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Pulmonary neuroendocrine tumors that arise from Kulchitzky cells of the bronchial mucosa consist of a spectrum of histologic features leading to a variable prognosis. Although typical carcinoid represents the most benign course, small-cell cancer has the grimmest outcome. Therefore, differentiating the spectrum of neuroendocrine tumors helps one not only to determine the prognosis, but also to guide the treatment options. In this part, we aim to discuss the treatment options in pulmonary neuroendocrine tumors except for small-cell lung cancer.

Pulmonary neuroendocrine tumors arise from Kulchitzky cells of the bronchial mucosa and include typical carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma, and small cell lung cancer. These tumors have a variable growth rate that determines their presentation and prognosis. Typical carcinoid has the lowest growth rate and better prognosis; in contrast, small cell lung cancer is an aggressive tumor with a very poor prognosis. Although there are some overlapping histologic features between these tumors, clinical, imaging, and immunohistochemical markers are useful in the differentiation of pulmonary neuroendocrine tumors. The treatment options differ on the basis of histologic characteristics. In this article, we aim to describe the spectrum of neuroendocrine tumors of the lung, except for small cell lung cancer, and their clinical, pathologic, and imaging findings, with a focus on treatment options.

Background: Mediastinal staging in patients with non-small cell lung cancer (NSCLC) with endobronchial ultrasound-guided fine-needle aspiration (EBUS-FNA) requires a high negative predictive value (NPV) (ie, low false negative rate). We provide a conservative calculation of NPV that calls for caution in the interpretation of EBUS results., Methods: We retrospectively analyzed our prospectively gathered database (January 2007 to November 2011) to include NSCLC patients who underwent EBUS-FNA for mediastinal staging. We excluded patients with metastatic NSCLC and other malignancies. We assessed FNAs with rapid on-site evaluation (ROSE). The calculation of NPV is NPV = true negatives/true negatives + false negatives. However, this definition ignores nondiagnostic samples. Nondiagnostic samples should be added to the NPV denominator because decisions based on nondiagnostic samples could be flawed. We conservatively calculated NPV for EBUS-FNA as NPV = true negatives/true negatives + false negatives + nondiagnostic. We defined false negatives as negative FNAs but NSCLC-positive surgical biopsy of the same site. Nondiagnostic FNAs were nonrepresentative of lymphoid tissue. We compared diagnostic performance with the inclusion and exclusion of nondiagnostic procedures., Results: We studied 120 patients with NSCLC who underwent EBUS-FNA; 5 patients had false negative findings and 10 additional patients had nondiagnostic results. The NPV with and without inclusion of nondiagnostic samples was 65.9% and 85.3%, respectively., Conclusions: The inclusion of nondiagnostic specimens into the conservative, worst-case-scenario calculation of NPV for EBUS-FNA in NSCLC lowers the NPV from 85.3% to 65.9%. The true NPV is likely higher than 65.9% as few nondiagnostic specimens are false negatives. Caution is imperative for the safe application of EBUS-FNA in NSCLC staging., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The effect of tumor location on long-term survival after lobectomy for stage I non-small-cell lung cancer is unclear. Current data are limited to a retrospective single-institution series. We sought to determine if tumor anatomic location (i.e., the particular lobe that was involved) confers a survival advantage based on population-based data., Methods: Using the Surveillance, Epidemiology and End Results database (1988-2007), we identified patients who underwent lobectomy for pathologic T1/T2 adenocarcinoma or squamous cell carcinomas. Wedge resections, segmentectomies, and pneumonectomies were excluded. We evaluated the association between the particular lobe that was involved, lymph node (LN) yield, and survival using the Kaplan-Meier method. To adjust for potential confounders, we used a Cox proportional hazards regression model., Results: We identified 13,650 patients who met our inclusion criteria. There were significant differences in unadjusted overall (P=0.03) and cancer-specific survivals (P=0.03) based on tumor location. However, after adjusting for patient factors, geographic location of treatment, and tumor characteristics, we found that tumor location was not associated with significant differences in survival. We found that male gender, black race, squamous cell histology, increasing grade, and age were independent negative predictors of survival. Higher LN yields were independently associated with improved survival. Although adjusted survival rates were not significantly different, there were significant differences (P<0.0001) in LN yield based on tumor location; right middle lobe had the lowest yield (5.1 nodes), and left upper lobe had the highest yield (eight nodes)., Conclusions: LN counts are independent predictors of survival. Although it is associated with significant difference in LN yield, tumor location is not an independent predictor of survival. Age, race, gender, tumor size, histology, and grade appear to be more important prognostic factors. These data suggest that treatment of T1/T2 non-small-cell lung cancer should be dictated by the same oncologic principles, regardless of tumor location., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: Surgical resection is standard treatment for early-stage non-small cell lung cancer; however, perception of postoperative risk may influence the decision to proceed for elderly patients. With population data, we analyzed postoperative complications and morbidity predictors for older patients undergoing lobectomy for stage I non-small cell lung cancer., Methods: The Surveillance Epidemiology and End-Results-Medicare linked database (2000-2005) identified patients (ages 66-80 years) undergoing lobectomy for stage I non-small cell lung cancer. We comprehensively evaluated in-hospital postoperative complications (pulmonary, cardiac, infectious, noncardiopulmonary) with International Classification of Diseases, Ninth Revision, diagnosis codes. Logistic regression models were constructed to identify patient, tumor, and treatment characteristics associated with complications., Results: In all, 4171 patients were included, 2329 of whom had 4097 in-hospital postoperative complications (55.8%). Pulmonary complications were most common (n = 1598; 38.3%) followed by cardiac (n = 1020; 24.5%). Complications were significantly associated with age at least 75 years, male sex, higher comorbidity index, larger tumors, and treatment at nonteaching hospitals (P < .05). Patients with complications had a longer median stay (8 days) than patients without (6 days; P < .001). The 30-day mortality was 4.2%., Conclusions: Population-based analysis demonstrated that perioperative complications after lobectomy for stage I non-small cell lung cancer in older patients exceeded 50% and were associated with specific patient, tumor, and treatment characteristics. Better understanding of the impact of these risk factors may facilitate surgical decision making and encourage implementation of more effective perioperative care guidelines for older surgical patients., (Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: We used a population-based data set to assess the association between the extent of pulmonary resection for bronchoalveolar carcinoma and survival. The reports thus far have been limited to small, institutional series., Methods: Using the Surveillance, Epidemiology, and End Results database (1988-2007), we identified patients with bronchoalveolar carcinoma who had undergone wedge resection, segmentectomy, or lobectomy. The bronchoalveolar carcinoma histologic findings were mucinous, nonmucinous, mixed, not otherwise specified, and alveolar carcinoma. To adjust for potential confounders, we used a Cox proportional hazards regression model., Results: A total of 6810 patients met the inclusion criteria. Compared with the sublobar resections (wedge resections and segmentectomies), lobectomy conferred superior 5-year overall (59.5% vs 43.9%) and cancer-specific (67.1% vs 53.1%) survival (P < .0001). After adjusting for potential confounding patient and tumor characteristics, we found that patients who underwent an anatomic resection had significantly better overall (segmentectomy: hazard ratio, 0.59; 95% confidence interval, 0.43-0.81; lobectomy: hazard ratio, 0.50; 95% confidence interval, 0.44-0.57) and cancer-specific (segmentectomy: hazard ratio, 0.51; 95% confidence interval, 0.34-0.75; lobectomy: hazard ratio, 0.46; 95% confidence