Decision making about operability in non-small cell lung cancer

With the introduction of combined modality therapy and better staging techniques, the role of surgical resection for non-small cell lung cancer is continuously redefined. The final aim of surgical treatment for lung cancer is complete resection, also after neoadjuvant or induction therapy. Precise criteria for complete resection have recently been defined. Definite indications for surgery include clinical stages I, II and resectable IIIA. The precise role for surgical resection in stage IIIA-N2 lung cancer remains controversial but only downstaged patients should be considered. Stage IIIB is mostly treated by chemoradiotherapy. Accurate peroperative or surgical staging is necessary, as well regarding the tumour as nodal factor, to determine the extent of resection. A systematic nodal dissection should be performed including at least three hilar and three mediastinal lymph node stations. Post-induction surgical therapy often represents a greater technical challenge due to a pronounced hilar and mediastinal fibrosis. Downstaging is an important prognostic factor and persisting mediastinal lymph node involvement carries a poor prognosis. The optimal restaging method has not been established yet, but a pathological proof should be obtained. Remediastinoscopy is feasible with an acceptable accuracy but less invasive techniques are currently evaluated.     

Complete mediastinal lymphadenectomy: the core component of the multidisciplinary therapy in resectable non-small cell lung cancer.

There is a great deal of concern about metastasis of lung cancer to regional lymph nodes, due partly to the work of groups of thoracic surgeons in Japan and North America beginning in the 1970s. The classification of regional lymph node stations for lung cancer staging published by Mountain and Dresler has been widely adopted for more than ten years. Anatomic landmarks for 14 levels of intrapulmonary, hilar, and mediastinal lymph nodes stations are designated. Skip transfer and occult lymph node metastasis, confirmed by studies regarding the mode of spread of intrathoracic lymphatic metastasis, are two theoretical bases for complete mediastinal lymphadenectomy of lung cancer. However, whether or not the degree of the dissection influences prognosis, the role of systematic nodal dissection (SND) vs mediastinal lymph node sampling (MLD) in resectable non-small cell lung cancer (NSCLC) remains controversial. A systematic literature search was performed to identify relevant reports, making full use of the 'Cited by,' 'Related Records,' 'References,' and 'Author Index' functions in the PubMed and ISI Web of Science databases. This paper presents a review of the role of mediastinal lymph node distribution and methods of determining suitability for hilar and mediastinal lymphadenectomy based on the four subsets of stage IIIA-N2, balancing the cost vs effect of mediastinal lymph node dissection in resectable NSCLC, focusing on the stage migration bias in clinical trials comparing SND and MLS, recommending a reasonable node dissection sequence, improving the prospects for the perioperative anti-tumor therapy based on mediastinal lymphadenectomy, and evaluating the various preoperative staging techniques. Finally, we believe that, besides the role of complete resection and accurate staging, the complete mediastinal lymphadenectomy is the core component of the lung cancer multidisciplinary therapy, and suggest that the values of lymphadenectomy should be further assessed using decision-tree analysis based on large-scale prospective randomized trials and pooled analysis to evaluate the costs vs effects.     

Is sampling really effective in staging non-small cell lung cancer? A prospective study

Is sampling really effective in staging non-small cell lung cancer? The aim of the study was to assess if systematic nodal dissection is necessary in order to stage non-small cell lung cancer correctly or whether mediastinal lymph node sampling can be used and whether in selected cases it could replace systematic nodal dissection for the treatment of lung cancer. A prospective study was conducted in 94 patients affected by clinically resectable non-small cell lung cancer (stages I-IIIB) who were surgically treated by the same team of surgeons. During surgery mediastinal lymph node sampling was done first and then another surgeon completed the systematic nodal dissection and performed the lung resection. One hundred and ninety-three mediastinal nodal stations were investigated using the American Thoracic Society lymph node map to identify them. On analysing the 193 mediastinal nodal stations investigated, it emerged that in 181 cases (94%) mediastinal lymph node sampling and systematic nodal dissection yielded the same histopathological findings, whereas in 12 cases (6%) there was no agreement between the two techniques. The negative predictive value of mediastinal lymph node sampling was 92.8% (103/111). The results of the study show no statistical difference between mediastinal lymph node sampling and systematic nodal dissection in staging non-small cell lung cancer. However, it is possible that in a limited percentage of cases a nodal station could be understaged and thus the surgical resection could prove incomplete if mediastinal lymph node sampling alone is performed. Moreover, in those cases where mediastinal lymph node sampling detects N2 disease and systematic nodal dissection has not been completed, the intervention cannot be considered radical.     

