Pleural effusion volume as a novel biomarker for prognostic and therapeutic stratification in small cell lung cancer: a translationally-focused cohort study

Introduction

Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma characterized by rapid proliferation and early metastasis (1-3). Despite advances with the incorporation of immune checkpoint inhibitors (ICIs) into first-line platinum-based chemotherapy for extensive-stage disease, median overall survival (OS) remains modest, typically ranging from 10 to 13 months (4-6). Malignant pleural effusion (MPE) is a common complication in advanced lung cancer, occurring in approximately 11–46% of SCLC patients during their disease course (7-10). By current staging systems, the presence of MPE automatically upstages SCLC to extensive-stage, implying a uniformly poor prognosis and influencing therapeutic aggressiveness (11,12).

This blanket classification, however, may not capture the intrinsic prognostic heterogeneity of MPE. In non-small cell lung cancer (NSCLC), emerging evidence suggests that the volume of pleural effusion (PE) carries significant prognostic weight, with minimal (“small”) effusions potentially having a less detrimental impact on survival than symptomatic, large-volume effusions (13,14). In SCLC, a seminal study by Ryu et al. (2016) reported that even small PE was associated with worse survival compared to no effusion in an era predominantly defined by chemotherapy (15). Whether this holds true in the contemporary landscape of chemoimmunotherapy, and whether a distinct prognostic threshold exists between small and moderate or greater effusions, remains unexplored.

Furthermore, while MPE traditionally signifies advanced disease and poorer outcomes (16,17), the specific impact of modern systemic therapies, particularly immunotherapy, on the survival of SCLC patients with MPE is poorly defined. Identifying robust prognostic factors within this subgroup is crucial for refining risk stratification, optimizing treatment selection, and designing future clinical trials.

Therefore, this large, single-center study aimed not only to describe the prognostic landscape but to evaluate PE volume as a translational biomarker capable of guiding clinical decision-making. Specifically, we sought to determine whether this simple radiographic measure could identify a subgroup of SCLC patients with MPE who have a fundamentally different prognosis and, potentially, a differential response to modern immunotherapy. Unraveling this clinical dichotomy could provide immediate therapeutic guidance and open new avenues for understanding the biology of pleural metastasis. We present this article in accordance with the REMARK reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0170/rc).

Methods

Study population and design

This retrospective cohort study included 1,026 consecutive patients diagnosed with histologically or cytologically confirmed SCLC at Nanjing Jinling Hospital between January 2008 and May 2024. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Nanjing Jinling Hospital (No. 2024DZKY-051-01), with a waiver of informed consent due to its retrospective nature. Patient confidentiality was maintained.

Data collection and definitions

Baseline demographic, clinical, treatment, and survival data were extracted from electronic medical records. The presence and characteristics of PE were ascertained by a systematic review of all chest imaging studies, including computed tomography (CT), positron emission tomography (PET)-CT, chest X-ray, and thoracic ultrasound.

PE and MPE

PE was defined as any detectable fluid in the pleural space on imaging. MPE was strictly defined by positive cytological identification of malignant cells in pleural fluid obtained via thoracentesis or indwelling pleural catheter (IPC) or histopathological confirmation of malignant tumor invasion via pleural biopsy (18). Imaging findings of PE combined with a history of SCLC alone can only establish a clinical suspicion but cannot confirm the diagnosis.

Effusion volume categorization

Based on the initial imaging study identifying the effusion (the effusion volume was evaluated exclusively based on the initial baseline imaging at clinical presentation, before any thoracentesis or pleural intervention), patients were categorized into three groups:

• No effusion: no radiographic evidence of PE.
• Small PE: detectable effusion that occupies ≤1/3 of the hemithorax and does not require therapeutic thoracentesis or IPC placement (14,15,19).
• Moderate or greater PE: effusion occupying >1/3 of the hemithorax or any effusion requiring therapeutic intervention (thoracentesis or IPC) due to symptomatic distress (20).

Treatment variables

First-line systemic therapy was categorized as chemotherapy alone (platinum-etoposide) or chemoimmunotherapy [platinum-etoposide plus a programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitor]. The use of chest radiotherapy and antiangiogenic therapy was also recorded.

Biomarker analysis

For patients with IPC, paired serum and pleural fluid levels of serum-Neuron Specific Enolase (s-NSE), lactate dehydrogenase (LDH), C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR) and other biomarkers were collected (21,22). Cut-off values for continuous variables (e.g., s-NSE >45.1 µg/L) were determined using X-tile software (Yale University, USA) based on survival outcomes (23).

