Patients with pathologically diagnosed involved mediastinal

MINI-SYMPOSIUM ON EMERGING TECHNIQUES FOR LUNG CANCER STAGING European Trends in Preoperative and Intraoperative Nodal Staging: ESTS Guidelines P. De Leyn, MF, PhD,* D. Lardinois, MD, P. Van Schil, MD, PhD, R. Rami-Porta, MD, B. Passlick, MD, M. Zielinski, MD, D. Waller, MD,# T. Lerut, MD, PhD,* and W. Weder, MD Abstract: Preoperative and intraoperative lymph node (LN) staging is of paramount importance for patients with non-small cell lung cancer. The Council of the European Society of Thoracic Surgery took the initiative to organize workshops on intraoperative and preoperative mediastinal LN staging. This resulted in specific guidelines. Relevant peer-reviewed publications on these subjects, the experience of the participants, and the opinion of the European Society of Thoracic Surgery members contributing online were used to reach a consensus. For primary staging, mediastinoscopy remains the gold standard for the superior mediastinal LNs. Invasive procedures can be omitted in patients with peripheral tumors and negative mediastinal and hilar nodes on positron emission tomography scan. Positron emission tomography-positive mediastinal findings should always be cytohistologically confirmed. New minimally invasive techniques that provide cytohistological diagnosis became available. Their specificity is high, but the negative predictive value is low. If they yield negative results, an invasive surgical technique remains indicated. For restaging, invasive techniques providing cytohistological information are advisable. Systematic nodal dissection is recommended in all cases to ensure complete resection. Lobespecific systematic nodal dissection is acceptable for peripheral squamous T1 tumors if hilar and interlobar nodes are negative on frozen section studies. The report from the pathologist should describe the number of LNs removed and studied, the overall number of metastatic LNs in each station, and the status of the LN capsule. We hope that the adherence to these guidelines will standardize and improve preoperative and intraoperative LN staging and pathologic evaluation of non-small cell lung cancer. *Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium; Department of Thoracic Surgery, University Hospital of Zurich, Switzerland; Department of Thoracic Surgery, University Hospital of Antwerp, Belgium; Department of Thoracic Surgery, Hopital Mutua de Terassa, Spain; Department of Thoracic Surgery, Albert- Ludwigs-University Freiberg, Germany; Department of Thoracic Surgery, Pulmonary Hospital Zakopane, Poland; #Department of Thoracic Surgery, Glenfield Hospital, Leicester, United Kingdom. Disclosure: The authors declare no conflict of interest. Address for correspondence: Paul De Leyn, MD, PhD, Department of Thoracic Surgery, University Hospitals Leuven, Herestraat 49, B 3000 Leuven, Belgium. Copyright 2007 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/07/0204-0357 Key words: Non-small cell lung cancer, Staging, Mediastinoscopy, Lymph node dissection. (J Thorac Oncol. 2007;2: 357 361) Patients with pathologically diagnosed involved mediastinal lymph nodes (LNs) have a dismal outcome when treated with surgery or radiotherapy alone. To improve the outcome for these patients, the concept of multimodality treatment has been introduced. Mainly patients with mediastinal down-staging will benefit from resection. Therefore, accurate preoperative staging and restaging of mediastinal LNs after induction therapy is of paramount importance. Over the last years, different techniques of mediastinal staging have become available. They vary in accuracy and procedure-related morbidity. However, clinical staging is not perfect. At thoracotomy, the surgeon has an important role in the assessment of local tumor spread and nodal involvement. The assessment of mediastinal LNs during surgery is even more controversial and variable than the preoperative LN staging. In the literature, many names of procedures are used, but they are not well described and defined. The Council of the European Society of Thoracic Surgery (ESTS) took the initiative to organize two workshops on intraoperative mediastinal LN staging and preoperative mediastinal LN staging. Relevant peer-reviewed publications on these subjects, the experience of the participants, and the opinion of the ESTS members contributing online were used to reach a consensus. ESTS GUIDELINES ON PREOPERATIVE LN STAGING IN NSCLC A Distinction between Pretreatment and Posttreatment Mediastinal LN Staging Is Made. PREOPERATIVE (PRETREATMENT) MEDIASTINAL LN STAGING Although computed tomographic (CT) scan is very accurate in detecting LN enlargement, the clinical relevance of LN enlargement for staging is poor because small nodes may contain metastases in up to 20% and large nodes may be benign. In a review, pooled data yielded a sensitivity of 57%, a specificity of 82%, a positive predictive value of 56%, and Journal of Thoracic Oncology Volume 2, Number 4, April 2007 357

