodes followed by placement of the scope to visualize and biopsy the appropriate lymph nodes. The N2 (levels 4 and 7) and N3 nodal stations (level 2, scalenus/supraclavicular) with the exception of the aortic nodes (levels 5 and 6), the inferior pulmonary ligament nodes (level 9), and the paraesophageal nodes (level 8), are accessible for biopsy using this technique. Lee and Ginsberg emphasized the importance of combining standard cervical mediastinoscopy with exploration of the scalenus fat pad48 in patients with central nonsquamous tumors. Extended cervical mediastinoscopy is a technique that combines cervical mediastinoscopy with mediastinoscopic evaluation of the subaortic space as a single procedure.49 More commonly, the subaortic space is approached using the Chamberlain procedure, which permits the surgeon to directly palpate the subaortic extrapleural space and biopsy the lymph nodes in this region.50 Some surgeons prefer to use a mediastinoscope through a small anterior incision in the left chest and not remove the costal cartilage to perform the Chamberlain procedure.

Video-assisted thoracoscopic surgery (VATS), a minimally invasive surgical technique, is an alternative method to assess levels 5 and 6, as well as the paraesophageal (level 8) and pulmonary ligament (level 9) nodes.51 Whether the ipsilateral and the contralateral mediastinal nodes are surgically staged in a lung cancer patient is being increasingly dictated by the use of PET scanning, although there are recommendations in the absence of PET scan findings (see below). In the absence of PET scanning availability, staging of the contralateral side usually is defined by nodal size on CT.

Mediastinoscopy and Mediastinotomy 

In 1954 using the Jackson laryngoscope, Harken described the visualization of the anterior mediastinum and Carlens advanced the technology using the cervical mediastinoscope, which allowed superior access to the contralateral mediastinal nodes, thereby providing a method for preresectional determination of operability.42 Preresectional staging of NSCLC using mediastinoscopy was pioneered by the thoracic surgical group in Toronto, which convincingly demonstrated the prognostic significance of involved lymph nodes identified at mediastinoscopy.43 Based on the relation between prognosis and the level of lymph node involvement, Naruke developed a thoracic lymph node map that illustrates the location of various lymph nodes.44 This map was revised most recently in 1997 by Mountain and Dresler.45 Each lymph node is assigned to a specific nodal station (N0, N1, N2, or N3) representing a prognostic subgroup or stage. In 1986 and subsequently in 1997, Mountain introduced and modified a new international staging system in which the extent of nodal spread serves as the principal prognostic determinant46, 47 and multiple reports have validated the prognostic value of this staging system.

Indications 

Mediastinal nodal enlargement by CT is an absolute indication for mediastinoscopy. For patients with mediastinal nodes of any size, the documentation of metabolic activity within single nodes or in multiple nodal basins in an individual with suspected lung cancer is also an indication for surgical staging of the suspicious mediastinum. For patients whose eligibility criteria require documentation of mediastinal disease, as in randomized or nonrandomized trials of induction therapy for locoregional lung cancer, mediastinal biopsy is mandated.

Several lung cancer situations are associated with a sufficiently high risk of mediastinal nodal spread that the presence of any one of them in a patient with known or suspected primary lung carcinoma warrants preresectional mediastinoscopy, even if the CT scan shows no mediastinal adenopathy. A large mass or a lesion of any size located within the inner third of the lung field, especially if it is an adenocarcinoma or large cell carcinoma, correlates with an increased incidence of N2 nodal spread despite the finding of a normal mediastinum on CT scan.52 Left-sided lung cancers also merit mediastinoscopy at certain centers. Due to the tendency for left lower lobe lesions to spread contralaterally, some centers recommend biopsy of bilateral mediastinal nodes, using mediastinoscopy to sample anterior 7, 2R, 4R, 2L, and 4L, and extended mediastinoscopy, mediastinotomy or EUS-FNA to sample 5L and 6L. Mediastinoscopy evaluation is also warranted for left upper lobe lesions in order to sample the level 4L nodes.53

Evidence of vocal cord palsy or hoarseness represents another indication for cervical mediastinoscopy. The left recurrent laryngeal nerve may be compromised by enlargement of the aortic nodes, resulting in ipsilateral vocal cord hemiparesis. This finding, along with enlarged lymph nodes on the CT, is taken as de facto evidence of level 5L involvement.

