Comparison of clinicopathologic features and prognosis between surgically resected pulmonary large-cell neuroendocrine carcinoma and small-cell lung cancer

Introduction

Lung neuroendocrine neoplasms (NENs) are epithelial tumors originating from lung neuroendocrine cells and accounting for approximately 20–25% of all lung cancers (1). In 2015, the World Health Organization (WHO) classification grouped NEN into four major subtypes: typical carcinoid (TC) and atypical carcinoid (AC), which were classified as low- and intermediate-grade NENs; large cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC), which represented high-grade neuroendocrine carcinomas (HGNECs) (2). SCLC and LCNEC respectively account for 75% and 15% of lung NENs and 15% and 2–3% of all lung cancers (3-5). Given the low incidence and difficulty in diagnosis, LCNEC tends to be misdiagnosed as SCLC, pulmonary carcinoid, or other non-small cell lung cancers (NSCLCs) (6). Previous studies have reported that LCNEC and SCLC share many biological, histological, and clinicopathologic aspects (7-11). Consequently, they tend to be subdivided into a single group of HGNECs. In recent years, with the development of diagnostic technology, the incidence of LCNEC has gradually increased, leading to a more comprehensive understanding of LCNEC (12-15). Studies have found that LCNEC differs from SCLC in clinical features, gene mutations, and prognosis (16-19).

Compared to other subtypes of lung cancer, research focused on HGNEC is spare, and the sample sizes of the related studies are small. In addition, LCNEC and SCLC have been further divided into the pure and combined subtypes. Combined LCNEC (C-LCNEC) is defined as LCNEC including other NSCLC components such as adenocarcinoma, squamous cell carcinoma, and spindle-cell carcinoma. When LCNEC or other NSCLC components are contained in SCLC, this is considered to be combined SCLC (C-SCLC). The differences in clinical features and prognosis between pure and combined HGNECs have not been elucidated. To this end, we collected clinical data of patients with surgically resected HGNEC to determine the similarities and differences between LCNEC and SCLC, as well as their subtypes, in order to generate novel insights into this malignant disease. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-345/rc).

Methods

Ethics statements

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of Shanghai Chest Hospital [No. KS(Y)1982]. The requirement for individual consent was waived due to the retrospective nature of the analysis.

Patients

In this study, we recruited 980 patients with HGNEC who underwent surgical treatment in Shanghai Chest Hospital from January 2012 to December 2021. All patients included in the study underwent R0 resection. For patients preoperatively diagnosed with SCLC at stage T1-2, N0, M0, we performed surgery. The decision to operate also took into account patient-specific factors such as overall health, lung function, and comorbidities, ensuring that patients were fit for surgery and likely to tolerate adjuvant therapies. All patients initially underwent minimally invasive surgery, with a conversion rate to open thoracotomy of 7%. The exclusion criteria for patients were as follows: (I) a history of other malignant tumors (n=26); (II) palliative surgery (n=20); (III) neoadjuvant therapy (n=28); and (IV) incomplete clinical medical records or follow-up data (n=18). Ultimately, 921 patients were eligible for enrollment, including 341 patients with LCNEC and 580 patients with SCLC.