Outcome measures

The primary endpoint was OS, defined as the time from the date of SCLC diagnosis to death from any cause. Patients alive at the last follow-up were censored.

Statistical analysis

Categorical variables are presented as frequencies and percentages, and continuous variables as medians with ranges. Survival curves were estimated using the Kaplan-Meier method and compared with the log-rank test. For the overall cohort: univariable and multivariable Cox proportional hazards models were used to assess the impact of PE (present/absent) and other clinical factors on OS. For the MPE cohort (primary analysis): univariable Cox regression was performed to identify potential prognostic factors. Variables with P<0.10 in univariable analysis and those of a priori clinical importance [including effusion volume category (small vs. moderate or greater)] were entered into a multivariable Cox proportional hazards model using a backward stepwise selection process (retention criterion P<0.05) to identify independent predictors of OS. Binary logistic regression was used to explore factors associated with the need for IPC (a surrogate for symptomatic, large-volume effusion). All statistical analyses were performed using SPSS version 26.0 (IBM Corp., USA), and a two-sided P value <0.05 was considered statistically significant.

Results

Patient characteristics

Among 1,026 SCLC patients, the median age was 65 years (range, 25–98 years), and 85.8% were male. PE was identified at any time during the disease course in 373 patients (36.4%), with 284 (27.6%) presenting at diagnosis and 89 (9.1%) developing it during progression. Of the 373 patients with PE, 129 (34.6%) required IPC placement. Pleural fluid cytology was performed in IPC patients, confirming MPE in 75 (58.1%). Thus, the cytologically confirmed MPE incidence in the entire cohort was 7.3% (75/1,026). The baseline characteristics of the overall cohort and the MPE subgroup are summarized in Table 1.

Impact of PE and effusion volume on survival in the overall cohort

In the overall cohort, the presence of any PE was an independent adverse prognostic factor for OS on multivariable analysis [hazard ratio (HR) =1.71, 95% confidence interval (CI): 1.27–2.29, P<0.001], alongside liver metastasis (Table S1).

Crucially, stratification by effusion volume revealed profound differences. CT imaging demonstrating typical PE volume classification is shown in Figure 1A-1C. Median OS was 14.8 months for patients without effusion and 9.6 months for those with any effusion (P<0.001) (Figure 1D). Patients with moderate or greater effusion had a markedly poor median OS of 5.2 months. In contrast, the median OS for patients with small effusion was 13.8 months, which was not statistically different from the 14.8-month OS of patients with no effusion (P=0.54) but was significantly longer than that of the moderate or greater effusion group (P<0.001, Figure 1E).

Figure 1 Thoracic CT images of pleural effusion and its impact on survival in small-cell lung cancer. CT images of the thorax show representative cases with (A) no effusion or (B) small pleural effusion, or (C) moderate or greater pleural effusion. (D) Survival of patients with SCLC according to the presence of pleural effusion. (E) Survival of patients with small-cell lung cancer according to the presence and amount of pleural effusion. CI, confidence interval; CT, computed tomography; HR, hazard ratio; SCLC, small cell lung cancer.

Prognostic determinants in patients with cytologically confirmed MPE

We focused subsequent analysis on the 75 patients with cytologically proven MPE. Univariable analysis identified several factors associated with worse OS, including ECOG PS ≥2, multiple distant metastatic sites, elevated s-NSE, and positive pleural fluid cytology. Immunotherapy use was associated with significantly improved OS (Table 2).

The key multivariable Cox regression model for the MPE cohort is presented in Table 2. Independent adverse factors were ECOG PS ≥2 (HR =4.64, 95% CI: 1.11–19.39, P=0.03) and elevated s-NSE (>45.1 µg/L, HR =4.78, 95% CI: 1.14–19.97, P=0.03). The use of immunotherapy was associated with a substantial 82% reduction in the risk of death (HR =0.18, 95% CI: 0.04–0.76, P=0.02). Survival curves stratified by these key factors are shown in Figure 2.

Figure 2 Kaplan-Meier survival curves of different variables (A) s-NSE, (B) performance status, (C) treatment regimens in patients with MPE. ECOG PS, Eastern Cooperative Oncology Group performance status; MPE, malignant pleural effusion; s-NSE, serum neuron-specific enolase.

