The continued importance of surgical resection in the management of pulmonary neuroendocrine tumours.

Introduction
Pulmonary neuroendocrine neoplasms (NENs) are a diverse group of lung tumours characterised by neuroendocrine morphology and immunophenotypic markers (1,2). According to the 5th edition of the World Health Organization (WHO) classification (2021), NENs comprise four distinct subtypes. Although these subtypes share morphological and immunohistochemical features, they differ significantly in their biological behaviour. Typical carcinoid [TC, grade 1 (G1)] and atypical carcinoid [AC, grade 2 (G2)] tumours are well-differentiated and categorised as low- and intermediate-grade, respectively, whereas large cell neuroendocrine carcinoma [LCNEC, grade 3 (G3)] and small cell lung carcinoma [SCLC, grade 4 (G4)] are poorly differentiated high-grade malignancies (1,3-5).
In contrast to TC and AC, which may arise from diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH)—a recognized preinvasive lesion within the spectrum of pulmonary neuroendocrine neoplasia (6)—no such precursor has been identified for LCNEC or SCLC (7). DIPNECH is also considered a precursor to tumourlets, defined as neuroendocrine cell proliferations extending beyond the basement membrane and measuring <5 mm in greatest dimension, in contrast to lesions exceeding 5 mm, which are classified as pulmonary neuroendocrine tumours (PNETs), commonly referred to as carcinoid tumours.
Recent data suggest that NENs account for approximately 20% of primary lung neoplasms (8), with SCLC comprising 15–20% of all invasive lung cancers (9).
The appropriate extent of surgical intervention in well-differentiated tumours and the role of surgery in poorly differentiated subtypes has been the subject of considerable debate in recent years. While several authors, including Daddi et al. (10) and Filosso et al. (11), have contributed to this discourse, the literature remains limited. Only a handful of studies (12-14) have systematically compared outcomes among the different neuroendocrine subtypes and examined prognostic factors following surgical treatment.
The aim of the present study was to determine the 5-year overall survival (OS) rates of patients with surgically resected PNETs and to identify key prognostic factors that influence clinical outcomes. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1407/rc).

Methods
Between 2008 and 2023, a total of 214 patients diagnosed with PNETs underwent surgical treatment at our thoracic surgery centre. Patients exhibiting mixed histology—specifically those with concurrent non-small cell lung cancer—or those diagnosed with DIPNECH were excluded from the study (Figure 1).
All patients underwent standard functional evaluation, including blood gas analysis and body plethysmography. Patients with compromised pulmonary function—defined by a forced expiratory volume in 1 second (FEV1) and/or diffusing capacity for carbon monoxide (DLCO) below 75%—as well as those over 80 years of age, individuals with a Revised Cardiac Risk Index (RCRI) score of 2 or higher, and those scheduled for extensive resections (e.g. sleeve resection, bilobectomy, pneumonectomy), underwent further pre-operative assessment. This included cardiopulmonary exercise testing and lung perfusion scintigraphy. Patients demonstrating cardiac limitations were referred for cardiology consultation, often leading to coronary angiography.
Three patients were deemed unfit for anatomical resection based on functional limitations and were excluded from the analysis.
Comprehensive staging was performed fluorodeoxyglucose (FDG) positron emission tomography (PET)-computed tomography (CT), chest CT, and brain magnetic resonance imaging (MRI). Given the overexpression of somatostatin receptors in PNETs, additional imaging was performed using DOTATOC PET‑CT or, in some cases, octreotide scintigraphy following the diagnosis of TC or AC.
Mediastinal staging was conducted via endobronchial ultrasound (EBUS) and video-assisted mediastinoscopic lymphadenectomy (VAMLA). Indications for VAMLA included left-sided tumours, mediastinal lymph node enlargement on CT, PET-positive nodal status, or a pre-operative histological diagnosis of LCNEC or SCLC obtained via bronchoscopy with EBUS or CT-guided biopsy.
One patient with a Pancoast tumour received neoadjuvant chemotherapy and mediastinal radiotherapy before surgery.
All resected specimens—including the primary tumour and systematically dissected hilar and mediastinal lymph nodes—were subjected to detailed histopathological analysis. Tumours were classified according to the 8th edition of the tumour-node-metastasis (TNM) staging system.
The surgical approach and extent of resection were determined in a multidisciplinary thoracic oncology meeting. Procedures were performed either via anterolateral thoracotomy or video-assisted thoracoscopic surgery (VATS), both under one-lung ventilation achieved with double-lumen endotracheal intubation. Thoracotomy was carried out through the 4th or 5th intercostal space. The three-port VATS technique included a utility incision in the 4th intercostal space anterior to the latissimus dorsi, with two additional ports positioned at the diaphragm level along the midaxillary and anterior axillary lines.
Patient data were retrospectively retrieved from histopathology records and discharge summaries. Mortality was cross-checked through the national health database, while survivors were contacted by telephone for follow-up. Outpatient evaluations were conducted at 3-month intervals during the first 2 years, including thoracic CT and chest radiography. In the 3rd and 4th years, follow-up was conducted semi-annually and annually during the 5th year.