Results 

These are summarized in Table 4. In a review of more than 5,687 patients undergoing mediastinoscopy between 1983 and 1999, the overall sensitivity of standard cervical mediastinoscopy was 81%, with a negative predictive value of 91%1 (Table 4). Extended cervical mediastinoscopy used in combination with standard cervical mediastinoscopy will increase the overall sensitivity by 17% to 44% and improve negative predictive value by 10% to 20% when compared directly to standard mediastinoscopy.1 The Chamberlain procedure or anterior mediastinotomy has a sensitivity of 63% to 86%, and its negative predictive value remains high whether it is performed alone (89%–100%) or in combination with standard cervical mediastinoscopy (89%–92%).1

Table 4. Pre-resection Surgical Staging of the Mediastinum
ProcedureNo. of PatientsSensitivitySpecificityPositive Predictive ValueNegative Predictive Value
Mediastinoscopy5,6870.811.01.00.91
Chamberlain procedure840.741.01.00.94
Extended cervical mediastinoscopy2060.731.01.00.34

Modified from Toloza et al.1

Complications 

Because of the risk of bleeding, the surgeon must always aspirate by needle any structure prior to its biopsy. Blood vessels are occasionally incorrectly identified as nodes, including bronchial vessels, the azygos vein, branches of the pulmonary artery near the region of the right tracheobronchial nodes, and other structures that may have been adherent to the lymph nodes that were biopsied. Hemostasis is usually obtained with electrocautery and packing. In the rare situation of significant bleeding, the mediastinoscope should not be removed, because direct tamponade is facilitated by the location of the scope near the source of hemorrhage. Packing with hemostatic materials and gauze packs for 5 minutes is the appropriate first attempt to achieve hemostasis. Damage to the main pulmonary artery, aortic arch, or innominate artery will likely require prompt operative exploration through an ipsilateral thoracotomy or median sternotomy. If thoracotomy is necessary, it should be performed on the side of the lung lesion to allow pulmonary resection after hemostasis has been achieved. Other rare complications of mediastinoscopy include recurrent laryngeal nerve injury, pneumothorax, and arrhythmias. A left-sided mediastinotomy can be associated with local pain from resection of the second costal cartilage, as well as injury to the internal mammary artery, pulmonary artery, pulmonary vein, phrenic nerve and left recurrent laryngeal nerve. Nevertheless, several reports document the safety of mediastinoscopy and mediastinotomy with mortality rates of 0% to 0.3% and morbidity rates of 1% to 2.3%.42

Video-Assisted Thoracic Surgery 

Thoracoscopy has been used not only to assess left-sided lymph node stations not accessible by standard mediastinoscopy and for inferior pulmonary ligament and paraesophageal lymph nodes, but also in very limited series to assess systematic nodal dissection for right-sided tumors. However, few series have described the surgical technique in its entirety and most operations involve the use of a 4.5- to 5-cm anterior incision, which enhances visibility, yet in expert hands subcarinal lymph node dissection is possible.54 It is generally concluded that VATS is used by a small group of surgeons in lung cancer mediastinal staging and its chief use involves the assessment of pleural effusions associated with lung cancer adenopathy, and the documentation of discontinuous pleural disease by direct visualization of roentgenographically negative pleural involvement.

Thoracotomy 

There is controversy over whether complete ipsilateral mediastinal nodal dissection as opposed to minimal or more extensive hilar and mediastinal lymph node sampling has greater efficacy in determining intraoperative stage and whether the degree of the dissection influences prognosis. A group of thoracic surgeons in North America and Japan feel that mediastinal lymph node dissection is important for both accurate staging and overall survival.44, 55, 56

Type of Lymphadenectomy 
Detection of occult disease 

A number of investigators have evaluated the extent of mediastinal biopsy necessary to obtain accurate staging information. Bollen et al found that systematic sampling of mediastinal lymph nodes was as successful as mediastinal lymph node dissection in identifying N2 disease (discovery ratio, 2.7; confidence interval, 1.04 to 4.2).57 These authors described more injuries to the recurrent laryngeal nerve with lymph node dissection when compared to historic controls and noted that lymph node dissection lengthens the operation. Izbicki et al58 conducted a randomized prospective trial with 182 patients comparing systematic mediastinal lymph node sampling to mediastinal lymph node dissection, and found that the number of N2-positive levels was greater in the patients who underwent complete dissection, although the percentage of patients found to have N1 or N2 disease was not significantly different between the two study arms. There were no differences in blood loss or blood replacement. A similar study was conducted by Sugi et al in 115 patients with clinical T1N0 tumors that were less than 2 cm in diameter and found mediastinal metastases in 13% of each group.59 From these data, it appears that systematic lymph node dissection is no more accurate than mediastinal dissection for staging NSCLC.