Pathological analysis

All cases of LCNEC and SCLC were diagnosed based on the 2015 WHO classification of lung tumors (2). The diagnosis of SCLC was based on its characteristic small cells with scant cytoplasm, finely granular chromatin, inconspicuous nucleoli, a high mitotic rate (≥60 mitoses per 2 mm²), and strong neuroendocrine marker expression (synaptophysin, chromogranin A, CD56). SCLC combined with LCNEC was identified as SCLC cases combined with a LCNEC component, where the tumor exhibits both small cell carcinoma and large cell neuroendocrine carcinoma features. SCLC combined with non-LCNEC was identified as SCLC cases combined with other non-LCNEC components, such as adenocarcinoma or squamous cell carcinoma, where the tumor exhibits both small cell carcinoma and non-neuroendocrine carcinoma features. The pathological criteria of LCNEC included: (I) neuroendocrine morphology [organoid nesting, trabecular, or rosette patterns, accompanied by medium to large tumor cells with prominent nucleoli, high mitotic activity (>10/2 mm²), and focal necrosis]; (II) neuroendocrine features which were determined by immunohistochemistry (IHC) expression at least one neuroendocrine marker [synaptophysin (SYN), chromogranin-A (CGA), and CD56] in ≥10% of tumor cells. C-LCNEC was defined as LCNEC containing a distinct non-neuroendocrine component (such as adenocarcinoma or squamous cell carcinoma) comprising at least 10% of the tumor. P-LCNEC referred to LCNEC tumors that fulfilled all LCNEC criteria but lacked a significant non-neuroendocrine component. All pathologic diagnoses were performed by at least two experienced thoracic pathologists at our institution. Each case was independently reviewed, and discrepancies, if any, were resolved through consensus discussion. In cases of diagnostic uncertainty, additional immunohistochemical stains and molecular analyses were performed to rule out atypical carcinoid. Central tumors were defined as those originating from the main bronchus, lobar bronchus, or segmental bronchus, located near the hilum (central region) of the lung. Peripheral tumors were defined as those arising beyond the segmental bronchi, typically in the outer one-third of the lung parenchyma. The tumor staging in this study was conducted according to the eighth edition of the TNM staging system formulated by International Association for the Study of Lung Cancer Research (IASLC) (20,21).

Preoperative diagnosis

Among the patients who were postoperatively diagnosed with SCLC, 256 cases did not undergo preoperative biopsy due to small lesions or biopsy difficulties. A total of 324 SCLC patients underwent bronchoscopic or percutaneous lung biopsy before surgery, but only 105 (32.4%) were diagnosed with SCLC, while 162 (50.0%) were diagnosed with NSCLC, and the remaining 57 (17.6%) were classified as lung cancer NOS (not otherwise specified). A total of 72 patients had preoperative imaging findings suggesting lymph node enlargement or metastasis. Among them, 24 patients underwent mediastinoscopy, and the results were negative; 48 patients did not undergo the examination due to concerns about the risks associated with the procedure. A total of 204 LCNEC patients underwent bronchoscopy or percutaneous lung biopsy preoperatively; 142 patients were diagnosed with LCNEC, 41 patients were diagnosed with NSCLC, and the remaining 21 patients were diagnosed with lung cancer of an undetermined type. The relatively low proportion of preoperative biopsies contributed to inaccurate clinical staging, resulting in significant discordance between clinical and pathological staging—with a 41.6% discrepancy rate in LCNEC patients and 58.6% in SCLC cases. The decision for surgery and neoadjuvant chemotherapy in LCNEC and SCLC patients should be based on a comprehensive assessment of pathological staging, the extent of metastasis, and biological characteristics. In LCNEC patients with stage IIIB/IV (such as multi-station lymph node metastasis or distant metastasis) or tumors involving critical structures (such as large blood vessels), surgery is generally not recommended. Neoadjuvant chemotherapy, typically with etoposide combined with platinum agents, is preferred to reduce tumor size. In cases of locally advanced LCNEC (stage IIIA) with N2 lymph node metastasis, neoadjuvant chemotherapy can improve the rate of surgical resection. For SCLC patients, extensive-stage disease (ES-SCLC, stage IV or with malignant pleural effusion/contralateral metastasis) should avoid surgery, with immunotherapy combined with chemotherapy (such as PD-L1 inhibitors plus platinum agents) being the main treatment. For limited-stage SCLC (LS-SCLC, stage I–IIIA), if T3–4 or N1–2 lesions are present, neoadjuvant chemotherapy (such as irinotecan plus carboplatin) followed by subsequent radiotherapy can improve prognosis. The surgical indications for LCNEC follow those of NSCLC. The indications for surgical treatment include stage I, stage II, and selectively chosen stage IIIA patients (e.g., T3N1M0, single-station N2).