Statistical analysis
Data entry was conducted using Microsoft Excel 365. For descriptive statistical analysis, SPSS for Windows version 23.09 (IBM-SPSS Inc., Armonk, NY, USA) was utilized. The Kruskal-Wallis rank test was employed to compare quantitative variables, followed by Dunn’s post hoc test. Non-parametric variables were analysed using the chi-square test. Continuous variables are presented as means with standard deviations (SDs) or medians with interquartile ranges, while categorical data are reported as counts and percentages. Statistical significance was set at P<0.05. Five-year OS and disease-free survival (DFS) were calculated using Kaplan-Meier analysis and are presented as the mean estimated survival.
Univariate analysis was conducted for factors expected to influence OS, such as tumour stage (T stage) and node stage (N stage), type of lung neuroendocrine neoplasms (L-NEN), and sex. Factors identified as impacting survival in the univariate analysis were included in the multivariate analysis using Cox regression. Variables with P<0.05 in the univariate analysis were included in the multivariate analysis, where statistical significance was set at a P value of less than 0.05.

Ethical statement
The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, the International Council for Harmonisation Good Clinical Practice (ICH-GCP) guidelines, and the applicable national regulations, including the European Union General Data Protection Regulation (EU GDPR). The responsible Ethics Committee was consulted. Due to the retrospective design of the study, which relied exclusively on existing treatment data without any additional data collection or patient contact, formal ethical approval was waived by the Ethics Committee of Westphalia-Lippe. All patient data used for the analysis were pseudonymized prior to evaluation to ensure data protection and confidentiality. Informed consent was also not required.

Results
Patient characteristics: between 2008 and 2023, 145 patients with a diagnosis of PNETs underwent anatomical resection. The gender distribution slightly favoured females (54%) over males (46%), and the mean age at diagnosis was 64 years (Table 1).
Among these patients, 62 were diagnosed with TC tumours, 18 with ACs, 18 with LCNEC, and 47 with SCLC. Histological confirmation was achieved via bronchoscopy with EBUS in 64 patients and through CT-guided biopsy in 11 cases.
Pre-operative nodal involvement was identified in 34 patients: 24 had N1 disease and 10 had N2 status. A total of 59 patients underwent video-assisted mediastinoscopy, which, together with EBUS, downstaged three patients previously classified as N2 based on PET-CT findings.
All patients underwent anatomical resection. The most frequently performed procedure was lobectomy (n=101), followed by sleeve resection (n=14) and double sleeve resection (n=6). Segmentectomy was performed in 12 cases, while bilobectomy and pneumonectomy were performed in 4 and 8 patients, respectively. Complete (R0) resection was achieved in all cases.
Postoperative complications are summarized in Table 2.
The 30-day mortality rate was 2.7% (4 cases). Among patients with poorly differentiated tumours, 65 received adjuvant chemotherapy and/or radiotherapy, primarily a cisplatin‑etoposide regimen.
The OS rate was 77%. OS varied significantly by histology (P=0.001). In total, 87% in TC, 83% in AC, 86% in LCNEC, and 59% in SCLC (Figure 2). The OS by T category was 87% T1, 68% T2, 50% T3, and 44% for T4 (P<0.01; Figure 3). Among SCLC patients, OS by T stage was 83% T1, 60% T2, 42% T3, and 20% for T4 (P=0.003). As shown in Figure 4, nodal status significantly impacted survival: OS was 80% (pN0), 78% (pN1), and 45% (pN2) (P<0.001). The DFS rate was 75%, differing by histology (P=0.002; Figure 5).
Univariable analysis identified older age, male sex, SCLC histology, T3/T4 stage, N2 status, Union for International Cancer Control (UICC) stage III, and pneumonectomy as negative prognostic factors, while TC histology and T1 status were favourable. In multivariable analysis, T3, T4, and N2 status remained independent negative factors, whereas T1 status was positive (Table 3).