interval, 0.40-0.53) survival compared with patients who underwent wedge resection. Additionally, gender, race, tumor size, and degree of tumor de-differentiation were negative prognostic factors. Our results were unchanged when we limited our analysis to early-stage disease., Conclusions: Using a population-based data set, we found that anatomic resections for bronchoalveolar carcinoma conferred superior overall and cancer-specific survival rates compared with wedge resection. Bronchoalveolar carcinoma's propensity for intraparenchymal spread might be the underlying biologic basis of our observation of improved survival after anatomic resection., (Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background: Data comparing survival after lobectomy versus that after segmentectomy for stage I non-small cell lung cancer (NSCLC) are limited to single-institution observational studies and 1 clinical trial. We sought to determine if lobectomy offers a survival advantage over segmentectomy for stage I NSCLC based on population-based data., Methods: Using the Surveillance Epidemiology and End Results (SEER) database (1998 to 2007), we identified patients who underwent either anatomic segmentectomy or lobectomy. Wedge resections were excluded. Analysis was limited to patients with stage I adenocarcinoma or squamous cell carcinoma. After stratifying patients based on tumor size (less than or equal to 2.0 cm, 2.1 to 3.0 cm, and 3.1 to 7.0 cm), we assessed for association between extent of resection and survival using the Kaplan-Meier method. To adjust for potential confounding variables, we used Cox proportional hazards regression models., Results: There were 14,473 patients who met our inclusion criteria. Lobectomy conferred superior unadjusted overall (p < 0.0001) and cancer-specific (p = 0.0053) 5-year survival compared with segmentectomy. Even after adjusting for patient factors, tumor characteristics, and geographic location, we noted that patients who underwent lobectomy had superior overall and cancer-specific survival rates, regardless of tumor size. Squamous cell histologic type, male sex, low lymph node counts, and increasing age, tumor size, and grade were all independent negative prognostic factors., Conclusions: Using a population-based data set, we found that lobectomy confers a significant survival advantage compared with segmentectomy. Our results provide additional evidence supporting the role of lobectomy as the standard of care for resection of stage I NSCLC regardless of tumor size., (Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: Surgical morbidity may influence long-term cancer survival. Because resection of early stage nonsmall cell lung cancer (NSCLC) is primary therapy, we sought to determine the survival impact of surgical complications for elderly patients undergoing resection of stage I NSCLC., Methods: Using the linked Surveillance Epidemiology and End Results-Medicare database (2000-2005), we identified elderly patients who underwent lobectomy for stage I NSCLC. We then assessed the unadjusted association between in-hospital, postoperative complications, and long-term survival for patients who survived more than 30 days after resection using the Kaplan-Meier method. Finally, we used Cox proportional hazards regression to evaluate the relationship between postoperative complications and 5-year cancer-specific (CSS) and overall survival (OS) after adjusting for patient, tumor, and treatment characteristics., Results: We identified 3996 eligible patients. The overall in-hospital, postoperative complication rate was 54.2%. Pulmonary complications were the most common (n = 1464) followed by cardiac (n = 916). Unadjusted 5-year CSS was significantly worse for those who had an in-hospital, postoperative complication (70.9%) compared to those who did not (78.9%, P < 0.001). OS was also significantly worse (P < 0.001) for patients who developed a complication. Complications continued to predict worse 5-year CSS and OS after adjusting for patient, tumor, and treatment characteristics (HR: 1.38, 95% CI, 1.17-1.64)., Conclusions: The occurrence of in-hospital postoperative complications was an independent predictor of worse 5-year CSS after resection of stage I NSCLC. Importantly, the impact of surgical complications extends well after the initial perioperative period. These findings may help identify important targets for best practice guidelines and quality-of-care measures.