Pulmonary T2N0 adenocarcinoma with metastasis to a lymph node in the thoracic wall.

We experienced a rare case of lung cancer without hilar/mediastinal nodal involvement or direct invasion to the thoracic wall, but with metastasis to a lymph node in the thoracic wall. A 72-year-old woman with lung cancer was admitted to our hospital for the surgical therapy. She had suffered from right pleuritis in her childhood. During the dissection of the pleural adhesion around the whole lung, one small black lymph node was found in the thoracic wall and resected. Then, right middle and lower lobectomy and systematic nodal dissection were performed. The postoperative pathological examination revealed that nodal involvement was not observed in all samples except in the lymph node in the thoracic wall. In lung cancer patients with broad pleural adhesion, we should pay attention to lymph nodes in the thoracic wall. If we find them, the nodes should be resected for accurate staging.     

Pulmonary T2N0 adenocarcinoma with metastasis to a lymph node in the thoracic wall

We experienced a rare case of lung cancer without hilar/mediastinal nodal involvement or direct invasion to the thoracic wall, but with metastasis to a lymph node in the thoracic wall. A 72-year-old woman with lung cancer was admitted to our hospital for the surgical therapy. She had suffered from right pleuritis in her childhood. During the dissection of the pleural adhesion around the whole lung, one small black lymph node was found in the thoracic wall and resected. Then, right middle and lower lobectomy and systematic nodal dissection were performed. The postoperative pathological examination revealed that nodal involvement was not observed in all samples except in the lymph node in the thoracic wall. In lung cancer patients with broad pleural adhesion, we should pay attention to lymph nodes in the thoracic wall. If we find them, the nodes should be resected for accurate staging.     

ESTS guidelines for intraoperative lymph node staging in non-small cell lung cancer.

The European Society of Thoracic Surgeons (ESTS) organized a workshop dealing with lymph node staging in non-small cell lung cancer. The objective of this workshop was to develop guidelines for definitions and the surgical procedures of intraoperative lymph node staging, and the pathologic evaluation of resected lymph nodes in patients with non-small cell lung cancer (NSCLC). Relevant peer-reviewed publications on the subjects, the experience of the participants, and the opinion of the ESTS members contributing on line, were used to reach a consensus. Systematic nodal dissection is recommended in all cases to ensure complete resection. Lobe-specific systematic nodal dissection is acceptable for peripheral squamous T1 tumors, if hilar and interlobar nodes are negative on frozen section studies; it implies removal of, at least, three hilar and interlobar nodes and three mediastinal nodes from three stations in which the subcarinal is always included. Selected lymph node biopsies and sampling are justified to prove nodal involvement when resection is not possible. Pathologic evaluation includes all lymph nodes resected separately and those remaining in the lung specimen. Sections are done at the site of gross abnormalities. If macroscopic inspection does not detect any abnormal site, 2-mm slices of the nodes in the longitudinal plane are recommended. Routine search for micrometastases or isolated tumor cells in hematoxylin-eosin negative nodes would be desirable. Randomized controlled trials to evaluate adjuvant therapies for patients with these conditions are recommended. The adherence to these guidelines will standardize the intraoperative lymph node staging and pathologic evaluation, and improve pathologic staging, which will help decide on the best adjuvant therapy.     

The role of lymphadenectomy in lung cancer surgery

Adequate lymphadenectomy represents a fundamental procedure in lung cancer surgery for accurate staging and potential survival benefit. Various techniques are used in current surgical practice for the intraoperative lymph node removal associated with pulmonary resection, without definitive indications concerning the preferable option. Different studies in the last decades have compared complete mediastinal lymph node dissection with lymph node sampling regarding their effect on long-term survival, recurrence rate, accuracy of pathologic staging, and surgical morbidity. Literature data and technical aspects of lymph node dissection are reported and discussed in this article.     