Adjuvant therapy

Chemotherapy is recommended for all postoperative patients with SCLC, radiotherapy is recommended for patients with lymph node metastasis. The majority of the patients were given etoposide plus cisplatin or carboplatin (EP/EC) regimen (448, 96.3%), of the rest 17 patients, the chemotherapy regimens included TC/TP (paclitaxel plus cisplatin or carboplatin) and AC/AP (pemetrexed plus cisplatin or carboplatin) or DC/DP (docetaxel plus cisplatin or carboplatin). A total of 115 patients (19.8%) did not receive adjuvant chemotherapy. Among these, 19 patients with C-SCLC had driver gene mutations, and 13 patients received targeted therapy. Additionally, 45 patients did not undergo chemotherapy due to poor postoperative recovery, including issues such as poor wound healing, bleeding, or other complications. Furthermore, 21 patients did not receive chemotherapy because they were elderly or had a frail physical condition, and 30 patients refused chemotherapy due to concerns about its side effects. The radiation field typically covered the primary tumor and regional lymph nodes. The standard radiation dose for thoracic radiation (to the primary tumor and involved lymph nodes) was 45–60 Gy, delivered in daily fractions of 1.8–2 Gy over a period of 4 to 6 weeks. For LCNEC patients, adjuvant chemotherapy was clustered as NSCLC regimens (AC/AP, TC/TP, DC/DP, gemcitabine or vinorelbine, n=106) and SCLC regimens (EP/EC, n=128).

Follow-up

The follow-up information was acquired by regular review of the patient’s medical records or telephone inquiries. All patients were examined every 3 months for 2 years after surgery, which included chest computed tomography (CT) scans, tests for tumor markers, and neck and abdominal ultrasound. Patients underwent cranial contrast-enhanced MRI every four months, and scans were performed as needed if neurological symptoms developed, based on clinical necessity. Patients were reviewed semiannually within 2 to 5 years and annually after 5 years. The primary endpoint was overall survival (OS), and the secondary endpoint was disease-free survival (DFS). OS was calculated from the date of operation to the date of death or last follow-up. DFS was calculated from the date of surgery to the date of recurrence or last follow-up.

Statistical analysis

For continuous variables with normal distribution, the mean ± standard deviation was calculated, and the intergroup differences were compared with the t-test. For variables with a nonnormal distribution, the Mann-Whitney test was used for statistical analysis. For categorical variables, the Chi-squared test was used for comparison. The Kaplan-Meier method was used to calculate the DFS and OS, and the log-rank test was used to compare the survival distribution. We included variables that were clinically or statistically significant in the univariable Cox analysis into the multivariable Cox analysis to further adjust for potential confounding factors and to ultimately establish independent prognostic factors. All the data were analyzed with the bilateral test, and a P value less than 0.05 was considered statistically significant. Statistical analysis was performed using SPSS software version 26 (IBM Corp., Armonk, NY, USA), and survival curves were plotted with GraphPad Prism version 8.2.1 (GraphPad Software, San Diego, CA, USA).