Background: Conditional cancer-specific survival rates account for changes in the risk of death from cancer over time. There may be a point during follow-up when patients who undergo lobectomy for stage I non-small cell lung cancer (NSCLC) are as likely to die of cardiovascular disease as of cancer., Methods: Using the Surveillance Epidemiology and End Results Database (1988 through 2005), we identified patients 50 years old and older who underwent lobectomy for stage I NSCLC. We used competing risks methods to calculate conditional survival rates and to ascertain if there is a point in follow-up where the risk of dying of cancer is equivalent to the risk of dying of cardiovascular disease., Results: In all, 22,518 patients met our inclusion criteria. The difference in the 5-year conditional probability of dying of cancer and the 5-year conditional probability of dying of cardiovascular disease decreased with time; in the whole cohort, these probabilities were equivalent if patients survived to 7 years after lobectomy (p = 0.11). With increasing age, the probability of dying of cancer and the probability of dying of cardiovascular disease became equivalent at earlier time points. Furthermore, the 5-year probability of dying of cardiovascular disease was significantly greater than the 5-year probability of dying of cancer for patients aged 70 to 79 years who survived to 7 years and for patients aged 80 years and older who survived to 5 years after lobectomy., Conclusions: For patients undergoing lobectomy for stage I NSCLC, cardiovascular-specific mortality becomes increasingly important over the course of follow-up, especially among elderly patients., (Copyright 2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

The current review focuses on a clinical comparison of lobectomy by means of video-assisted thoracoscopic surgery (VATS) and open lobectomy. The best available evidence strongly suggests that VATS lobectomy is less morbid than open lobectomy, and that VATS lobectomy is less immunosuppressive and elicits a milder inflammatory response than open lobectomy. Midterm to long-term oncologic results of patients with early-stage non-small cell lung cancer appear to be equivalent for VATS and open lobectomy. Because a large, prospective, randomized, multiinstitutional trial of open versus VATS lobectomy will likely never take place, we are dependent on the summarized information to draw practical conclusions., (2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: The objectives of our study are to (1) describe our experience with endobronchial ultrasound-guided fine-needle aspiration of mediastinal lymph nodes and (2) illustrate how thoracic surgeons facile with ultrasound-guided fine-needle aspiration have the potential to streamline patient care., Methods: We performed a retrospective review of all patients within our prospectively maintained database who underwent endobronchial ultrasound-guided fine-needle aspiration of mediastinal lymph nodes by thoracic surgeons at the University of Minnesota from September 1, 2006, to April 15, 2009. We included patients in our analysis if (1) their malignancy diagnosis was based on immediate endobronchial ultrasound-guided fine-needle aspiration cytology or (2) they underwent a confirmatory procedure (ie, mediastinoscopy or thoracoscopy) that sampled the same mediastinal lymph node stations biopsied by endobronchial ultrasound-guided fine-needle aspiration to verify normal, benign, or nondiagnostic endobronchial ultrasound-guided fine-needle aspiration findings. We also collected data on additional diagnostic or therapeutic procedures performed in the same anesthesia setting as endobronchial ultrasound-guided fine-needle aspiration., Results: Over the study period, 192 patients underwent endobronchial ultrasound-guided fine-needle aspiration; 98 patients met our inclusion criteria. We achieved a sensitivity of 87.9%, specificity of 97.4%, and diagnostic accuracy of 91.7%. For patients undergoing lung cancer staging, we sampled a mean of 3.0 +/- 0.9 mediastinal lymph node stations. Half of our patients underwent an additional diagnostic or therapeutic procedure at the time of endobronchial ultrasound-guided fine-needle aspiration., Conclusion: Thoracic surgeons who perform endobronchial ultrasound-guided fine-needle aspiration can achieve excellent sensitivity, specificity, and diagnostic accuracy while adhering to sound oncologic principles. Endobronchial ultrasound-guided fine-needle aspiration adds to the thoracic surgeon's unique capacity to expedite a diagnostic workup and treatment, thereby streamlining patient care., (Copyright 2010. Published by Mosby, Inc.)

Mediastinoscopy is the gold standard for mediastinal lymph node (MLN) staging for non-small cell lung cancer patients; however, mediastinoscopy is invasive and allows access to a limited number of American Thoracic Society MLN stations (1, 2, 3, 4, and 7). Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is emerging as a useful, less invasive staging technique that offers access to a wider range of MLN stations (2, 3, 4, 7, 10, and 11). Although EBUS-TBNA has excellent sensitivity and diagnostic accuracy, an alternative MLN biopsy technique (i.e., mediastinoscopy or thoracoscopy) is required to confirm negative cytology findings, especially after induction therapy. Additionally, an experienced cytopathologist is critical to establishing an effective EBUS-TBNA program.