Survival 

Whether regional lymph node sampling or complete ipsilateral lymphadenectomy affects long-term survival is unclear. There has been no long-term study of the effects of a complete mediastinal lymphadenectomy. However, a retrospective study by Funatsu et al has shown that 5-year survival was significantly better in 64 patients who underwent a lymph node sampling, when compared to 61 patients who underwent a radical mediastinal lymphadenectomy.60 Conversely, in a series of 151 patients at Memorial Sloan-Kettering Cancer Center who had positive mediastinal lymph nodes, a 30% five-year survival was observed and is one of the highest in the literature today with mediastinal lymphadenectomy.61 In the randomized trial by Izbicki et al comparing mediastinal node sampling with mediastinal lymphadenectomy, no increase in morbidity or mortality was noted for lymphadenectomy and there were no differences in survival. However, this trial was underpowered to show differences in locoregional recurrence or survival.58

The Intergroup trial 0115 of adjuvant therapy in patients with completely resected stages II and IIIA NSCLC stratified patients by the type of lymph node dissection before participation (dissection v sampling). Of 373 eligible patients accrued to the study, 187 underwent sampling and 186 had dissection. Although no significant difference in stage distribution was observed between the two surgical procedures, complete dissection identified significantly more N2 level disease and was associated with improved survival with right-sided NSCLC compared to systematic sampling.62

Wu et al recently presented the results of the largest randomized trial to date that compared the two techniques.63 In this study of 471 eligible patients with stages I-IIIA NSCLC followed for up to 10 years after resection, complete dissection was associated with significant improvement in median survival of 59 months versus 34 months. Significant differences in survival were present for all pathologic stages of disease and multivariate analysis found the type of lymph node dissection to be an independent predictor of survival.

Sentinel Lymph Node Mapping and Mediastinal Staging 

The first draining node from a primary lesion is known as the sentinel node (SN), and determination of the SN has been used to individualize lymph node dissection for melanoma and breast cancer patients, as well as to target those nodes for which thin-section immunohistochemical analysis for micrometastases is warranted. SN mapping could be most beneficial for patients with lung cancer with small tumors and clinically negative lymph nodes, since this group has a 15% to 20% incidence of occult nodal metastatic disease. The safety and efficacy of the SN technique has already been documented in patients with lung cancer. Liptay et al64, 65 established the feasibility of this technique by defining the SN in 82% of patients with lung cancer intraoperatively with technetium colloid and reported that upstaging from NO to N1 could occur in as many as 7% of patients. Schmidt et al,66 Nomori et al,67 and Sugi et al68 achieved identification rates for sentinel lymph nodes of more than 80%, 87%, and 63%, respectively. Although most of the SN were identified at station 12, the rate of mediastinal SN (skip metastases) was 20% to 35%. These detection rates had a false negative rate of 2% to 5%, and may have been influenced by the degree of the patients’ chronic obstructive pulmonary disease with loss of lymphatic channels due to emphysema and/or the presence of large necrotic tumors.

The implications and utility of SN mapping will become more evident as greater experience with the technique is published to determine the appropriate isotope, timing, and intraoperative or preoperative injection, as well as the ability to determine nodal status intraoperatively using molecular techniques. By selecting only those lymph nodes with a high probability of metastases, molecular or protein identification of these occult metastases could radically stage-shift these patients and could have implications for therapy, either intraoperatively or postoperatively.

Back to Article Outline

Restaging After Induction Therapy 

Probably the most challenging aspect of mediastinal staging is the re-evaluation of the lymph node or T status after induction chemotherapy or induction chemoradiotherapy. Patients with documented mediastinal lymph node disease will be found at surgery to be downstaged to N0 after multimodality therapy in approximately 45% of the cases.69, 70, 71 The recent report using docetaxel-cisplatin induction therapy described mediastinal nodal sterilization in 65% of patients.72 Mediastinal clearance and complete resection of disease in these patients were associated with 3-year survival rates of 53% to 61%, compared to 11% to 18% for those without mediastinal clearance. These studies suggest that surgical resection should be avoided in patients after induction therapy who have definite, biopsy-proven residual tumor in the mediastinal nodes.