De Leyn et al. Journal of Thoracic Oncology Volume 2, Number 4, April 2007 a negative predictive value (NPV) of 83%, with a marked heterogeneity among individual studies. 1 This performance is insufficient for clinical decision making. The involvement of mediastinal LNs in patients with small LNs on CT scan is very much dependent on the histological type and T-stage of the tumor. 2 Positron emission tomography with 18 F-fluoro-2-deoxy- D-glucose is superior to CT for mediastinal LN staging in potentially operable NSCLC. Sensitivities and NPVs were comparable for PET compared with mediastinoscopy. 1 Because of the high NPV of PET scan, invasive staging procedures can generally be omitted in patients with clinical stage I NSCLC with negative mediastinal PET images. This implementation should be dealt with caution in the case of patients with central tumors, hilar N1-disease on PET scan, bronchio-alveolar cell carcinoma, 3 and large mediastinal PET-negative LNs ( 16 mm) on CT scan. 4 The positive predictive value of PET scan is only 79%. In the case of positive mediastinal PET, tissue confirmation is still needed to confirm LN metastasis. Mediastinoscopy remains the gold standard for invasive staging of tumors for patients with potentially operable lung cancer. Different forms of mediastinoscopy have been described. Cervical mediastinoscopy is the most commonly used. The sensitivity of cervical mediastinoscopy varies between 72% and 89%, with an average of 81% and a NPV of 91%. 1 There is no internationally accepted recommendation on how many LN stations should be examined at cervical mediastinoscopy. There are no data indicating that more systematic sampling at mediastinoscopy makes a difference, but extrapolation from data on occasional and systematic sampling at thoracotomy suggests that this may be important. 5 The ESTS working group recommends systematically exploring and always performing a biopsy of the right and left lower paratracheal nodes and the subcarinal nodes. Additionally, if present, the upper paratracheal LNs should be sampled and biopsied. More recently, mediastinoscopy is performed by the use of a videomediastinoscope. 6 This improves visualization of the operative field (Figure 1) and may lead to a higher accuracy in staging and a better standardization of the technique. The learning curve of video-assisted mediastinoscopy is short compared with conventional mediastinoscopy. Endoscopic techniques are minimally invasive approaches that provide histological or cytological confirmation of nodal tumor involvement. A sensitivity of 76% and a false-negative rate of 29% were reported for conventional transbronchial needle aspiration (TBNA) in clinical N2 disease. 1 This high false-negative rate compromises the use of conventional TBNA for routine mediastinal LN staging; however, it can be used as a preliminary diagnostic test complemented in negative cases with surgical staging. The sensitivity of TBNA critically depends on the prevalence of mediastinal LN metastases. In populations with a lower prevalence of mediastinal metastases, the sensitivity of TBNA is much lower than reported in recent lung cancer guidelines. 7 The accuracy can be improved by guidance with endoscopic ultrasonography (EBUS-TBNA). Esophageal ultrasound-guided fine needle aspiration (EUS-FNA) is mainly suitable for the assessment of LNs in the posterior part of levels 4L, 5, and 7 and in the inferior mediastinum at levels 8 and 9 as described on the Mountain-Dresler map. 8 ESTS GUIDELINES FOR BASELINE MEDIASTINAL LN STAGING Chest CT is still the basic imaging modality in lung cancer. However, CT scan of the chest is not accurate enough for mediastinal LN staging. When only CT scan is available, invasive staging is advised for every patient except for a T1 squamous cell tumor with no or small LNs on CT scan. Invasive staging can be omitted for patients with stage I NSCLC and negative mediastinal PET images. However, in the case of central tumors, PET hilar N1 disease, low positron emission tomography with 18 F-fluoro-2-deoxy-D-glucose uptake of the primary tumor and large LNs on CT ( 16 mm), invasive staging remains indicated. PET-Positive Mediastinal Findings Should Be Histologically or Cytologically Confirmed. TBNA, EBUS-FNA, EUS-FNA, and transthoracic needle aspiration are minimally invasive techniques that provide FIGURE 1. 358 Improved visualization by cervical videomediastinoscopy. Copyright 2007 by the International Association for the Study of Lung Cancer

Journal of Thoracic Oncology Volume 2, Number 4, April 2007 European Trends in Nodal Staging cytohistological diagnosis. They can be complementary to surgical invasive staging techniques. Their specificity is high, but their NPV is low. For this reason, an invasive surgical technique remains indicated if they yield negative results. However, if fine needle aspiration is positive, this result may be valid as proof of N2 or N3 disease. Cervical mediastinoscopy provides the advantage that a more complete mapping of mediastinal LNs can be performed. Ideally, all accessible LN stations should be explored and biopsied. At least one ipsilateral, one contralateral and the subcarinal LNs should be biopsied. The proposed algorithm for primary mediastinal staging is detailed in Figure 2. MEDIASTINAL LN RESTAGING AFTER INDUCTION THERAPY The mediastinum can be restaged by the same techniques as applied in primary staging. For mediastinal restaging after induction chemotherapy, the PET scan is more accurate than the CT scan but is clearly not as accurate as in untreated patients. In most FIGURE 2. Proposed algorithm for mediastinal staging. Copyright 2007 by the International Association for the Study of Lung Cancer 359