Clinical feasibility and surgical benefits of video-assisted mediastinoscopic lymphadenectomy in the treatment of resectable lung cancer

Objective: This study was performed to assess the clinical feasibility and surgical outcomes of video-assisted mediastinoscopic lymphadenectomy in the treatment of resectable lung cancer. Methods: Between July 2004 and December 2009, we retrospectively analyzed 108 consecutive video-assisted mediastinoscopic lymphadenectomies in lung cancer patients from a prospectively collected database. Ninety-seven (89.8%) patients underwent combined operation during the same anesthesia and six (5.3%) patients underwent a staged operation for the resection of lung cancer and systematic lymphadenectomy. We reviewed the indication and duration of video-assisted mediastinoscopic lymphadenectomy, its complication, combined or staged operation type, the number of dissected lymph nodes and nodal stations, and pathologic staging of the mediastinal node. Results: Mean operative time of video-assisted mediastinoscopic lymphadenectomy was 39.8 ± 12.3 min (range of 14–85 min). Mean number of resected lymph nodes was 16.0 ± 7.7 (range of 3–37). In video-assisted mediastinoscopic lymphadenectomy, the rates of lymph node dissection of stations 4R, 4L, and 7 were 71.3%, 88.0%, and 100%, respectively, whereas the rates of dissection of lymph nodes in station 2R and 2L were only 22.2% and 17.6%, respectively. There was no operative mortality. We identified five complications of recurrent nerve palsy. Conclusions: Video-assisted mediastinoscopic lymphadenectomy is a clinically feasible procedure with acceptable complication rate and provides more accurate staging of mediastinal node in lung cancer patients. It may be also an excellent supplementary technique used for complete mediastinal node dissection at minimal invasive surgery for cancer resection, especially with left-sided video-assisted thoracoscopic lobectomy.     

Surgical assessment and intraoperative management of mediastinal lymph nodes in non-small cell lung cancer

Mediastinal lymph node status has important prognostic and therapeutic implications for nonsmall cell lung cancer patients. Consequently, an accurate pathologic assessment of mediastinal lymph nodes for metastasis is essential. Despite the significance of nodal assessment, practice patterns among surgeons vary widely. Therefore we reviewed the literature to provide evidence-based recommendations regarding the ideal means and extent of preoperative and intraoperative pathologic mediastinal lymph node staging in non-small cell lung cancer patients. We found that the most sensitive and accurate intraoperative method is a complete mediastinal lymph node dissection. Pathologic evaluation of at least 10 mediastinal lymph node from at least three stations should be performed at the time of surgery.     

Mediastinal Staging Prior to Surgical Resection

In our current conception of cancer, lymph nodes represent a pivotal transition between a primary tumor treated by surgical therapy alone and metastatic disease treated by an evolving combination of multimodality therapy. Invasive mediastinal staging provides an opportunity for pre-resectional histologic examination of these pivotal lymph nodes. The disadvantages of mediastinoscopy is that it requires general anesthesia and, in many cases, a delay in surgical resection. The advantages of mediastinoscopy are that it is safe and effective.¹⁶ In patients with suspected mediastinal lung cancer (stage III), mediastinoscopy provides lymph node staging and histologic confirmation of tumor type. In these selected patients, we perform sufficiently extensive mediastinal sampling that it is impractical to examine the entire specimen by frozen section. The price of a thorough examination of the lymph nodes is that the therapeutic resection may be delayed a week; nonetheless, the mediastinoscopy is low risk and can be performed as an outpatient procedure. In appropriately selected patients, invasive mediastinal staging provides important histologic information with minimal morbidity.     

Mediastinal lymph nodes: Ignore? Sample? Dissect? The role of mediastinal node dissection in the surgical management of primary lung cancer

The role of mediastinal lymph node dissection (MLND) during the resection of non-small-cell lung cancer is still unclear although most surgeons agree that a minimum of hilar and mediastinal nodes must be examined for appropriate pathological staging. Current surgical practices vary from visual inspection of the mediastinum with biopsy of only abnormal looking nodes to systematic mediastinal node sampling which is to the biopsy of lymph nodes from multiple levels whether they appear abnormal or not to MLND which involves the systematic removal of all lymph node bearing tissue from multiple sites unilaterally or bilaterally within the mediastinum. This review article looks at the evidence and arguments in favour of lymphadenectomy, including improved pathological staging, better locoregional control, and ultimately longer disease-free survival and those against which are longer operating time, increased operative morbidity, and lack of evidence for survival benefit.     