Histologic Confirmation of Restaging 

Since mediastinal status after therapy appears to be a strong predictor of survival, the ability to restage the mediastinum in the least invasive fashion could guide therapeutic decisions with regard to (1) feasibility of surgical resection or (2) modification of nonsurgical strategies, such as changing chemotherapy regimens if a response is not being achieved. Examination of the Southwest Oncology Group (SWOG) 8805 multimodality study revealed that typical radiographic interpretations of response, such as with conventional CT, are not reliable in the restaging of the mediastinum unless there is a complete disappearance of disease (potential complete remission) or if the disease is obviously progressing.17 Thus, there has been a desire to define histologically the status of treated mediastinal adenopathy using less invasive techniques than thoracotomy with mediastinal lymph node dissection and intraoperative frozen section assessment of mediastinal disease clearance. There are only anecdotal data in this regard using EUS and EBUS, while there are controversial data to suggest that repeat mediastinoscopy is feasible and may supply information in selected populations of patients. In a study by Mateu-Navarro et al,73 24 patients underwent re-mediastinoscopy after receiving neoadjuvant chemotherapy with mitomycin, ifosfamide, and cisplatin or cisplatin plus gemcitabine. In 12 (50%) patients, re-mediastinoscopy was positive. The 12 remaining patients were operated on, and residual disease in mediastinal lymph nodes was detected in five patients (pN2) and hilar lymph nodes in one patient (pN1). The other six patients were free of nodal disease. The sensitivity, specificity, and accuracy of remediastinoscopy were 0.7, 1.0, and 0.8, respectively. In a similar study by van Schil, 27 of 31 identified candidates had re-mediastinoscopy without major technical difficulties after neoadjuvant therapy.74 Re-mediastinoscopy was positive in 11 patients (40.7%) and negative in 16 (59.3%). Of these 16, four were false negative, for a sensitivity of 71%, specificity of 100%, and accuracy of 84%. These data, although promising, do not establish re-mediastinoscopy as the gold standard for histologic verification of mediastinal restaging, and do not address the issues that may occur with re-mediastinoscopy after induction chemoradiotherapy.

PET Scanning 

The role of PET scanning after both induction chemotherapy and chemoradiotherapy with regard to the status of the mediastinum has been reported by various groups with mixed degrees of enthusiasm. The problems inherent in PET scanning as a definitive answer to mediastinal restaging center around the inability of the technique to detect micrometastases, the timing of when to perform the PET scan after therapy, the influence of radiotherapy along with the chemotherapy, and the persistence of inflammatory fluorodeoxyglucose (FDG) uptake, and discrimination as to differentially reporting a decrease in nodal versus primary tumor standardized uptake value (SUV). A recent report indicated that FDG PET scanning can be performed as early as 4 to 12 weeks after radiotherapy with or without chemotherapy.75 In addition, it is a better predictor of survival in these patients than CT75 and survival and time to progression in stage IIIb and IV patients are longer in individuals who have a 46% to 60% reduction in SUV as early as 21 days after commencing therapy. Nevertheless, these studies do not involve surgical verification of the lymphadenopathy after therapy, and do not comment on nodal basin SUV as a separate region of interest.

The majority of the studies attempting to correlate SUV changes after induction therapy and histologic confirmation of lymph node status have been facilitated by thoracic surgical groups. One of the initial reports involved 15 surgically staged N2 NSCLC patients who underwent a first PET scan before three cycles of platinum-based induction chemotherapy.76 After induction, a second PET was performed and locoregional therapy consolidated with surgery in nine and radiotherapy in six. Correlation with pathology of the nine resection specimens revealed that the accuracy of PET in predicting mediastinal lymph node downstaging was 100% (six true negatives; three true positives). Survival was significantly better in patients with mediastinal clearance (P = .01) or with a greater than 50% decrease in the SUV of the primary tumor (P = .03) after induction chemotherapy. A study from the Massachusetts General Hospital77 investigated PET restaging in 26 patients with histologically confirmed stage III NSCLC (21 with stage IIIA [N2] NSCLC and five with a highly selected subset of stage IIIB) who were treated with preoperative chemoradiotherapy. All patients had an initial FDG-PET and another performed 2 weeks after completion of preoperative therapy. The FDG-PET images were evaluated qualitatively for uptake at the primary tumor sites and mediastinal lymph nodes. When a value of 3.0 was used as the SUV cut-off, sensitivity and specificity were 88% and 67%, respectively, for the primary tumor site restaging. The sensitivity and specificity of FDG-PET for mediastinal restaging were 58.0% and 93.0%. These results indicated that FDG-PET may be useful for monitoring the therapeutic effect of neoadjuvant chemoradiotherapy in patients with stage III NSCLC. For the primary lesions, SUV-based analysis has high sensitivity but limited specificity for detecting residual tumor. In contrast, for restaging of mediastinal lymph nodes, FDG-PET is highly specific, but has limited sensitivity. In a study from Memorial Sloan-Kettering Cancer Center,78 FDG-PET was accurate in the detection of the presence or absence of disease in the primary site (positive and negative predictive values of the FDG scan 98% and 29%, respectively) of 56 patients restaged post-induction therapy with FDG-PET. Most of the errors in tumor staging were related to under staging T4 disease. In predicting the presence of residual mediastinal nodal disease, the positive predictive value, the negative predictive value, sensitivity, and specificity for PET in all assessable patients were 46%, 79%, 67%, and 61%, respectively. However, this study was limited by the absence of a majority of pre-induction FDG-PET scans. More promising data for regional accuracy of lymph node prediction were reported by Cerfolio et al79 in a small group of 11 patients with N2 disease, in whom repeat FDG-PET scans correctly predicted the absence or presence of cancer in all the N2 paratracheal lymph nodes in all patients. FDG-PET scanning was not as accurate in the other N2 stations, however, including levels 5, 6, and 7.

