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 significance of preoperative serum carcinoembryonic antigen level in lung adenocarcinoma but not squamous cell carcinoma.

OBJECTIVES: Clinical significance of measurement of preoperative serum carcinoembryonic antigen (CEA) level in patients with non-small cell lung cancer was investigated. METHODS: Consecutive 271 adenocarcinoma and 112 squamous cell carcinoma patients of non-small cell lung cancer referred to our institute were included in this study. There were 214 men and 169 women, ages ranged from 19 to 90 years, with an average of 64.46 years. Curative resection was performed for 220 adenocarcinoma and 93 squamous cell carcinoma patients. Serum level of CEA was measured before staging or resection of cancer. RESULTS: There is a trend toward a correlation between serum CEA level and stage of the diseases, however, serum CEA level was not always related to tumor node metastasis (TNM) status. In patients with adenocarcinoma, survival rate of patients with an elevated serum CEA level was significantly lower than that with a normal serum CEA level. Multivariate analysis showed that prognostic significance of serum CEA level was TNM staging independent in patients with adenocarcinoma. On the other hand, serum CEA level was not related to patients' survival in patients with squamous cell carcinoma. CONCLUSIONS: Elevated preoperative serum CEA level is a TNM staging independent prognostic factor for patients with adenocarcinoma but not for those with squamous cell carcinoma.     

支气管内超声引导针吸活检术在非小细胞肺癌术前分期中的临床应用

目的探讨支气管内超声引导针吸活检术(EBUS-TBNA)在非小细胞肺癌纵隔淋巴结分期中的应用价值。 方法2010年9月至2012年9月,北京大学人民医院利用EBUS-TBNA对术前确诊或CT扫描高度怀疑非小细胞肺癌且伴有纵隔淋巴结肿大(N₂站淋巴结短径≥1.0cm,或N₁站淋巴结短径≥1.0cm且N₂多站短径≥0.5cm者),有手术切除可能,术前无放、化疗史的126例患者进行纵隔淋巴结分期。最终入组82例非小细胞肺癌患者。 结果该组82例患者,经EBUS-TBNA检查证实纵隔淋巴结转移(阳性)者54例,未见纵隔淋巴结转移(阴性)者28例。EBUS-TBNA在该组肺癌术前纵隔淋巴结分期中的敏感度、特异度和准确性分别为94.7%(54/57)、100.0%(25/25)和96.3%(79/82),阳性预测值及阴性预测值分别为100.0%(54/54)和89.3%(25/28)。而CT对于本组患者纵隔淋巴结分期中的敏感度、特异度和准确性分别为98.2%(55/56)、38.5%(10/26)和79.3%(65/82),阳性预测值及阴性预测值分别为77.5%(55/71)和90.9%(10/11)。CT在术前纵隔淋巴结分期中的假阳性率为22.5%(16/71)。全组中,16例(19.5%)肺癌患者因EBUS-TBNA病理结果改变了治疗策略。 结论EBUS-TBNA用于非小细胞肺癌纵隔淋巴结分期的敏感性、特异性和准确性较高。EBUS-TBNA可以作为非小细胞肺癌术前分期、指导治疗策略的检查手段。     

Invasive staging of non-small cell lung cancer--a prospective study.

OBJECTIVES: Clinical prognosis and treatment schedules of non-small cell lung cancer (NSCLC) are dependent on tumor stage. This explains the importance of an exact pretreatment staging of the primary tumor and lymph nodes especially in locally advanced NSCLC, to differentiate between resectable and non-resectable disease. To assess the lymph node status of the upper mediastinum, the diagnostic value of mediastinoscopy is accepted to be superior to radiological methods. In contrast, thoracoscopy is not yet established as a standard staging tool. PATIENTS AND METHODS: Seventy-three consecutive patients with CT-based suspicion of advanced NSCLC have been investigated as part of a phase II study on neoadjuvant treatment of NSCLC. All patients underwent mediastinoscopy and mediastinal lymph node sampling. In the case of a negative result we performed additional thoracoscopy. RESULTS: In 52.1% (n = 38) of the patients the invasive diagnostic methods led to results that were effectively different from those of the radiological findings. In 11 patients (15.1%) CT-assessed lymph node metastases could invasively not be confirmed, whereas nine patients (12.3%) had positive mediastinal lymph nodes but no corresponding CT signs (diameter <1 cm). The results were achieved by mediastinoscopy in 15 (20.5%) and by thoracoscopy in five (6.8.%) patients. A radiologically unexpected T4 stage has been found in four (5.5%) and a M1 stage in four (5.5%) patients by thoracoscopy. On the contrary, in seven patients a suspected infiltration of mediastinum or parietal pleura could be thoracoscopically excluded. Four patients have been in an unexpected high stage of tumor progression at the moment of diagnostic procedures and therefore have been included in palliative therapy schedules. Ten patients have been 'overstaged' by radiological methods and benefited from a primarily curative resection after invasive staging. CONCLUSIONS: Of the 73 prospectively studied patients with locally advanced NSCLC, 12 (16.4%) have been staged too low and 13 (17.8%) too high. If exclusively staged by radiological methods, about 34% of lung cancers have been classified incorrectly. Therefore, these tools are not a sufficient basis for diagnosis of stage III NSCLC disease. Mediastinoscopy with consecutive thoracoscopy is an essential part of the therapeutic planning in locally advanced NSCLC, and results are significantly superior to clinical staging.     