The utilization of later-line systemic treatments was evaluated to assess the potential impact of treatment attrition on survival outcomes. Patients in the MPE group were significantly less likely to receive subsequent therapies compared to the non-MPE cohort [22.7% (17/75) vs. 36.6% (109/298); χ²=5.183, P=0.02]. This disparity highlights a diminished opportunity for therapeutic rescue in patients presenting with malignant pleural involvement at baseline.

Associated with large-volume effusion requiring IPC

Logistic regression analysis of the overall PE cohort (n=373) indicated that age ≥65 years, ECOG PS ≥2, and extensive-stage disease at diagnosis were independent factors associated with the subsequent need for IPC placement (indicative of moderate or greater, symptomatic effusion) (Table S2).

Discussion

Our findings establish radiographic PE volume as an accessible prognostic marker in SCLC. Notably, survival outcomes for patients with small effusions were comparable to those of no-effusion patients. This observation challenges the traditional view that any PE uniformly indicates a poor prognosis. Moderate or greater effusions, however, defined a distinct high-risk cohort with a median OS of just 5.2 months. This volume-based stratification offers clinicians a simple metric to guide clinical staging and individualize therapeutic approaches.

Contrary to previous reports (13,15,24), we did not observe a statistically significant survival difference between SCLC patients without PE and those with small effusions. This discrepancy may reflect differences in study populations, treatment eras, or effusion definitions. Ryu et al. (15) studied patients diagnosed between 2003 and 2013, when chemotherapy alone was standard, whereas our cohort included patients treated with chemoimmunotherapy. Immunotherapy has reshaped the treatment landscape of SCLC. Multiple landmark trials and real-world studies have consistently demonstrated survival benefits with chemoimmunotherapy (5,25,26). ICIs have been shown to modulate the pleural immune microenvironment (27), potentially attenuating the unfavorable prognosis associated with minimal malignant cells seeding.

Due to the technical challenges of pathological confirmation for trace amounts of fluid, small PE is often clinical rather than cytological. Pathophysiologically, the development of small PEs in SCLC is highly heterogeneous and distinct from the extensive pleural dissemination seen in large effusions. Rather than overt metastasis, these trace-to-small fluid collections are frequently driven by benign, secondary reactive processes. For instance, central SCLC masses routinely cause bronchial compression, leading to post-obstructive pneumonia or atelectasis; the resulting locoregional inflammation transiently increases pleural capillary permeability and produces a sterile exudate (28,29). Furthermore, prominent mediastinal and hilar lymphadenopathy can mechanically impede normal lymphatic drainage. This partial blockade alters hydrostatic pressure gradients, causing slow fluid accumulation without direct pleural invasion (30,31). Even when small effusions contain malignant cells, the small volume indicates a micro-metastatic stage. At this point, the tumor burden remains insufficient to induce the severe, VEGF-driven vascular hyperpermeability characteristic of moderate or greater effusions (32), allowing local immune surveillance to restrict rapid disease progression. Ultimately, these predominantly non-aggressive etiologies explain why patients with small effusions share a favorable survival profile with those lacking pleural involvement.

In our MPE cohort, patients who received chemoimmunotherapy achieved longer OS. The MPE microenvironment is notoriously hostile to antitumor immunity, driven by a cytokine-rich [e.g., transforming growth factor-beta (TGF-β) and interleukin-6 (IL-6)] and regulatory T cells (Treg) infiltration (10,27,33). However, the dysfunctional state of CD8⁺ T cells within this space is often a reversible impairment mediated by the PD-1/PD-L1 axis rather than irreversible terminal exhaustion (34). By disrupting this inhibitory signaling, systemic ICIs can re-energize local T-cell responses while bolstering systemic surveillance. This dual action likely explains the improved clinical outcomes observed in lung cancer patients, even amidst the traditionally poor prognosis of pleural dissemination (35).

Our study has several limitations. The retrospective, single-center design may introduce selection bias. Admittedly, our longitudinal data (2008–2024) may be subject to era-related bias, as the therapeutic landscape evolved significantly from chemotherapy to ICIs. Although advancements in staging precision and supportive management have refined outcomes in the modern era, the prognostic value of PE at diagnosis appears resilient to these changes. To definitively isolate this effect, future prospective studies with standardized regimens are warranted. Additionally, the sample size of the cytologically confirmed cohort was modest, and detailed molecular tumor profiles were unavailable for deeper analysis.