These small studies emphasize the need for future prospective trials of the utility of FDG-PET scanning to predict nodal clearance after induction therapy and that all PET scans in potentially operable, post-induction patients must be validated by histologic confirmation of disease either by intraoperative mediastinal dissection or by combining PET scanning with targeted positive nodes for re-mediastinoscopy80 or EUS.81 The technology will be evolving with fusion PET-CT machines, which could further improve the accuracy for anatomic nodal regions of interest.

Back to Article Outline

Conclusion 

Although there seems to be a greater movement towards the use of noninvasive tools for the staging of the patient with lung cancer, clinicians must still rely on histologic confirmation for accuracy of staging. Once trials are performed that demonstrate the proper timing of noninvasive radiologic techniques such as PET after induction therapy, patients may be able to forego tissue harvest for staging. At this time, however, we must continue to expand the horizons both of minimally invasive endoscopic techniques as well as completely noninvasive methodologies so that the two will be blended in the future for greatest sensitivity and specificity.

Back to Article Outline

References 

  1. Toloza EM , Harpole L , Detterbeck F , et al.   Invasive staging of non-small cell lung cancer (A review of the current evidence) . Chest . 2003;123(suppl):157S–166S
  2. Toloza EM , Harpole L , McCrory DC . Noninvasive staging of non-small cell lung cancer (A review of the current evidence) . Chest . 2003;123(suppl):137S–146S
  3. Rusch VW . Surgery for stage III non-small cell lung cancer . Cancer Control . 1994;1:455–466
  4. van Rens MT , de la Riviere AB , Elbers HR , et al.   Prognostic assessment of 2,361 patients who underwent pulmonary resection for non-small cell lung cancer, stage I, II, and IIIA . Chest . 2000;117:374–379
  5. Martini N , Flehinger BJ , Zaman MB , et al.   Results of resection in non-oat cell carcinoma of the lung with mediastinal lymph node metastases . Ann Surg . 1983;198:386–397
  6. Mountain CF . Surgery for stage IIIa-N2 non-small cell lung cancer . Cancer . 1994;73:2589–2598
  7. Pearson FG , Delarue NC , Ilves R , et al.   Significance of positive superior mediastinal nodes identified at mediastinoscopy in patients with resectable cancer of the lung . J Thorac Cardiovasc Surg . 1982;83:1–11
  8. Vansteenkiste JF , De Leyn PR , Deneffe GJ , et al.  Leuven Lung Cancer Group   Survival and prognostic factors in resected N2 non-small cell lung cancer (A study of 140 cases) . Ann Thorac Surg . 1997;63:1441–1450
  9. Abe K , Kato N , Miki K , et al.   Malignant mesothelioma of testicular tunica vaginalis . Int J Urol . 2002;9:602–603
  10. Miller DL , McManus KG , Allen MS , et al.   Results of surgical resection in patients with N2 non-small cell lung cancer . Ann Thorac Surg . 1994;57:1095–1100
  11. Watanabe Y , Hayashi Y , Shimizu J , et al.   Mediastinal nodal involvement and the prognosis of non-small cell lung cancer . Chest . 1991;100:422–428
  12. Martini N , Flehinger BJ , Zaman MB , et al.   Results of resection in non-oat cell carcinoma of the lung with mediastinal lymph node metastases . Ann Surg . 1983;198:386–397
  13. Goldstraw P , Mannam GC , Kaplan DK , et al.   Surgical management of non-small-cell lung cancer with ipsilateral mediastinal node metastasis (N2 disease) . J Thorac Cardiovasc Surg . 1994;107:19–27
  14. Naruke T , Suemasu K , Ishikawa S . Lymph node mapping and curability at various levels of metastasis in resected lung cancer . J Thorac Cardiovasc Surg . 1978;76:832–839
  15. Conill C , Astudillo J , Verger E . Prognostic significance of metastases to mediastinal lymph node levels in resected non-small cell lung carcinoma . Cancer . 1993;72:1199–1202
  16. Okada M , Tsubota N , Yoshimura M , et al.   Prognosis of completely resected pN2 non-small cell lung carcinomas (What is the significant node that affects survival?) . J Thorac Cardiovasc Surg . 1999;118:270–275