Discussion
Between 2008 and 2023, we performed 145 anatomical resections for neuroendocrine lung tumours. These cases were retrospectively reviewed to assess 5-year overall and DFS rates, as well as to identify key prognostic factors influencing outcomes.
PNETs exhibit distinct prognostic profiles based on histological subtype and biological aggressiveness. A well-established distinction exists between well-differentiated and poorly differentiated subtypes, with the former generally associated with more favourable outcomes and the latter with significantly poorer survival. This division is supported by findings from Filosso et al. (11), which are consistent with our results.
Importantly, our analysis highlights the critical prognostic role of nodal status in patients with poorly differentiated NENs. This is corroborated by Girelli et al. (14), who reported inferior survival in patients with LCNEC and nodal metastases compared to those without. Similar results were described by Lim et al. (15), whose cohort also included patients with small cell lung cancer SCLC, reinforcing the high prevalence and prognostic burden of nodal involvement in poorly differentiated tumours.
Interestingly, our findings diverge from previous reports in that nodal involvement among patients with LCNEC was lower in our cohort. This discrepancy may explain the comparatively higher survival rates observed in this subgroup and underscores the importance of early lung cancer detection (16).
Another potential explanation for the improved OS and lower 30-day mortality rate in our cohort lies in the surgical selection criteria. In addition to favouring anatomical resections in patients with peripheral tumours, we preferred parenchyma-sparing sleeve resections over pneumonectomy or bilobectomy for centrally located tumours (17-20). In contrast, series by Lim et al. (15), Veronesi et al. (21), and Raman et al. (22), which focused on SCLC and LCNEC, reported lower survival rates—likely due, in part, to their higher rates of pneumonectomy, a procedure we identified as a negative prognostic factor in our univariate analysis. This is further supported by a series from Strand et al. (23), which reported higher 30-day mortality associated with pneumonectomy.
Furthermore, our data demonstrate a clear correlation between increasing T category and reduced OS across all histological subtypes (P<0.001). This finding is consistent with the work of Cattoni et al. (24) and Travis et al. (25), who identified T stage as an important prognostic indicator in bronchial carcinoids and LCNEC. In contrast, Lim et al. (12) reported no significant association between T stage and survival in SCLC patients. However, our analysis revealed favourable survival outcomes among SCLC patients with T1 tumours and a marked decline in those with T4 tumours (P<0.01), two of whom underwent pneumonectomy. These results further support the prognostic value of T classification, even in aggressive subtypes such as SCLC, and challenge the concept of definitive chemoradiotherapy in patients with localized SCLC disease.

Limitations
This retrospective study included a relatively small cohort of 145 patients, limiting generalisability.
Although the findings for LCNEC and SCLC appear promising, the limited sample sizes in these subgroups reduce the statistical power of the analyses, and thus the results should be interpreted cautiously.
Detailed data on adjuvant therapy (duration, toxicity) were unavailable and may have influenced survival.
Propensity score matching was not employed, potentially introducing selection bias.

Conclusions
Tumour histology, nodal status, and T category significantly influence prognosis in PNETs. Early diagnosis, particularly for poorly differentiated tumours, reduces nodal involvement and improves survival.
Anatomical resection with systematic mediastinal lymphadenectomy remains the treatment cornerstone. Parenchyma-sparing techniques such as sleeve resection should be preferred over pneumonectomy whenever feasible.

Supplementary
The article’s supplementary files as