Conclusions

In conclusion, this large cohort study redefines the prognostic landscape of MPE in SCLC. Effusion volume serves as a simple yet powerful stratification tool: small PE is not associated with inferior survival compared to no effusion, whereas moderate or greater PE identifies a subgroup with extremely poor outcomes. Furthermore, immunotherapy confers a profound survival benefit in MPE patients. The restricted access to later-line therapies in MPE patients underscores the need for early, more aggressive upfront interventions. These insights argue against the uniform high-risk classification of all MPE and advocate for a more nuanced, volume-adapted approach to prognosis, patient counseling, and therapeutic decision-making in SCLC.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the REMARK reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0170/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0170/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0170/prf

Funding: This work was supported by the 16th Batch ‘summit of the Six Top Talents’ Program of Jiangsu Province (No. WSN-154), China Postdoctoral Science Foundation 12th Batch Special Fund (No. 45786), Jiangsu Provincial Postdoctoral Science Foundation (No. 2018K049A), Natural Science Foundation of Jiangsu Province (No. BK20180139), and the Jiangsu Provincial Health Committee Medical Projects (No. M2022110).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0170/coif). Y.S. serves as the Editor-in-Chief of Translational Lung Cancer Research. 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. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Nanjing Jinling Hospital (No. 2024DZKY-051-01), with a waiver of informed consent due to its retrospective nature. Patient confidentiality was maintained.

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/.