Thoracoscopic mediastinal lymph node dissection for lung cancer

Mediastinal lymph node staging is an important component of the assessment and management of patients with operable non-small cell lung cancer and is necessary to achieve complete resection. During minimally invasive surgery, performance of an equivalent oncologic resection, including adequate lymph node dissection similar in extent to open thoracotomy, is absolutely necessary. We describe our techniques for video-assisted thoracic surgery (VATS) and Robot-assisted VATS (R-VATS) mediastinal lymph node dissection when performing thoracoscopic lobectomy for lung cancer. Between 2008 and 2011, 200 consecutive patients who underwent VATS or R-VATS lobectomies for early stage lung cancer were analyzed. In our series, we removed about 25 lymph nodes per case in both complete VATS and R-VATS. A thorough lymph node dissection in lung cancer is possible with either VATS or R-VATS technique without oncological compromise.     

Sarcoidosis development during induction chemotherapy for lung cancer mimicked progressive disease

We report a rare case of sarcoidosis that developed during induction chemotherapy for primary lung cancer, mimicking progressive disease. A 63-year-old man had an abnormal shadow in the right upper lung, and a bronchoscopic examination revealed a squamous cell carcinoma. Swelling of a pretracheal lymph node was also noted. Thus, we gave induction chemotherapy consisting of paclitaxel (days 1, 8) + carboplatin (days 1, 8) for two cycles under clinical staging of T2N2M0. After induction chemotherapy, ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) showed positive accumulation of FDG in mediastinal and bilateral hilar lymph nodes that had been negative in a previous FDG-PET examination, which led us to suspect disease progression. Transbronchial lymph node biopsy results showed sarcoid granulomas in the specimens. Following complete resection of the lung cancer, sarcoid granulomas were revealed in both nonneoplastic lung tissue and lymph nodes, which resulted in a diagnosis of lung cancer accompanied with sarcoidosis.     

Indication of limited pulmonary resection for small-sized lung cancer based on preoperative clinical data

Limited pulmonary resection is performed mostly based on the size of lung cancer and ground-glass opacity (GGO). It has been proposed to determine the indication of segmentectomy according to hilar lymph node involvement. There is a potential risk of underestimation for lymph node involvement since there may be a skip mediastinal lymph node metastasis without hilar involvement. We propose to use standardized uptake value( SUV) max of primary lung cancer as an indicator of non-invasive lung cancer. None of 44 small-sized lung cancers with SUVmax lower than 1 had lymph node metastasis or vessel invasion. A small-sized lung cancer ≤ 2 cm with SUVmax ≤ 1 is indicated wedge resection if GGO area is greater than 75% of tumor. Segmentectomy is indicated if the GGO area is less than 75%. We also propose selective lymphadenectomy for small-sized lung cancer. The lower mediastinal lymphadenectomy may be omitted if a small-sized tumor is located in the right upper lobe or the left upper segment. The upper mediastinal lymphadenectomy may be omitted if a small-sized lung cancer is located in the lower lobe and if the lower mediastinal lymph node involvement is excluded.     