De Leyn et al. Journal of Thoracic Oncology Volume 2, Number 4, April 2007 studies, the sensitivity is reported to be 50% to 60% with a good specificity of 85% to 90%. In a high proportion of patients, the PET scan is false negative regarding mediastinal nodal involvement after induction therapy. In a prospective study, 9 the use of PET-CT fusion images significantly increased accuracy through better localization of focal, even moderate, positron emission tomography with 18 F-fluoro-2- deoxy-d-glucose update in mediastinal LNs or other vascular-mediastinal structures. Repeat mediastinoscopy, although technically more difficult than the first procedure, offers the advantage of providing histological evidence of response after induction therapy. Only a few centers have reported their experience with repeat mediastinoscopy. Some series reported sensitivities of 70%. 10 12 A prospective study evaluated the accuracy of re-mediastinoscopy and PET-CT in restaging the mediastinum. 9 The sensitivity to detect residual positive mediastinal LNs was only 29%. Although there is no clear answer to explain the different results, the authors suggested that the degree of adhesions and mediastinal fibrosis is mainly secondary to pre-induction mediastinoscopy, rather than to the induction treatment itself. A study from The Netherlands reported results from 19 patients with proven N2 disease that were restaged by EUS after induction chemotherapy. 13 Diagnostic accuracy in this study was 83%. ESTS GUIDELINES FOR RESTAGING At the present time, CT, PET, or PET-CT is not accurate enough to make final further therapeutic decisions. An invasive technique providing cytohistological information is recommended. For restaging, endoscopic techniques or surgical invasive techniques can be used. If they yield a positive result, non-surgical treatment seems to be indicated for most patients. The choice of invasive techniques may be dependent on the availability of the technique and expertise of the center. ESTS GUIDELINES ON INTRAOPERATIVE LN STAGING IN NSCLC Mapping of LNs to the Appropriate LN Station In 1997, the latest revised International Staging System was released. 8 The ESTS working group identified five areas in which the demarcation among the LN stations was either arbitrary or not identifiable at mediastinoscopy or intraoperative staging. The limitations of the present nodal charts will be addressed in a new International Nodal Charts that will be included in the next revision of the UICC Staging System to be implemented in January 2009. Moreover, the working group found that the importance of the number of investigated versus involved nodes and LN stations has not been addressed in the current staging systems. Rationale for Intraoperative LN Assessment There are data that clearly show that systematic sampling or nodal dissection improves intraoperative staging in contrast to selected LN sampling, especially regarding the detection of multi-level N2 disease. The rate of unforeseen N2 disease will also depend on the methods applied for preoperative staging. There is controversy whether extending the LN dissection influences survival or recurrence rate of the disease. A removal of at least six LNs (UICC) from hilar and mediastinal stations is recommended to define nodal staging accurately and to determine pn0 status. ESTS Definitions for Intraoperative LN Assessment. The ESTS provided clear definitions for the following procedures: selected LN biopsy, sampling, systematic sampling, systematic nodal dissection, lobe-specific systematic LN dissection, and extended LN dissection. 5 ESTS Recommendation of Intraoperative LN Assessment For complete resection of NSCLC, a systematic nodal dissection is recommended in all cases. 14,15 All the mediastinal tissue containing the LNs is dissected and removed systematically within anatomical landmarks. It is important that the nodal stations are excised and put into different vials with separate labeling. The highest removed mediastinal node should be identified. Lymph node assessment is performed before lung resection. In some cases, especially after induction treatment, nodal information may change surgical procedure. For peripheral squamous cell T1 tumors, a more selective nodal dissection depending on the lobar location of the primary tumor (lobe specific systematic nodal dissection) is acceptable. The probability of unforeseen N2 disease is very low (less than 5%) for these patients. 2,3 In high-risk patients, intraoperative LN assessment can be reduced, but if the patient can tolerate a lobectomy, systematic nodal dissection should be performed. ESTS Recommendations on Histopathological Evaluation of the Removed LNs The ESTS working group gives recommendations on how LNs should be examined in resected specimens of patients with NSCLC. 5 The report from the pathologist should describe the number of LNs removed and studied, the overall number of metastatic LNs in each station, and the status of the LN capsule. Full text of the guidelines are available. 5,16 ACKNOWLEDGMENTS Members of workshop on intraoperative LN staging in NSCLC: P. De Leyn, D. Lardinois, F. Detterbeck, K. Junker, T. Lerut, J. Hasse, B. Passlick, R. Rami Porta, E. Rendina, H.B. Ris, P. Van Schil, D. Waller, W. Weder, and M. Zielinski. REFERENCES 1. Toloza EM, Harpole L, Detterbeck F. 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