Results

Comparison of LCNEC and SCLC

A total of 921 patients with surgically resected pulmonary HGNEC were included from January 2012 to December 2021, including 341 cases of LCNEC and 580 cases of SCLC. The last follow-up date is October 2024, with a median follow-up time of 95 months. Among the 341 patients with LCNEC, 221 were pure LCNEC (P-LCNEC) and 120 were C-LCNEC. Among the 580 patients with SCLC, 357 were pure SCLC (P-SCLC) and 223 were C-SCLC, of whom 150 had an LCNEC component (SCLC/LCNEC) and 73 had a non-LCNEC component (SCLC/non-LCNEC). The pathological subtype classification and definitions of HGNEC are provided in Figure S1. The baseline clinical features are shown in Table 1 and Table S1. The patients in the LCNEC and SCLC groups were mainly male and smokers, but the SCLC group had a higher percentage of smokers (70.3% vs. 63.6%; P=0.04). LCNEC was mainly located in the upper and peripheral lobe of the lung, while this was not the case for SCLC (upper: 63.3% vs. 42.2%, P=0.001; peripheral: 78.3% vs. 43.4%, P=0.001); meanwhile, SCLC was more likely to be found in the lower and central lobe as compared to LCNEC (lower: 44.3% vs. 30.3%, P=0.001; central: 56.6% vs. 21.7%, P=0.001). The patients with SCLC were at a later stage of disease, with a higher proportion of stage N1–2 cases than the LCNEC group (60.0% vs. 36.4%; P<0.001) and stage III (45.2% vs. 29.9%; P<0.001). The incidence of visceral pleural invasion (VPI) in the SCLC group was higher than that of the LCNEC group (91.9% vs. 40.8%; P=0.001). The SCLC group, as compared to the LCNEC group, also demonstrated a higher proportion of adjuvant chemotherapy (80.2% vs. 68.6%; P<0.001) and radiotherapy (31.6% vs. 13.2%; P<0.001). There were no significant differences in Ki-67 or neuroendocrine markers (CD56, SYN, and CGA) between the two groups (P>0.050). The clinical staging distribution revealed that approximately 73.4% of patients presented with cT1-2 disease [73.9% in LCNEC (n=252) vs. 73.1% in SCLC (n=424)], while 20.4% had cT3-4 tumors [19.1% in LCNEC (n=65) vs. 21.2% in SCLC (n=123)]. Regarding nodal status, 58.1% were cN0 [63.3% in LCNEC (n=216) vs. 55.0% in SCLC (n=319)], with combined cN1-2 involvement observed in 26.3% of cases [19.1% in LCNEC (n=65) vs. 30.5% in SCLC (n=177)]. At initial staging, stage I predominated (37.2% overall), showing higher frequency in LCNEC (39.6%, n=135) than SCLC (35.9%, n=208), whereas stage II accounted for 28.2% of cases [22.3% in LCNEC (n=76) vs. 31.7% in SCLC (n=184)]. Unknown staging status occurred in 18.1% [20.8% in LCNEC (n=71) vs. 16.5% in SCLC (n=96)]. In the subgroup analysis of stage I cases, significant differences in clinicopathologic features observed between LCNEC and SCLC (Table S2). In terms of prognosis, we found that the LCNEC group, as compared to the SCLC group, had a significantly longer median DFS (56 vs. 44 months; P=0.008; Figure 1A) and OS (73 vs. 56 months; P=0.005; Figure 1B). We used propensity score matching (PSM) to reduce selection bias between LCNEC and SCLC. After PSM, DFS and OS were still significantly higher in the LCNEC group compared with the SCLC group (DFS: P=0.003, Figure 1C; OS: P=0.002, Figure 1D). Further subgroup analysis based on TNM staging revealed that the survival benefit was only present in patients with stage I (DFS: P=0.01, Figure 2A; OS: P=0.03; Figure 2B) or stage II disease (DFS: P=0.048, Figure 2C; OS: P=0.047; Figure 2D). There was no significant difference in survival outcomes among patients with stage III disease (DFS: P=0.72, Figure 2E; OS: P=0.43, Figure 2F). After adjustment were made for gender, age, smoking history, primary site, laterality, tumor location, pathological (p)T stage, pN stage, pTNM stage, VPI, adjuvant chemotherapy, radiotherapy, and other confounding factors via multivariable Cox regression, it was found that the LCNEC group, as compared to the SCLC group, was associated with a significantly longer DFS [hazard ratio (HR) 1.40, 95% confidence interval (CI): 1.15–1.71; P=0.001] and OS (HR 1.55, 95% CI: 1.25–1.92; P=0.001) (Table 2).

Figure 1 Comparison of (A,C) DFS and (B,D) OS before and after PSM between the LCNEC and SCLC groups. DFS, disease-free survival; LCNEC, large cell neuroendocrine carcinoma; OS, overall survival; PSM, propensity score matching; SCLC, small-cell lung cancer.

Figure 2 Comparison of DFS and OS between the LCNEC and SCLC groups according to TNM stage (A,B: stage I; C,D: stage II; E,F: stage III). DFS, disease-free survival; LCNEC, large cell neuroendocrine carcinoma; OS, overall survival; SCLC, small-cell lung cancer; TNM, tumor-node-metastasis.