References

1. Kim SY, Park HS, Chiang AC. Small Cell Lung Cancer: A Review. JAMA 2025;333:1906-17. [Crossref] [PubMed]
2. Wang Q, Gümüş ZH, Colarossi C, et al. SCLC: Epidemiology, Risk Factors, Genetic Susceptibility, Molecular Pathology, Screening, and Early Detection. J Thorac Oncol 2023;18:31-46. [Crossref] [PubMed]
3. Zhang J, Zeng X, Guo Q, et al. Small cell lung cancer: emerging subtypes, signaling pathways, and therapeutic vulnerabilities. Exp Hematol Oncol 2024;13:78. [Crossref] [PubMed]
4. Horn L, Mansfield AS, Szczęsna A, et al. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med 2018;379:2220-9. [Crossref] [PubMed]
5. Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet 2019;394:1929-39. [Crossref] [PubMed]
6. Paz-Ares L, Borghaei H, Liu SV, et al. Efficacy and safety of first-line maintenance therapy with lurbinectedin plus atezolizumab in extensive-stage small-cell lung cancer (IMforte): a randomised, multicentre, open-label, phase 3 trial. Lancet 2025;405:2129-43. [Crossref] [PubMed]
7. Zhao Y, Yu L, Wang L, et al. Current status of and progress in the treatment of malignant pleural effusion of lung cancer. Front Oncol 2022;12:961440. [Crossref] [PubMed]
8. Hu X, Zhao S, Li Y, et al. Development and validation of a machine learning-based nomogram for predicting prognosis in lung cancer patients with malignant pleural effusion. Sci Rep 2025;15:9714. [Crossref] [PubMed]
9. Shojaee S, Singh I, Solsky I, et al. Malignant Pleural Effusion at Presentation in Patients with Small-Cell Lung Cancer. Respiration 2019;98:198-202. [Crossref] [PubMed]
10. Rath B, Stickler S, Hochmair MJ, et al. Expression of cytokines in pleural effusions and corresponding cell lines of small cell lung cancer. Transl Lung Cancer Res 2024;13:5-15. [Crossref] [PubMed]
11. Kashima A, Fukuda Y, Shimamura M, et al. Successful treatment of extensive-stage small cell lung cancer with concurrent pleural and pericardial effusions: Case report. Front Oncol 2022;12:1040452. [Crossref] [PubMed]
12. Keidan N, Aujayeb A. Small Cell Lung Cancer and Pleural Effusion: An Analysis from a District General Hospital. Pulm Ther 2023;9:359-65. [Crossref] [PubMed]
13. Ryu JS, Ryu HJ, Lee SN, et al. Prognostic impact of minimal pleural effusion in non-small-cell lung cancer. J Clin Oncol 2014;32:960-7. [Crossref] [PubMed]
14. Light RW. Clinical practice. Pleural effusion. N Engl J Med 2002;346:1971-7.
15. Ryu JS, Lim JH, Lee JM, et al. Minimal Pleural Effusion in Small Cell Lung Cancer: Proportion, Mechanisms, and Prognostic Effect. Radiology 2016;278:593-600. [Crossref] [PubMed]
16. Gonnelli F, Hassan W, Bonifazi M, et al. Malignant pleural effusion: current understanding and therapeutic approach. Respir Res 2024;25:47. [Crossref] [PubMed]
17. Scherpereel A, Opitz I, Berghmans T, et al. ERS/ESTS/EACTS/ESTRO guidelines for the management of malignant pleural mesothelioma. Eur Respir J 2020;55:1900953. [Crossref] [PubMed]
18. Feller-Kopman DJ, Reddy CB, DeCamp MM, et al. Management of Malignant Pleural Effusions. An Official ATS/STS/STR Clinical Practice Guideline. Am J Respir Crit Care Med 2018;198:839-49.
19. Management of malignant pleural effusions. Am J Respir Crit Care Med 2000;162:1987-2001.
20. Psallidas I, Kalomenidis I, Porcel JM, et al. Malignant pleural effusion: from bench to bedside. Eur Respir Rev 2016;25:189-98. [Crossref] [PubMed]
21. Porcel JM. Biomarkers in the diagnosis of pleural diseases: a 2018 update. Ther Adv Respir Dis 2018;12:1753466618808660. [Crossref] [PubMed]
22. Xu K, Wu X, Chen L, et al. Risk factors for symptomatic malignant pleural effusion recurrence in patients with actionable mutations in advanced lung adenocarcinoma. Transl Lung Cancer Res 2023;12:1887-95. [Crossref] [PubMed]
23. Camp RL, Dolled-Filhart M, Rimm DL. X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res 2004;10:7252-9. [Crossref] [PubMed]
24. Porcel JM. Malignant pleural effusions because of lung cancer. Curr Opin Pulm Med 2016;22:356-61. [Crossref] [PubMed]
25. Mansfield AS, Każarnowicz A, Karaseva N, et al. Safety and patient-reported outcomes of atezolizumab, carboplatin, and etoposide in extensive-stage small-cell lung cancer (IMpower133): a randomized phase I/III trial. Ann Oncol 2020;31:310-7. [Crossref] [PubMed]
26. Wang J, Zhou C, Yao W, et al. Adebrelimab or placebo plus carboplatin and etoposide as first-line treatment for extensive-stage small-cell lung cancer (CAPSTONE-1): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2022;23:739-47. [Crossref] [PubMed]
27. Ge S, Zhao Y, Liang J, et al. Immune modulation in malignant pleural effusion: from microenvironment to therapeutic implications. Cancer Cell Int 2024;24:105. [Crossref] [PubMed]
28. Light RW. Parapneumonic effusions and empyema. Proc Am Thorac Soc 2006;3:75-80. [Crossref] [PubMed]
29. Sahn SA. The pathophysiology of pleural effusions. Annu Rev Med 1990;41:7-13. [Crossref] [PubMed]
30. Meyer PC. Metastatic carcinoma of the pleura. Thorax 1966;21:437-43. [Crossref] [PubMed]
31. Thomas JM, Musani AI. Malignant pleural effusions: a review. Clin Chest Med 2013;34:459-71. [Crossref] [PubMed]
32. Stathopoulos GT, Kalomenidis I. Malignant pleural effusion: tumor-host interactions unleashed. Am J Respir Crit Care Med 2012;186:487-92. [Crossref] [PubMed]
33. Wang S, An J, Hu X, et al. Single-cell RNA sequencing reveals immune microenvironment of small cell lung cancer-associated malignant pleural effusion. Thorac Cancer 2024;15:98-103. [Crossref] [PubMed]
34. Prado-Garcia H, Romero-Garcia S, Puerto-Aquino A, et al. The PD-L1/PD-1 pathway promotes dysfunction, but not "exhaustion", in tumor-responding T cells from pleural effusions in lung cancer patients. Cancer Immunol Immunother 2017;66:765-76. [Crossref] [PubMed]
35. Wei Q, Deng T, Wu J, et al. Immune checkpoint inhibitor plus chemotherapy as first-line treatment for non-small cell lung cancer with malignant pleural effusion: a retrospective multicenter study. BMC Cancer 2024;24:393. [Crossref] [PubMed]