  17. Albain KS . Induction chemotherapy or chemoradiotherapy before surgery for non-small-cell lung cancer . Curr Oncol Rep . 2000;2:54–63
  18. Hensing TA , Detterbeck F , Socinski MA . The role of induction therapy in the management of resectable non-small cell lung cancer . Cancer Control . 2000;7:45–55
  19. Albain KS . Induction chemotherapy with/without radiation followed by surgery in stage III non-small-cell lung cancer . Oncology (Huntingt) . 1997;11(suppl 9):51–57
  20. Scagliotti GV , Novello S . Adjuvant therapy in completely resected non-small-cell lung cancer . Curr Oncol Rep . 2003;5:318–325
  21. Movsas B . Role of adjuvant therapy in resected stage II/IIIA non-small-cell lung cancer . Oncology (Huntingt) . 2002;16:90–95 100
  22. Keller SM , Adak S , Wagner H , et al.  Eastern Cooperative Oncology Group   A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer . N Engl J Med . 2000;343:1217–1222
  23. Andre F , Grunenwald D , Pignon JP , et al.   Survival of patients with resected N2 non-small-cell lung cancer (Evidence for a subclassification and implications) . J Clin Oncol . 2000;18:2981–2989
  24. Detterbeck F , Kiser A . T3 non-small cell lung cancer (stage IIB-IIIA) . In:  Detterbeck F ,  Rivera M ,  Socinski MA , et al. editor. Diagnosis and Treatment of Lung Cancer (An Evidence-Based Guide for he Practicing Clinician) . Philadelphia, PA: Saunders; 2001;p. 223–232
  25. Silvestri GA , Tanoue LT , Margolis ML , et al.   The noninvasive staging of non-small cell lung cancer (the guidelines) . Chest . 2003;123(suppl):147S–156S
  26. Schaefer-Prokop C , Prokop M . New imaging techniques in the treatment guidelines for lung cancer . Eur Respir J . 2002;35(suppl):71s–83s
  27. Margery J , Grahek D , Vaylet F , et al.   Impact of FDG PET imaging on clinical management in patients with resectable NSCLC (A prospective multicentric French study) . Lung Cancer . 2003;41(suppl 2):s13; (abstr)
  28. Yap CS , Schiepers C , Fishbein MC , et al.   FDG-PET imaging in lung cancer (How sensitive is it for bronchioloalveolar carcinoma?) . Eur J Nucl Med Mol Imaging . 2002;29:1166–1173
  29. Baek HJ , Jung JH , Choi CW . The possible mechanism of false staging of mediastinal nodes by FDG-PET in the non-small cell lung cancer . Lung Cancer . 2003;41(suppl 2):S13; (abstr)
  30. Shure D , Fedullo PF , Plummer M . Carinal forceps biopsy via the fiberoptic bronchoscope in the routine staging of lung cancer . West J Med . 1985;142:511–513
  31. Sutedja TG , Codrington H , Risse EK , et al.   Autofluorescence bronchoscopy improves staging of radiographically occult lung cancer and has an impact on therapeutic strategy . Chest . 2001;120:1327–1332
  32. Shure D , Fedullo PF . Transbronchial needle aspiration in the diagnosis of submucosal and peribronchial bronchogenic carcinoma . Chest . 1985;88:49–51
  33. Shure D , Fedullo PF . The role of transcarinal needle aspiration in the staging of bronchogenic carcinoma . Chest . 1984;86:693–696
  34. Chin R , McCain TW , Lucia MA , et al.   Transbronchial needle aspiration in diagnosing and staging lung cancer (How many aspirates are needed?) . Am J Respir Crit Care Med . 2002;166:377–381
  35. Sutedja G . New techniques for early detection of lung cancer . Eur Respir J . 2003;39(suppl):57s–66s
  36. Herth FJ , Becker HD , Ernst A . Ultrasound-guided transbronchial needle aspiration (An experience in 242 patients) . Chest . 2003;123:604–607
  37. Silvestri GA , Hoffman B , Reed CE . One from column A (Choosing between CT, positron emission tomography, endoscopic ultrasound with fine-needle aspiration, transbronchial needle aspiration, thoracoscopy, mediastinoscopy, and mediastinotomy for staging lung cancer) . Chest . 2003;123:333–335
  38. Wallace MB , Silvestri GA , Sahai AV , et al.   Endoscopic ultrasound-guided fine needle aspiration for staging patients with carcinoma of the lung . Ann Thorac Surg . 2001;72:1861–1866