Multimodal treatment of non small cell lung cancer

The primary treatment of lung cancer depends on tumor stage. Chest CT scan and bronchoscopy are used to define the TNM stage and resectability. In case of lung cancer without mediastinal lymph node enlargement or direct mediastinal involvement (clinical stage I-IIb + T3N1) surgical treatment is recommended. The use of adjuvant chemotherapy has to be defined, but will be indicated in stage II and IIIa. Expected 5-year survival achieves 40 to 80 % depending on tumor stage. Exceeds the shorter diameter of mediastinal lymph nodes in chest CT scan more than 1 cm (or in case of positive PET scan) mediastinoscopy is indicated. In case of N2-disease and after tumor response to preoperative chemotherapy (about 60 %) secondary resection of the tumor leads to higher 5-year survival rates (20-40 %) compared to patients without induction therapy (5-20 %). In these patients and after unexpected detection of solitary lymph node metastasis by primary resection adjuvant mediastinal radiotherapy should be added. If the tumor has infiltrated the mediastinum or the upper sulcus (T3/4) and/or mediastinal lymph nodes are obviously tumor burden (e. g. > 3 cm, N2 bulky, N3) radical primary resection may not be possible. In these patients combined radio- and chemotherapy induces a high percentage of tumor regression and can be used before secondary resection (5-year survival 5-20 %). Locally advanced tumors infiltrating the main bronchus close to the carina or the carina itself and tumors with metastases in the same lobe, both without mediastinal lymph node metastases (T3/4N0-1), can be resected by sleeve pneumonectomy and lobectomy with satisfactory results respectively. In patients with resectable lung cancer and no clinical sign of tumor disease (f. e. anemia, weight loss, pain) limited staging procedure with chest CT scan including upper abdomen and bronchoscopy is reasonable. In the remaining patients complete staging is necessary. We recommend an interdisciplinary approach to patients with lung cancer.     

Does Surgical Resection of Pulmonary Metastases of Head and Neck Cancer Improve Survival?

Background  The prognosis of patients with metastasized head and neck cancer is poor. Limited experience exists with the benefit of resection of lung metastases and systematic mediastinal and hilar lymph node dissection on survival of patients with head and neck carcinoma. Methods  Eighty patients undergoing metastasectomy for pulmonary metastases of primary head and neck cancer entered the study. Multivariate analysis was performed by Cox regression analysis. Survival differences between patients operated and those not operated on were analyzed by matched pair analysis. Results  From 1984 until 2006, pulmonary metastases were diagnosed in 332 patients treated for head and neck cancer; 80 of these were admitted to our department for resection. Metastases of the primary head and neck tumor were confirmed histologically in 67 patients. The median overall survival after resection of lung metastases was 19.4 months and was statistically significantly better compared with patients who were not operated on (P < .001). The multivariate analysis after metastasectomy revealed that incomplete resection of pulmonary lesions, complications associated with surgery, and adjuvant therapy of the primary tumor are independent negative prognostic factors for survival. We observed a trend to improved survival in patients without hilar or mediastinal lymph node metastases. Conclusion  The survival rate of patients operated on was statistically significantly higher than that of patients with conservative treatment. Even patients with multiple or bilateral pulmonary lesions after curative treatment of a primary tumor should be operated on if there is no contraindication against an extended surgical procedure and a complete resection of the metastases seems achievable. The first two authors contributed equally to this work.     

ESTS guidelines for preoperative lymph node staging for non-small cell lung cancer.

Accurate preoperative staging and restaging of mediastinal lymph nodes in patients with non-small cell lung cancer (NSCLC) is of paramount importance. It will guide choices of treatment and determine prognosis and outcome. Over the last years, different techniques have become available. They vary in accuracy and procedure-related morbidity. The Council of the ESTS initiated a workshop on preoperative mediastinal lymph node staging. This resulted in guidelines for primary staging and restaging. For primary staging, mediastinoscopy remains the gold standard for the superior mediastinal lymph nodes. Invasive procedures can be omitted in patients with peripheral tumors and negative mediastinal positron emission tomography (PET) images. However, in case of central tumors, PET hilar N1 disease, low fluorodeoxyglucose uptake of the primary tumor and LNs > or = 16 mm on CT scan, invasive staging remains indicated. PET positive mediastinal findings should always be cyto-histologically confirmed. Transbronchial needle aspiration (TBNA), ultrasound-guided bronchoscopy with fine needle aspiration (EBUS-FNA) and endoscopic esophageal ultrasound-guided fine needle aspiration (EUS-FNA) are new techniques that provide cyto-histological diagnosis and are minimally invasive. Their specificity is high but the negative predictive value is low. Because of this, if they yield negative results, an invasive surgical technique is indicated. However, if fine needle aspiration is positive, this result may be valid as proof for N2 or N3 disease. For restaging, invasive techniques providing cyto-histological information are advisable despite the encouraging results supported with the use of PET/CT imaging. Both endoscopic techniques and surgical procedures are available. If they yield a positive result, non-surgical treatment is indicated in most patients.     