PET, CT, and MRI with Combidex for mediastinal staging in non-small cell lung carcinoma.

BACKGROUND: To determine the relative utility of positron emission tomography (PET), computed tomography (CT), and magnetic resonance imaging with Combidex (MRI-C) in the non-invasive staging of non-small cell lung cancer (NSCLC) mediastinal lymph nodes (MLN), we compared the three tests' individual performance with surgical mediastinal sampling. In contrast to prior studies, cytology was not used. METHODS: The MLN were evaluated using PET and CT in 64 NSCLC patients. MRI-C was performed in 9 of these patients. MLN with a PET standard uptake value greater than or equal to 2.5, or greater than 1 cm in the short axis by CT or lack of MRI-C signal change were considered positive for metastatic disease. All MLN were sampled and subjected to standard pathologic analysis. PET, CT, and MRI-C scans were interpreted blinded to the histopathological results. Sensitivity, specificity, and accuracy for each scan type to appropriately stage MLN was determined using pathologic results as the standard. RESULTS: Thirty patients had stage I disease, 8 stage II, 9 stage IIIA, 7 stage IIIB, and 10 stage IV. Two-hundred-and-thirty MLN were sampled. Sixteen patients had metastatic mediastinal disease. Compared to the pathological results, PET, CT, and MRI-C had a sensitivity, specificity, and accuracy of 70%, 86%, 84%; 65%, 79%, 76%; 86%, 82%, and 83%, respectively. PET and MRI-C were statistically more accurate than CT (p<0.001). In cases where PET and CT did not identify MLN involvement with NSCLC, 8% (2/25) were pathologically positive. CONCLUSIONS: PET and MRI-C are statistically more accurate than CT. However, the differences are small and may not be clinically relevant. No technique was sensitive or specific enough to change the current recommendation to perform mediastinoscopy for MLN staging in NSCLC.     

Comparison of clinical and surgical-pathologic staging of the patients with non-small cell lung carcinoma

Objective: Clinical staging of non-small cell lung cancer helps to determine the extent of disease and separate patients with potentially resectable disease from those that are unresectable. Since, clinical staging is based on radiologic and bronchoscopic findings, overstaging or understaging may occur comparing to the final surgical-pathologic evaluation. We aimed to analyze preoperative and postoperative stagings in order to evaluate stage migrations and our surgical strategy for marginally resectable patients. Methods: We did a retrospective analysis of 180 patients with non-small cell lung cancer who underwent resectional surgery between 1994 and 2000. In all patients, a thoracic computerized tomography and bronchoscopy were performed to define clinical staging (cTNM). Results: In 86 patients (47.7%) clinical and surgical-pathologic staging concurred. When comparing T subsets alone, correct staging, overstaging and understaging occurred in 133 (73.9%), 28 (15.5%), 47 (26.1%) patients, respectively. Only 13 of 21 patients (61.9%) who were thought to have T4 tumor preoperatively were found to have pT4. Also six patients with cT2 and five patients with cT3 were subsequently found to have T4 disease according to pathology. Clinical staging overestimated the nodal staging in 35 patients (19.4%), while underestimated the lymph node involvement in 45 patients (25%). Conclusion: Construction of cTNM stage remains a crude evaluation, preoperative mediastinoscopy in every patient must be performed. Preoperative limited T4 disease is not to deny surgery to patients since a considerable number of patients with cT4 are to be understaged following surgery.     