  39. Silvestri GA , Hoffman BJ , Bhutani MS , et al.   Endoscopic Ultrasound With Fine-Needle Aspiration in the diagnosis and staging of lung cancer . Ann Thorac Surg . 1996;61:1441–1447
  40. Wiersema M , Edell E , Midthun D . Prospective comparison of transbronchial needle aspirate (TBNA) and endosonography guided biopsy (EUS-FNA) of mediastinal lymph nodes in patients with known or suspected non small cell lung cancer . Gastrointest Endosc . 2002;55:115; (abstr)
  41. LeBlanc JK , Devereaux BM , Imperiale TF , et al.   Endoscopic ultrasound in non-small cell lung cancer and negative mediastinum on computed tomography . Am J Respir Crit Care Med . 2005;171:177–182
  42. Abolhoda A , Keller S . Surgical staging of the mediastinum . In:  Pass HI ,  Mitchell JB ,  Johnson DH , et al. editor. Lung Cancer (Principles and Practice) . Philadelphia, PA: Lippincott Williams & Wilkins; 2000;p. 628–646
  43. Pearson FG . An evaluation of mediastinoscopy in the management of presumably operable bronchial carcinoma . J Thorac Cardiovasc Surg . 1968;55:617–625
  44. Naruke T . Significance of lymph node metastases in lung cancer . Semin Thorac Cardiovasc Surg . 1993;5:210–218
  45. Mountain CF , Dresler CM . Regional lymph node classification for lung cancer staging . Chest . 1997;111:1718–1723
  46. Mountain CF . Revision in the International System for Staging Lung Cancer . Chest . 1997;111:1710–1717
  47. Mountain CF . A new international staging system for lung cancer . Chest . 1986;89(suppl):225S–233S
  48. Lee JD , Ginsberg RJ . Lung cancer staging (The value of ipsilateral scalene lymph node biopsy performed at mediastinoscopy) . Ann Thorac Surg . 1996;62:338–341
  49. Ginsberg RJ . Extended cervical mediastinoscopy . Chest Surg Clin North Am . 1996;6:21–30
  50. Olak J . Parasternal mediastinotomy (Chamberlain procedure) . Chest Surg Clin North Am . 1996;6:31–40
  51. Landreneau RJ , Hazelrigg SR , Mack MJ , et al.   Thoracoscopic mediastinal lymph node sampling (useful for mediastinal lymph node stations inaccessible by cervical mediastinoscopy) . J Thorac Cardiovasc Surg . 1993;106:554–558
  52. Daly BD , Mueller JD , Faling LJ , et al.   N2 lung cancer (Outcome in patients with false-negative computed tomographic scans of the chest) . J Thorac Cardiovasc Surg . 1993;105:904–910
  53. Detterbeck F , Jones DR , Parker LA . Intrathoracic staging . In:  Detterbeck F ,  Rivera M ,  Socinski MA , et al. editor. Diagnosis and Treatment of Lung Cancer (An Evidence-Based Guide for the Practicing Physician) . Philadelphia, PA: Saunders; 2001;p. 73–93
  54. Krasna MJ . Role of thoracoscopic lymph node staging for lung and esophageal cancer . Oncology (Huntingt) . 1996;10:793–802
  55. Ishida T , Yano T , Maeda K , et al.   Strategy for lymphadenectomy in lung cancer three centimeters or less in diameter . Ann Thorac Surg . 1990;50:708–713
  56. Martini N , Beattie EJ . Results of surgical treatment in stage I lung cancer . J Thorac Cardiovasc Surg . 1977;74:499–505
  57. Bollen EC , van Duin CJ , Theunissen PH , et al.   Mediastinal lymph node dissection in resected lung cancer (Morbidity and accuracy of staging) . Ann Thorac Surg . 1993;55:961–966
  58. Izbicki JR , Thetter O , Habekost M , et al.   Radical systematic mediastinal lymphadenectomy in non-small cell lung cancer (A randomized controlled trial) . Br J Surg . 1994;81:229–235
  59. Sugi K , Nawata K , Fujita N , et al.   Systematic lymph node dissection for clinically diagnosed peripheral non-small-cell lung cancer less than 2 cm in diameter . World J Surg . 1998;22:290–294
  60. Funatsu T , Matsubara Y , Ikeda S , et al.   Preoperative mediastinoscopic assessment of N factors and the need for mediastinal lymph node dissection in T1 lung cancer . J Thorac Cardiovasc Surg . 1994;108:321–328
  61. Martini N , Flehinger BJ . The role of surgery in N2 lung cancer . Surg Clin North Am . 1987;67:1037–1049
  62. Keller SM , Adak S , Wagner H , et al.  Eastern Cooperative Oncology Group   Mediastinal lymph node dissection improves survival in patients with stages II and IIIa non-small cell lung cancer . Ann Thorac Surg . 2000;70:358–365
