Pseudoprogression of pleural effusion in lung cancer treated with immunotherapy: a case report

Introduction

Lung cancer is a leading cause of morbidity and mortality worldwide. In recent years, immune checkpoint inhibitors (ICIs) have revolutionized treatment strategies of advanced lung cancer. In clinical practice, a novel tumor response pattern known as pseudoprogression (PsP) has emerged during ICI therapy and is increasingly recognized as a novel concept in tumor assessment (1). This atypical response pattern complicates the evaluation of treatment efficacy and treatment decision-making. PsP was first described in patients with malignant melanoma treated with anti-cytotoxic T-lymphocyte-associated protein 4 antibodies and has been reported in approximately 10% of cases (2).

The emergence of PsP in non-small cell lung cancer (NSCLC) is very rare (3), and reports of PsP involving malignant pleural effusion are extremely scarce. A better understanding of the mechanisms behind PsP is needed. PsP is characterized by an initial increase in tumor size or the appearance of new lesions due to lymphocytic infiltration induced by immunotherapy (4,5). This phenomenon can mimic disease progression on radiologic imaging, making it challenging to distinguish from true progression. While some patients may indeed experience true tumor growth or new metastases due to treatment failure, differentiating PsP from true progression is a major clinical challenge.

Here, we present a rare case of PsP of malignant pleural effusion in a patient with recurrent pleural dissemination of lung adenocarcinoma, treated with anti-programmed death-1 (PD-1) therapy. We present this case in accordance with the CARE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-397/rc).

Case presentation

A 56-year-old woman was found to have a 10-mm peripheral pulmonary nodule with pleural indentation in the right upper lobe on chest computed tomography (CT) during pre-dialysis evaluation at Osaka Metropolitan University hospital. Positron emission tomography-CT revealed fluorodeoxyglucose uptake in the right upper lobe nodule [standardized uptake value maximum (SUVmax) 11.6] and mediastinal lymph node (4R, SUVmax 6.3), leading to a clinical diagnosis of lung cancer (c-T1cN2M0, stage IIIA). Due to the difficulty in obtaining a definitive preoperative diagnosis, the patient underwent surgical resection. Video-assisted thoracoscopic partial resection of the right upper lobe with mediastinal lymphadenectomy was performed. Intraoperative cytology of the pleural effusion was positive for malignancy. The pathological stage was p-T2aN2 (2R, 4R) M1a, stage IVa, with programmed death-ligand 1 expression of 5%, and a Kirsten rat sarcoma virus non-G12C mutation. Postoperative chemotherapy was necessary; however, it was not administered due to the patient’s renal impairment requiring dialysis.

Two months later, follow-up chest CT revealed multiple mediastinal lymph node recurrences and pleural dissemination without pleural effusion (Figure 1A,1B). Pembrolizumab monotherapy was initiated as the first-line treatment. Three weeks later, chest radiography revealed a new-onset right pleural effusion with no symptoms (Figure 1A), and diagnostic thoracentesis was performed to determine the etiology of the effusion. The pleural fluid analysis revealed an increased cell count with a predominance of lymphocytes (lymphocytes: 46%; neutrophils: 1.0%; others: 45%), elevated lactate dehydrogenase (161 U/L), increased total protein (5,340 mg/dL), and a low adenosine deaminase level of 27.0 U/L. Cytologic evaluation of pleural effusion confirmed adenocarcinoma cells. Both mycobacterial and bacterial cultures were negative. As shown in Figure 1A, there was no cardiomegaly on imaging, and serum human atrial natriuretic peptide levels, routinely monitored during dialysis, remained within normal limits. There were no clinical signs of heart failure, such as weight gain or peripheral edema. Additionally, contrast-enhanced CT ruled out pulmonary embolism. Since the patient remained asymptomatic, a second cycle of pembrolizumab was administered 1 week later. Subsequently, serum tumor marker levels (CYFRA and CEA) decreased, and the pleural effusion showed no further progression and gradually resolved spontaneously. By the fourth cycle, the pleural effusion had completely disappeared, and CT imaging demonstrated regression of both mediastinal lymph node metastases and pleural dissemination (Figure 1C). The patient remained on pembrolizumab for 14 months; however, follow-up CT revealed disease progression with worsening pleural dissemination and the emergence of brain metastases, leading to treatment discontinuation and initiation of a subsequent therapy.

Figure 1 The clinical course of the patient by imaging. (A) Chest radiographic examinations were performed at baseline, at the onset of pleural effusion 3 weeks later, and during cycles 3, 4, and 5. (B,C) Computed tomography of the chest at baseline (B) and 3 months later (C). Pleural dissemination (circles).