Improving clinical efficacy of computed tomographic scan in the preoperative assessment of patients with non-small cell lung cancer

The criterion of choice for computed tomographic scan identification of metastatic mediastinal nodes is not clearly fixed. This prospective study was designed to define the most suitable computed tomographic criterion for detection of nodal metastasis, enabling improvement of the test's clinical efficacy. One hundred twenty-three patients with potentially operable non-small cell lung cancer underwent mediastinal evaluation by computed tomographic scan and cervical mediastinoscopy followed by thoracotomy with mediastinal node dissection. There were 116 men and seven women; the mean age was 59.3 +/- 9.1 years. Forty-six tumors were classified after operation as stage I, 20 as stage II, 27 as stage IIIa, and 30 as stage IIIb. Mediastinal nodes were classified as metastatic according to the following computed tomographic scan criteria: (1) shorter axis 1 cm or larger; (2) shorter axis 1.5 cm or larger (nodes less than 1 cm were classified as negative and those 1 to 1.5 cm as indeterminate); and (3a) shorter axis 1 cm or larger, plus evidence of central necrosis or discontinued capsule, or (3b) shorter axis 2 cm or more, regardless of the nodal morphologic condition. The highest sensitivity rate was achieved by using criterion 1 (90%) and the poorest by criterion 3 (75%). The greatest specificity rate was obtained by applying criterion 3 (90%) and the lowest by criterion 1 (54%). The prediction by using computed tomographic criterion 3 correlated better with pathologic findings than that derived by adopting the criterion 1 or 2. When mediastinal nodes were identified as negative according to criterion 1, 2, or 3, the complete resection rate was 92%, 92%, or 95%, respectively, rendering cervical mediastinoscopy unnecessary. When mediastinal nodes were classified as positive, the resectability rate was 55%, 27%, or 13%, respectively. In these instances cervical mediastinoscopy allowed identification of different degrees of mediastinal involvement; it proved to be the most useful procedure for preoperative selection of those patients with N2 tumors who are amenable to a complete resection. In conclusion, the use of computed tomographic criterion 3 does improve the clinical efficacy of the test, by sparing a large number of unnecessary mediastinal explorations, without increasing the rate of useless thoracotomies.     

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.     

Morbidity after surgery for non-small cell lung carcinoma is not related to neoadjuvant chemotherapy.

OBJECTIVES: To compare postoperative morbidity and mortality rates in two groups of operated non-small cell lung carcinoma patients (NSCLC) with or without induction chemotherapy. METHODS: This is a case-control study on 42 cases and 42 controls. Cases (Group A) underwent induction chemotherapy. Chemotherapy indications and regimens were variable. Control cases (Group B) were randomly selected among 494 NSCLC comparable patients operated on in the same period of time. The selection criteria for operation were the same in both groups. Dependent outcomes were operative death and complications. Independent selected variables were: age, co-morbidity, predicted postoperative FEV1% (1 s forced expiratory volume in percentage), type of surgery and clinical and pathological staging. All postoperative events and independent variables were prospectively registered. Chi-square and risk calculations on contingence tables and one-way ANOVA have been tested. RESULTS: Both series are comparable in demographics, preoperative variables and type of surgery. No mortality has been registered. In Group A, the overall morbidity was 26.2% (11 out of 42 cases), and in Group B, this was 42.9% (18 out of 42 cases; P=0.084). Morbidity was not related to the type of surgery (pneumonectomy vs. other; P=0.205 in Group A and P=0.08 in Group B). Pathological staging did not influence the postoperative outcome, either in Group A (P=0.72; odds ratio, 1.515; 95% confidence interval (CI), 0.375-6.122) or Group B (P=0.299; odds ratio, 0.4; 95% CI, 0.089-1.797). CONCLUSIONS: Induction chemotherapy in NSCLC has no influence on postoperative morbidity.     

Integrated FDG-PET/CT does not make invasive staging of the intrathoracic lymph nodes in non-small cell lung cancer redundant: a prospective study

BACKGROUND: Staging of non-small cell lung cancer (NSCLC) is important for determining choice of treatment and prognosis. The accuracy of FDG-PET scans for staging of lymph nodes is too low to replace invasive nodal staging. It is unknown whether the accuracy of integrated FDG-PET/CT scanning makes invasive staging redundant. METHODS: In a prospective study, the mediastinal and/or hilar lymph nodes in patients with proven NSCLC were investigated with integrated FDG-PET/CT scanning. Pathological confirmation of all suspect lymph nodes was obtained to calculate the accuracy of the fusion images. In addition, the use of the standardised uptake value (SUV) in the staging of intrathoracic lymph nodes was analysed. RESULTS: 105 intrathoracic lymph node stations from 52 patients with NSCLC were characterised. The prevalence of malignancy in the lymph nodes was 36%. The sensitivity of the integrated FDG-PET/CT scan to detect malignant lymph nodes was 84% and its specificity was 85% (positive likelihood ratio 5.64, negative likelihood ratio 0.19). SUV(max), SUV(mean) and the SUV(max)/SUV(liver) ratio were all significantly higher in malignant than in benign lymph nodes. The area under the receiver operating curve did not differ between these three quantitative variables, but the highest accuracy was found with the SUV(max)/SUV(liver) ratio. At a cut-off value of 1.5 for the SUV(max)/SUV(liver )ratio, the sensitivity and specificity to detect malignant lymph node invasion were 82% and 93%, respectively. CONCLUSION: The accuracy of integrated FDG-PET/CT scanning is too low to replace invasive intrathoracic lymph node staging in patients with NSCLC. The visual interpretation of the fusion images of the integrated FDG-PET/CT scan can be replaced by the quantitative variable SUV(max)/SUV(liver) without loss of accuracy for intrathoracic lymph node staging.     