Prognostic impact of lymph node involvement in pulmonary metastases from colorectal cancer.

OBJECTIVE: The purpose of this study was to identify the prognostic impact of unexpected lymph node metastases in patients undergoing resection of pulmonary metastases from colorectal cancer and specify the influence of pulmonary and mediastinal nodal involvement according to the modified Narukes lymph node mapping [Mountain CF, Dresler CM. Regional lymph node classification for lung cancer. Chest 1997;111(6):1718-23.]. METHODS: From January 1993 to December 2003, 175 patients were diagnosed and resected for pulmonary metastases of colorectal cancer. Follow up informations were collected for 169 patients and an analysis of prognostic factors was performed. Ninety-six men (56.8%) and 73 women (43.2%) with a median age of 62 (range 34-81) were identified, 28 (16.7%) patients were found to have lymph node metastases, five of them were identified during a recurrent procedure. Probability of survival was calculated according to the method of Kaplan-Meier. The prognostic influence of lymph node metastases on survival was analyzed with the log-rank test. RESULTS: Median survival was 47.2 months after first metastasectomy. Ten patients with intrapulmonary nodal involvement had a median survival of 86 months whereas 12 patients with hilar and six patients with mediastinal lymph node metastases had a median survival of 24.5 and 34.7 months. The survival difference between pulmonary and hilar/mediastinal metastases was statistically significant (p=0.008/p=0.07). Five year survival with pulmonary, hilar, and mediastinal metastases was 78.5, 0, and 0%, respectively. Perioperative mortality was 0%. CONCLUSIONS: Resection of pulmonary metastases secondary to colorectal cancer is safe and indicated in highly selected patients. Because tumor involvement of lymph nodes has a strong impact on survival; depending on their location, at least a lymph node sampling should always be performed. Adjuvant chemotherapy in case of proven lymph node metastases might be a good option to improve prognosis.     

Limited operation of lung cancer: the role of video-assisted thoracic surgery for lung cancer

Lobectomy with systemic nodal dissection is recognized as a standard operation for lung cancer. Partial resection and segmental resection are classified as limited resections for lung cancer to preserve pulmonary function. Minor complications occur more frequently with limited resection than with lobectomy. Partial resection of the lung and simple lobectomy can be performed as video-assisted thoracic surgery (VATS). Systemic hilar and mediastinal lymph node dissection is not yet standardized using VATS. On the other hand, VATS preserves chest wall muscles. The difference between standard thoracotomy and VATS is a difference of approach to the thoracic cavity. It is most important for lung cancer surgery to be performed in the thoracic cavity with the minimum burden on patients.     

Accuracy of computed tomographic scan and surgical assessment for staging of bronchial carcinoma. A prospective study.

There is an increasing demand for accurate preoperative and intraoperative staging of bronchial carcinoma with respect to neoadjuvant therapy protocols and parenchyma-sparing operations. This study prospectively evaluated accuracy of computed tomographic scan and surgical assessment for staging of bronchial carcinoma in 108 consecutive patients. The stage of the primary tumor (T stage) was correctly determined in 85% of the patients, and surgical evaluation correctly determined the T stage in 92%. Invasion of major mediastinal structures posed a major problem for computed tomographic scan. On a node-by-node basis, computed tomographic scan predicted involvement of lymph nodes in 81% (sensitivity 29%, specificity 93%, positive predictive value 49%, negative predictive value 85%). The surgeon correctly determined the lymph node status in 69% of lymph nodes (sensitivity 90%, specificity 63%, positive predictive value 39%, negative predictive value 96%). On a patient-by-patient basis, computed tomographic scan correctly predicted the nodal status in 58% of patients. Accuracy of computed tomographic scan and surgical assessment in determination of the lymph node status strongly depended on tumor type and lymph node region (hilar or mediastinal region) studied. This was partly due to the fact that adenocarcinomas exhibited a high proportion of tumor-positive normal-sized lymph nodes, whereas squamous cell carcinomas showed a high proportion of enlarged tumor-free lymph nodes. In conclusion, computed tomographic scan and surgical assessment are sufficiently accurate for determination of the tumor stage but are insufficient in determining the nodal status.