  63. Wu Y , Huang ZF , Wang SY , et al.   A randomized trial of systematic nodal dissection in resectable non-small cell lung cancer . Lung Cancer . 2002;36:1–6
  64. 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 . 2002;20:1984–1988
  65. Liptay MJ , Masters GA , Winchester DJ , et al.   Intraoperative radioisotope sentinel lymph node mapping in non-small cell lung cancer . Ann Thorac Surg . 2000;70:384–389
  66. Schmidt FE , Woltering EA , Webb WR , et al.   Sentinel nodal assessment in patients with carcinoma of the lung . Ann Thorac Surg . 2002;74:870–874
  67. Nomori H , Horio H , Naruke T , et al.   Use of technetium-99m tin colloid for sentinel lymph node identification in non-small cell lung cancer . J Thorac Cardiovasc Surg . 2002;124:486–492
  68. Sugi K , Fukuda M , Nakamura H , et al.   Comparison of three tracers for detecting sentinel lymph nodes in patients with clinical N0 lung cancer . Lung Cancer . 2003;39:37–40
  69. Albain KS , Rusch VW , Crowley JJ , et al.   Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer (Mature results of Southwest Oncology Group phase II study 8805) . J Clin Oncol . 1995;13:1880–1892
  70. Pass HI , Pogrebniak HW , Steinberg SM , et al.   Randomized trial of neoadjuvant therapy for lung cancer (Interim analysis) . Ann Thorac Surg . 1992;53:992–998
  71. Bueno R , Richards WG , Swanson SJ , et al.   Nodal stage after induction therapy for stage IIIA lung cancer determines patient survival . Ann Thorac Surg . 2000;70:1826–1831
  72. Betticher DC , Hsu Schmitz SF , Totsch M , et al.   Mediastinal lymph node clearance after docetaxel-cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stage IIIA pN2 non-small-cell lung cancer (A multicenter phase II trial) . J Clin Oncol . 2003;21:1752–1759
  73. Mateu-Navarro M , Rami-Porta R , Bastus-Piulats R , et al.   Remediastinoscopy after induction chemotherapy in non-small cell lung cancer . Ann Thorac Surg . 2000;70:391–395
  74. Van Schil P , van der Schoot J , Poniewierski J , et al.   Remediastinoscopy after neoadjuvant therapy for non-small cell lung cancer . Lung Cancer . 2002;37:281–285
  75. MacManus MR , Hicks R , Fisher R , et al.   FDG-PET-detected extracranial metastasis in patients with non-small cell lung cancer undergoing staging for surgery or radical radiotherapy—Survival correlates with metastatic disease burden . Acta Oncol . 2003;42:48–54
  76. Vansteenkiste JF , Stroobants SG , De Leyn PR , et al.  The Leuven Lung Cancer Group   Potential use of FDG-PET scan after induction chemotherapy in surgically staged IIIa-N2 non-small-cell lung cancer (A prospective pilot study) . Ann Oncol . 1998;9:1193–1198
  77. Ryu JS , Choi NC , Fischman AJ , et al.   FDG-PET in staging and restaging non-small cell lung cancer after neoadjuvant chemoradiotherapy (Correlation with histopathology) . Lung Cancer . 2002;35:179–187
  78. Akhurst T , Downey RJ , Ginsberg MS , et al.   An initial experience with FDG-PET in the imaging of residual disease after induction therapy for lung cancer . Ann Thorac Surg . 2002;73:259–264
  79. Cerfolio RJ , Ojha B , Mukherjee S , et al.   Positron emission tomography scanning with 2-fluoro-2-deoxy-d-glucose as a predictor of response of neoadjuvant treatment for non-small cell carcinoma . J Thorac Cardiovasc Surg . 2003;125:938–944
  80. Lardinois D , Schallberger A , Betticher D , et al.   Postinduction video-mediastinoscopy is as accurate and safe as video-mediastinoscopy in patients without pretreatment for potentially operable non-small cell lung cancer . Ann Thorac Surg . 2003;75:1102–1106
  81. Kramer H , Douma WR , van Putten J , et al.   Endoscopic Ultrasonography with fine needle aspiration in the staging of non-small cell lung cancer after a positive mediastinal PET . Lung Cancer . 2003;41(suppl 2):S204; (abstr)

PII: S0093-7754(05)00085-0

doi:10.1053/j.seminoncol.2005.02.014

Seminars in Oncology
Volume 32, Issue 3 , Pages 269-278, June 2005

Article Tools