Comparison between LCNEC and SCLC subtypes

As indicated in Table 3, the baseline data between the P-LCNEC (n=221) and C-LCNEC (n=120) subtypes were compared with those of the SCLC/LCNEC (n=150) and SCLC/non-LCNEC (n=73) subtypes. The analysis indicated that compared to SCLC/LCNEC, P-LCNEC was more likely to occur in the upper lobe of the lung (65.2% vs. 54.0%; P=0.001) and peripheral areas (76.5% vs. 60.7%; P=0.001); additionally, P-LCNEC exhibited a higher proportion of patients with stage N0 (66.1% vs. 40%; P<0.001) or stage I disease (44.8% vs. 26.7%; P=0.003). Compared to the P-LCNEC group, the SCLC/LCNEC group had a higher proportion of adjuvant chemotherapy (80.0% vs. 65.6%; P=0.001) and radiotherapy (29.3% vs. 12.2%; P<0.001). In the comparison of the prognosis between the two groups, it was observed that P-LCNEC was associated with a more favorable prognosis as compared to SCLC/LCNEC, as evidenced by both a longer median DFS (72 vs. 42 months, P=0.001; Figure 3A) and OS (83 vs. 55 months, P=0.005; Figure 3B).

Figure 3 Comparative analysis of DFS and OS between LCNEC and SCLC subtypes. (A,C) Comparison of DFS and (B,D) OS among the LCNEC and SCLC subtypes. (A) The DFS and (B) OS among the P-LCNEC and SCLC/LCNEC groups. The (C) DFS and (D) OS among the C-LCNEC and SCLC/non-LCNEC groups. C-LCNEC, combined large cell neuroendocrine carcinoma; DFS, disease-free survival; OS, overall survival; P-LCNEC, pure large cell neuroendocrine carcinoma; SCLC, small-cell lung cancer.

Compared to C-LCNEC, SCLC/non-LCNEC had a higher proportion of smokers (71.2% vs. 56.7%; P=0.03) and central lung cancer (32.9% vs. 18.3%; P=0.02). In terms of T, N, and TNM staging, C-LCNEC tended to be diagnosed at an earlier stage compared to SCLC/non-LCNEC (P=0.01, P=0.02, and P=0.003, respectively). However, the incidence of VPI was higher in the C-LCNEC group compared to the SCLC/non-LCNEC subtype (55.0% vs. 52.1%; P=0.002). In the comparison of prognosis between the two groups, it was found that the median DFS and OS of the C-LCNEC group was significantly longer than that of the SCLC/non-LCNEC group (DFS: 78 vs. 28 months, P=0.049, Figure 3C; OS: 85 vs. 43 months, P=0.006; Figure 3D).

Effect of adjuvant chemotherapy on the prognosis of patients with stage I HGNEC

Among the 153 (44.9%) patients with stage I LCNEC, 96 (62.7%) received adjuvant chemotherapy, while 57 (37.3%) did not. Of the 161 (27.8%) patients with stage I SCLC, 125 (77.6%) received adjuvant chemotherapy and 36 (22.4%) did not. We compared the baseline characteristics between patients, and found there were no statistically significant differences between patients receiving chemotherapy and those who did not receive chemotherapy (Table 4). In the comparison of the prognosis in both the stage I LCNEC and SCLC groups, it was found that patients who received adjuvant chemotherapy, as compared to those who did not, had a longer DFS (P=0.005 and P=0.048; Figure 4A,4B) and OS (P=0.004 and P=0.03; Figure 4A,4B).

Figure 4 Kaplan-Meier survival curves of DFS and OS among patients with stage I LCNEC and SCLC treated with adjuvant chemotherapy and those not treated with adjuvant therapy (A: LCNEC; B: SCLC). DFS, disease-free survival; LCNEC, large cell neuroendocrine carcinoma; OS, overall survival; SCLC, small-cell lung cancer.

Discussion

There is relatively little research on HGNEC, and the similarities and differences between LCNEC and SCLC remain controversial. Due to the difficulty in the diagnosis of the pure and combined subtypes, few studies have compared the subtypes of LCNEC and SCLC, and thus HGNEC remains poorly understood. In this study, we compared the clinicopathological features and prognosis between LCNEC and SCLC and their subtypes in a large, Chinese, population-based cohort. Our findings constitute valuable insights into HGNEC and may have implications for the clinical management and treatment strategies related to this disease.