Background: Video-assisted thoracoscopic surgery (VATS) for patients with early-stage non-small-cell lung cancer is associated with lower stress responses and potentially improved outcomes, as compared with thoracotomy. The goal of our study was to examine the cellular components of the postoperative immune response. Specifically, we assessed the cytotoxic capacity of peripheral blood mononuclear cells (PBMCs) of patients undergoing lobectomy for non-small-cell lung cancer by either VATS or thoracotomy., Methods: We performed a prospective cohort study of lobectomy patients undergoing either VATS or thoracotomy. We isolated PBMCs from perioperative blood samples, and performed cytokine analysis on plasma fractions. Using flow cytometry, we analyzed PBMC phenotype (CD3, CD16/56, CD4, CD8) and T-cell activation markers (CD25, CD69, HLA-DR). Using a chromium release assay, we quantified cellular cytotoxicity. To assess gene expression differences, we used Affymetrix messenger ribonucleic acid microarray and polymerase chain reaction analysis., Results: A total of 13 patients enrolled in our study: 6, VATS; 7, thoracotomy. On postoperative day 1, interleukin-6 and matrix metalloproteinase-9 were significantly different between the two groups. On day 2, cellular cytotoxicity (0.34) was significantly greater (p < 0.05) after VATS, as compared with thoracotomy (0.18). In both groups, cytotoxicity returned to baseline and was equivalent at first follow-up (VATS, 29.4 days versus thoracotomy, 29.3 days; p > 0.05). We noted minimal yet significant differences in PBMC phenotype, but no differences in T-cell activation makers. A 9-gene polymerase chain reaction-validated subset clustered the two groups with complete concordance., Conclusions: Video-assisted thoracoscopic surgery lobectomy for non-small-cell lung cancer is associated with less impairment of cellular cytotoxicity, as compared with thoracotomy. We found that this difference was not accounted for by PBMC phenotypic changes. Instead, PBMC gene expression changes likely represent the molecular basis of this differential immune response.

Endobronchial ultrasound-guided transbronchial fine-needle aspiration (EBUS-TBNA) is a new technique that facilitates cytologic sampling of mediastinal lymph nodes. We describe our initial experience with this method, including adequacy assessment, impact on cytopathologists' work, and diagnostic pitfalls. There were 229 EBUS-TBNA samples obtained from 100 patients; a mean of 22 minutes was spent with an average of 3 passes performed and 6 slides prepared per site. Of 193 aspirates, 5 were categorized as atypical, 54 as positive, and 134 as negative for malignancy; 36 (15.7%) aspirates were nondiagnostic. We found EBUS-TBNA to have a high specificity (100%) and good sensitivity (86%) in our institution, in which a cytopathologist is available on-site to ensure sample adequacy. Most true-negative samples had moderate to abundant lymphocytes, confirming lymphocyte numbers as a marker of adequacy. For pathologists, this was a relatively time-consuming procedure. Recognizing bronchial contamination, especially with metaplastic or dysplastic cells, is important for avoiding diagnostic pitfalls.

Background: Lobectomy for patients with clinical stage I non-small cell lung cancer (NSCLC) can be performed by thoracotomy or by video-assisted thoracoscopic surgery (VATS). We compared the operative characteristics and postoperative course for patients with clinical stage I NSCLC who underwent lobectomy by VATS or thoracotomy., Methods: We retrospectively reviewed the charts of all patients undergoing lobectomy for clinical stage I NSCLC from January 1, 1998, through June 30, 2005., Results: We performed 147 lobectomies (88 thoracotomy, 59 VATS) in 147 patients with clinical stage I NSCLC. Patient demographics were similar between groups; however, VATS patients had more hypertension (p = 0.0114), chronic renal insufficiency (p = 0.0479), and previous malignancies (p = 0.0086). The two groups did not differ in pathologic stage, tumor size, histologic results, or number of positive nodes. More total nodes were identified in thoracotomy patients (p = 0.0001), and they had a shorter intensive care unit stay (p = 0.0224). VATS patients had significantly less postoperative pneumonia (p = 0.0023). VATS patients trended toward fewer chest tube days and a shorter hospital length of stay. The two groups did not differ in operative time, blood loss, atrial fibrillation, or number of ventilator days. Median survival between the cohorts was similar (>7.9 years thoracotomy versus >4.6 years VATS, log-rank p = 0.6939)., Conclusions: Patients undergoing VATS lobectomy for clinical stage I NSCLC, despite having more comorbidities, had fewer postoperative complications. The approaches are equivalent in operative time, blood loss, length of stay, and survival rate. Compared with thoracotomy, VATS lobectomy for patients with clinical stage I NSCLC appears to be a less morbid operation.