肺内淋巴结精准取材对肺癌患者术后N分期的影响

目的探讨非小细胞肺癌(NSCLC)患者肺内淋巴结转移情况及其对病理分期的影响。 方法选取2015年1月1日至2016年3月31日期间在天津市胸科医院胸外科接受肺叶或全肺切除及系统性淋巴结清扫术的177例肺癌患者进行分析。首先按照外科医师清扫的淋巴结常规取材进行病理诊断,得出N分期;由病理科医师再对第12、13组淋巴结进行分检精准取材,得出一个新的N分期,比较并分析前后两个N分期的差异。同时,进一步分析这两组淋巴结转移的危险因素。 结果全组患者共检出N1站淋巴结1 268枚,常规取材(第10、11组淋巴结)共检出736枚,精准取材(第12、13组淋巴结)共检出532枚。联合NSCLC的常规取材和肺内淋巴结的精准取材,患者的N1淋巴结检出的中位数为7枚(2～24枚),与NSCLC的常规取材相差4枚(0～18枚),N1淋巴结的检出数明显增加(P<0.001)。联合NSCLC的常规取材和肺内淋巴结的精准取材,共检出转移N1淋巴结240枚,中位转移数量为0枚(区间：0～7枚;第75百分位数：1枚;第90百分位数：3枚),与NSCLC的常规取材相比(区间：0～5枚;第75百分位数：0枚;第90百分位数：2枚),N1淋巴结的转移个数明显增加(P<0.001)。分层分析结果显示：第12、13组淋巴结的转移与手术方式、手术部位、病理类型、肿瘤大小以及纵隔淋巴结转移存在一定相关性(P<0.05),但与患者的年龄、性别以及术后病理是否存在脉管癌栓无明显相关性(P>0.05)。有15例患者的N分期由于肺内淋巴结的精准取材由N0升为N1,占全组患者的8.4%。 结论常规NSCLC取材方式容易漏检N1区域的淋巴结,并且相当一部分还是转移淋巴结。因此,提倡NSCLC肺内淋巴结精准取材以提高病理分期的准确性。     

非小细胞肺癌分期的分子影像学研究进展

分子影像学是当今医学研究的热点之一。本文主要综述几种常用分子影像学成像技术在非小细胞肺癌（NSCLC）TNM分期中的应用。     

A biological staging model for operable non-small cell lung cancer

BACKGROUND: Currently the best prognostic index for operable non-small cell lung cancer (NSCLC) is the TNM staging system. Molecular biology holds the promise of predicting outcome for the individual patient and identifying novel therapeutic targets. Angiogenesis, matrix metalloproteinases (MMP)-2 and -9, and the erb/HER type I tyrosine kinase receptors are all implicated in the pathogenesis of NSCLC. METHODS: A retrospective analysis of 167 patients with resected stage I-IIIa NSCLC and >60 days postoperative survival with a minimum follow up of 2 years was undertaken. Immunohistochemical analysis was performed on paraffin embedded sections for the microvessel marker CD34, MMP-2 and MMP-9, EGFR, and c-erbB-2 to evaluate the relationships between and impact on survival of these molecular markers. RESULTS: Tumour cell MMP-9 (HR 1.91 (1.23-2.97)), a high microvessel count (HR 1.97 (1.28-3.03)), and stage (stage II HR 1.44 (0.87-2.40), stage IIIa HR 2.21 (1.31-3.74)) were independent prognostic factors. Patients with a high microvessel count and tumour cell MMP-9 expression had a worse outcome than cases with only one (HR 1.68 (1.04-2.73)) or neither (HR 4.43 (2.29-8.57)) of these markers. EGFR expression correlated with tumour cell MMP-9 expression (p<0.001). Immunoreactivity for both of these factors within the same tumour was associated with a poor prognosis (HR 2.22 (1.45-3.41)). CONCLUSION: Angiogenesis, EGFR, and MMP-9 expression provide prognostic information independent of TNM stage, allowing a more accurate outcome prediction for the individual patient. The development of novel anti-angiogenic agents, EGFR targeted therapies, and MMP inhibitors suggests that target specific adjuvant treatments may become a therapeutic option in patients with resected NSCLC.