The low percentage of pneumonectomies observed in this study may reflect the crucial role of precise preoperative assessment in surgical decision-making. Comprehensive evaluations, including imaging studies [such as CT and positron emission tomography/computed tomography (PET-CT)], pulmonary function tests, and multidisciplinary team (MDT) discussions, enable accurate assessment of disease extent and patient tolerance, allowing for the selection of the most appropriate surgical approach while minimizing unnecessary resections. In our study, we discovered that, in contrast to SCLC, LCNEC had a lower proportion of lymph node metastases, and the patients were diagnosed at an earlier pathological stage. This finding is consistent with that reported in a large retrospective study from the Netherlands Cancer Registry (13). Apart from the differences mentioned above, there were also significant differences in smoking history, tumor location, and VPI between the SCLC and LCNEC groups, which is consistent with previous studies (8,13,22). However, other research indicates that the biological characteristics of LCNEC and SCLC are similar and that these disease types have no statistical differences (9,23,24). Therefore, additional investigation needs to be conducted to confirm these various findings.

Previous studies have suggested that the prognosis of surgically resected SCLC is similar to that of LCNEC (7,9,25). For stage I SCLC and LCNEC, the reported 5-year survival rates ranged from 36% to 58% (23,26-28) and from 33% to 67%, respectively (27,29-31), representing a nonsignificant difference. However, one study based on the Surveillance, Epidemiology, and End Results (SEER) database indicated that the OS of early-stage (T1N0M0) LCNEC was comparable to that of large-cell carcinoma and superior to that of SCLC (22). This finding suggests that LCNEC may have a more favorable prognosis in early-stage disease as compared to SCLC. Similarly, a study from the Netherlands Cancer Registry also confirmed that LCNEC was associated with a longer OS as compared to SCLC in early-stage disease (13). In our study, we found that the overall DFS and OS of the LCNEC group were longer than those of the SCLC group. Further subgroup analysis revealed that this survival advantage was only observed in patients with stage I and II disease, and there was no statistical difference between the two groups in those with stage III disease. This suggests that LCNEC may be associated with longer survival as compared to SCLC in early-stage disease but not in advanced-stage disease. It is important to consider these findings in the assessment of the prognosis and treatment options for patients with LCNEC and SCLC at different stages of the disease.

Studies on LCNEC and SCLC have generally compared the gross types, but the oncologic differences between their subtypes have not been extensively examined (9,19,32). We only found one small-sample study in which the subtypes were compared. In this study, the clinicopathological features of 52 patients with P-LCNEC, 50 patients with C-LCNEC, and 53 patients with C-SCLC/LCNEC were compared. The only difference between the three groups was that patients with C-LCNEC had a higher likelihood of having VPI (33). In our study, we conducted a comprehensive comparison of the clinical features and outcomes among the subgroups of LCNEC (P-LCNEC and C-LCNEC) and SCLC (SCLC/LCNEC and SCLC/non-LCNEC). We compared P-LCNEC with SCLC/LCNEC because P-LCNEC exhibits a poor prognosis and biological behavior more similar to SCLC, whereas SCLC/LCNEC has a relatively better prognosis. This comparison allowed us to further explore their biological differences and potential implications for treatment strategies. Additionally, we analyzed C-LCNEC and SCLC/non-LCNEC, as both contain NSCLC components such as adenocarcinoma and squamous cell carcinoma. This comparison helped assess whether their biological behavior aligns more closely with NSCLC or SCLC, providing insights into their classification and clinical management. Our study results indicate that neuroendocrine tumors containing an SCLC component are more aggressive compared to those containing an LCNEC component. Considering this difference, we recommend that not only LCNEC and SCLC be distinguished but also their subtypes.