Objective: Several studies have suggested that positron emission tomography is more accurate than computed tomography for the staging of non-small cell lung cancer and can reduce the rate of unnecessary thoracotomy in patients with potentially resectable disease. However, there are few data on the utility of positron emission tomography in the diagnosis of patients with tumors of 2 cm or less in size., Methods: Patients with cT1/cT2 tumors of 2 cm or less in size were retrospectively reviewed. All had a computed tomographic scan, as well as a positron emission tomographic scan on a dedicated scanner, with a standard uptake value reported. A standard uptake value of 2.5 g/mL or greater was considered positive. The results of computed tomography and positron emission tomography were correlated with pathologic results after either resection (n = 60) or mediastinoscopy (n = 4)., Results: Sixty-four patients (38 women; mean age, 66 years) had a mean tumor size of 1.4 cm (range, 0.7-2.0 cm). Forty-three patients had adenocarcinoma, 13 had adenocarcinoma-bronchioloalveolar carcinoma, 5 had squamous cell carcinoma, and 3 had other tumor types. Twenty-nine (45%) tumors had negative positron emission tomographic results. Both tumor size (>1 cm vs < or =1 cm) and cell type (adenocarcinoma-bronchioloalveolar carcinoma vs all other cell types) were significant predictors of positron emission tomography uptake in the primary tumor (P = .05 and .01, respectively). Nodal metastases were detected pathologically in 11 (17%) patients (5 N1 and 6 N2). Positron emission tomographic sensitivity and specificity for nodal metastases were only 45% and 89%, respectively. There was no statistically demonstrable survival difference between positron emission tomography-positive and positron emission tomography-negative tumors (3-year survival of 87% vs 100%, respectively)., Conclusion: Positron emission tomographic scanning has no demonstrable benefit in the diagnosis, staging, or prognosis of patients with tumors of 2 cm or less in size.

Background: Treatment of nonseminomatous germ cell tumors frequently requires bleomycin-combination chemotherapy followed by resection of residual disease. Bleomycin administration however raises concerns with respect to postoperative respiratory complications, particularly for patients undergoing large pulmonary resections. We undertook an institutional review to determine the outcome of large pulmonary resections after bleomycin-combination chemotherapy., Methods: Between 1981 and 2001, 530 patients presented to our institution for resection of residual intrathoracic disease for either metastatic testicular or primary mediastinal nonseminomatous germ cell tumors. We subsequently reviewed 32 of these patients who required pneumonectomy (n = 19; RIGHT = 9, LEFT = 10) or bilobectomy (n = 13) after bleomycin-combination chemotherapy., Results: There were four operative deaths (13%). All postoperative deaths occurred in patients undergoing right-sided resections (pneumonectomy, n = 2; bilobectomy, n = 2) as a consequence of pulmonary complications. Operative survivors had a pulmonary morbidity of 18%. Fourteen of 20 long-term survivors were found to have a satisfactory performance status at follow-up., Conclusions: Otherwise young and healthy male nonseminomatous germ cell tumors patients requiring large pulmonary resections after bleomycin-combination chemotherapy appear to be at higher than anticipated risk for pulmonary-related morbidity and mortality. However long-term survivors report an acceptable functional status.