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s), and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompany images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

In lung cancer patients receiving immunotherapy, the emergence or increase of pleural effusion is typically considered a sign of disease progression or an immune-related adverse event (irAE). In several phase III clinical trials of ICIs for NSCLC, pleural effusion has not been commonly reported as an irAE (6,7). Reports of malignant pleural effusion as PsP during immunotherapy in patients with NSCLC are extremely limited, suggesting that this phenomenon is likely to be unrecognized. In our case, the rapid increase in pleural effusion after pembrolizumab initiation raised concerns of hyperprogressive disease. Pleural fluid cytology revealed malignant cells: however, the patient remained asymptomatic without fever, dyspnea, or chest pain, the general condition was stable, and there were no imaging findings suggestive of recurrence. Given the multifactorial nature of pleural effusion, a thorough differential diagnosis was conducted, taking into account the patient’s end-stage renal disease and ongoing ICI therapy. In addition to disease progression, we carefully excluded other potential etiologies such as heart failure–related effusion, uremic pleuritis secondary to renal dysfunction, tuberculous pleuritis, and pulmonary embolism. When considering PsP as a potential cause, it is crucial to rule out these alternative causes through systematic evaluation. A comprehensive assessment that incorporates radiological findings, clinical course, and, when necessary, histopathological evaluation is essential for accurate diagnosis of PsP (8-10). Interestingly, despite the presence of malignant cells in pleural effusion, the effusion resolved spontaneously with continued immunotherapy. Our case, along with a few reported cases (11,12), suggests a potential association between the development of pleural effusion in patients receiving ICIs and PsP.

Clinical features of pleural effusions associated with PsP may be more likely to occur in patients with pre-existing pleural effusions prior to ICI treatment, usually within the first month of ICI initiation (11). Although there is no universally established definition for the onset timing of PsP, the 12-week mark after ICI initiation has been widely adopted in clinical literature as a pragmatic cutoff to categorize PsP into early and late onset forms (3,13-15). PsP-related pleural effusion is often cytologically positive in the early treatment phase but may become cytologically negative with continued therapy. However, pleural effusions due to true progressive disease (TPD) is persistently cytologically positive (16). It is clinically difficult to perform continuous pleural fluid cytology testing while treating ICI. The identification of reliable biomarkers is critical in the development of ICIs. Since PsP can occur in a subset of patients receiving ICIs, there is a need for markers that not only predict response but also aid in treatment evaluation. The differential diagnosis of pleural effusion during ICI therapy includes PsP, irAE, and TPD; however, definitive criteria remain unclear. In malignant pleural mesothelioma, higher baseline levels of PD-1 soluble forms in pleural effusion were a predictive marker for better response to anti-PD-1 monotherapy (17). Additionally, a high CD4/CD8 ratio in pleural effusion has been reported to correlate with favorable treatment response to ICIs, particularly when exceeding 1.93, in NSCLC patients treated with ICIs (16). Currently, there are no factors that can be used to correctly determine the ICI decision-making process when a pleural effusion emerges during ICI treatment. Identifying these factors will improve diagnostic differentiation between PsP, irAE, and TPD.

When PsP is suspected, continuation of ICIs may be the best option if the overall tumor burden remains controlled and pleural effusion is manageable. Unlike true disease progression, PsP has been associated with more favorable outcomes (10,13,14), and distinguishing between the two is essential to avoid premature discontinuation of effective immunotherapy. Accordingly, current clinical recommendations emphasize that when progression is suspected during immunotherapy, treatment should not be halted solely based on radiographic findings if the patient’s general condition is stable and irAEs are manageable (18,19). To support this decision-making process, the immune-modified Response Evaluation Criteria in Solid Tumors (iRECIST) guidelines were introduced. Under iRECIST, initial radiographic progression is categorized as immune unconfirmed progressive disease, and treatment continuation is permitted until progression is confirmed by follow-up imaging after 4–8 weeks (20). Thus, continued treatment and close observation in the context of suspected PsP should be regarded as an evidence-based, proactive medical intervention rather than a passive approach. Our case highlights that PsP can occur even in patients without pre-existing pleural effusion, suggesting that continued ICI therapy may provide clinical benefit in such cases. The distinction between PsP and irAE remains unclear. Unlike PsP, irAE-related pleural effusion does not resolve spontaneously with continued immunotherapy (11,21), and discontinuation of treatment or steroid therapy is often effective for irAE-related pleural effusion. Some reports suggest that pleural effusion appearing after ICI initiation may resolve with a combination of continued ICI therapy and corticosteroids. Cytological analysis of pleural effusion caused by irAEs has been reported to yield negative results (21,22). A case report analyzed flow cytometry of pleural effusions in a patient with renal cell carcinoma who developed pleuritis after nivolumab treatment and suggested a possible mechanism of tumor-infiltrating lymphocytes-mediated pleural effusions (22). We made a clinical diagnosis of PsP by the clinical course of the patient using pathological evaluations which were less extensive; however, we feel that clinical judgement is the most important consideration in patients presenting with pleural effusion during ICI therapy

The timing of treatment evaluation is crucial when pleural effusion occurs during ICI therapy. If true disease progression is present, delaying treatment adjustments may lead to lost therapeutic opportunities. Therefore, follow-up imaging evaluations should be performed within 4 weeks to avoid missing TPD, although no definitive guidelines exist. Given the sparse research and limited case reports, further studies are needed to accurately distinguish PsP from irAEs and TPD.

Conclusions

This case underscores the importance of recognizing PsP in patients receiving ICIs and highlights challenges in distinguishing PsP from true progression and irAEs. Clinicians should consider PsP in cases of early pleural effusion during ICI therapy and carefully evaluate the potential for continued immunotherapy before making treatment decisions.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-397/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-397/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-397/coif). H.K. reports a relationship with MSD, Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., and Bristol Myers Squibb Co., and AstraZeneca that includes speaking and lecture fees. 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. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s), and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompany images. A copy of the written consent is available for review by the editorial office of this journal.

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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