Adjuvant chemotherapy is recommended for stage I patients with SCLC due to its aggressive nature and high sensitivity to chemotherapy (26,34-36). Similarly, for LCNEC, which shares neuroendocrine properties with SCLC, the same adjuvant chemotherapy regimen as that for SCLC is recommended (36,37). However, the current guidelines for LCNEC do not recommend adjuvant therapy for stage I disease, which may explain the lower proportion of patients with LCNEC receiving adjuvant chemotherapy compared to those with SCLC. Wakeam et al. analyzed 1,770 patients with LCNEC and reported that adjuvant chemotherapy was associated with better OS, particularly when tumors were larger than 3 cm, while patients with tumors smaller than 2 cm received no survival benefit (38). Raman et al. examined 2,642 patients with stage I LCNEC and found that while there was a significant improvement in OS for the adjuvant chemotherapy group among the general population, there was no survival benefit observed for those patients with stage IA disease (39). In contrast, Kujtan et al. enrolled 1,232 patients with stage I LCNEC and discovered that adjuvant chemotherapy significantly improved OS in both patients with stage IA and stage IB disease (40). In our study, adjuvant chemotherapy was associated with a reduced risk of recurrence and death in both patients with stage I LCNEC and SCLC. Accordingly, we suggest that patients with stage I LCNEC also receive adjuvant chemotherapy.

While the present study primarily examines the clinicopathological characteristics and outcomes of surgically resected HGNECs, it is important to consider the potential implications of recent breakthroughs in immune checkpoint inhibitor (ICI) therapy for extensive-stage SCLC on the management of resectable cases. Although current evidence supporting ICIs [e.g., programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors] in operable SCLC remains limited, several ongoing clinical trials are actively investigating their potential benefits in this setting. Emerging data suggest that ICIs, whether administered as neoadjuvant, adjuvant, or consolidation therapy, may enhance systemic immune responses and potentially reduce postoperative recurrence risk. As our understanding of the tumor microenvironment and immune evasion mechanisms in SCLC continues to evolve, immunotherapeutic approaches are anticipated to become integral components of multimodal treatment strategies, even for early-stage disease. Future research should focus on biomarker-driven patient selection (e.g., PD-L1 expression, tumor mutational burden) and optimization of combination regimens with chemotherapy or targeted therapies to validate their efficacy as adjuvant treatment for surgical candidates.

There are several limitations to this study which should be acknowledged. First, despite the relatively large sample size, bias or incomplete information inherent to the retrospective design could not be avoided. Second, no genomic or transcriptomic analysis was conducted in any of the patients, and thus molecular-level interpretation of HGNEC was not feasible. Third, some patients refused preoperative biopsy for the confirmation of pathological types and lymph node status due to personal reasons. Additionally, due to financial constraints, some patients could not undergo PET-CT, which led to inaccurate staging prior to surgery. Finally, although our center achieved a high rate of minimally invasive surgery, the feasibility of this approach in complex cases may depend heavily on institutional expertise and multidisciplinary support, which could restrict its generalizability to other centers. Therefore, to obtain a more robust and reliable conclusions, further multicenter, prospectively designed studies should be conducted to validate and expand upon our results.

Conclusions

Our findings redefine therapeutic decision-making for pulmonary HGNECs by: (I) establishing LCNEC and SCLC as clinically distinct entities; (II) validating adjuvant chemotherapy’s survival benefit in stage I LCNEC; and (III) identifying unmet needs for biomarker-driven strategies. This work provides a framework for both current practice and future trial design.

Acknowledgments

The authors would like to thank the study participants for their contribution to this research.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-345/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-345/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-345/prf

Funding: This research was supported by the Shandong Provincial Medical Association (No. YXH2022ZX02020), the Qingdao Natural Science Fund (No. 23-2-1-189-zyyd-jch), and the Shandong Provincial Natural Science Fund (No. ZR2024QH605).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-345/coif). R.A.R. has received consulting fees from ITM Radiopharma, Regeneron, TerSera Therapeutics, Exelixis, Novartis, and Lantheus, serves on the speakers bureau for AstraZeneca, and is an unpaid Board of Directors member for the North American Neuroendocrine Tumor Society. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of Shanghai Chest Hospital [No. KS(Y)1982]. The requirement for individual consent was waived due to the retrospective nature of the analysis.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: J. Gray)