The granulomatous pulmonary nodules induced by tislelizumab in advanced squamous NSCLC: a case report with challenging differential diagnosis

Introduction

Immune checkpoint inhibitors (ICIs) targeting programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) have become a cornerstone in advanced non-small cell lung cancer (NSCLC) treatment. While immune-related pneumonitis is a recognized complication, granulomatous lung reactions are rare and can be challenging to be differentiated from infection or tumor progression (1). We present a case of tislelizumab-induced granulomatous pulmonary nodules with biphasic steroid-dependent and self-limiting behavior, emphasizing the importance of pathologic confirmation and multidisciplinary management. We present this case in accordance with the CARE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-598/rc).

Case presentation

A 59-year-old male smoker presented with cough, sputum, and chest pain. The chest computed tomography (CT) scan revealed that the lesion was located in the upper left lung, accompanied by cancer-related lymphangitis and local involvement of the left pleura (Figure 1), also had multiple lymph node metastases in mediastinum and left hilar region (Figure 1A). Bronchoscopic examination demonstrated a neoplastic lesion blocking the upper lobe of the left lung (Figure 2). Pathologic examination confirmed that the lesion was a moderately differentiated squamous cell carcinoma (Figure 3A), and subsequent pathological results revealed key nodes in the disease progression (Figures 3,4). The patient was diagnosed with left upper lobe squamous cell carcinoma (cT4N2M1a, stage IVA) based on the 8th edition of the tumor-node-metastasis (TNM) staging system.

Figure 1 CT scan of the patient. At baseline (A) with initial lesion (yellow arrow) in the left lung (January 2019); (B) significant shrinkage of the primary lesion (yellow arrow) and (C) emergence of a new lesion (red arrow) in the right lung (April 2019); (D) partial absorption of the right lung lesion (red arrow) with new small nodules (blue arrows) in the left lung (August 2019); (E) absorption of newly developed nodules (blue arrow and red arrow) in both lungs (September 2019); (F) further reduction of lesions (red arrow) (April 2020); (G) enlargement of a metastatic nodule (red arrow) with cavitation (green arrow) in the right lower lung (October 2022); (H) consolidation (red arrow) in the posterior segment of the right upper lung, suggestive of radiation-induced inflammation (September 2024). CT, computed tomography.

Figure 2 Bronchoscopy of the patient at baseline, revealing a neoplasm (yellow arrow) in the left upper lobe (January 2019).

Figure 3 Histopathological evolution of pulmonary lesions. (A) Initial diagnosis of moderately differentiated squamous cell carcinoma (yellow arrows) in the left lung (January 16, 2019); (B) new lesion in the right lung identified as epithelioid granulomatous inflammation (June 20, 2019); (C) new lesion in the left lung showed granulomatous inflammation with necrosis, fibrous tissue hyperplasia, and carbon deposition, with no definitive malignancy observed (August 16, 2019); (D) new lesion in the right lung showing fibrous tissue proliferation with focal nests of atypical cells, suggestive of squamous cell carcinoma (yellow arrows) (November 21, 2022). Hematoxylin and eosin stain: left ×100, right ×400.

Figure 4 Flowchart of the diagnostic and treatment journey of the patient from January 2019 to September 2024. The timeline outlines the sequence of interventions, including combinations of chemotherapy and immunotherapy, anti-tuberculosis therapy, adjustments in maintenance therapy, and corresponding clinical outcomes. It also incorporates CT scan and pathological findings at each stage, demonstrating the dynamic and adaptive management of the patient’s condition. CT, computed tomography; HRZE, isoniazid, rifampin, pyrazinamide, ethambutol (anti-tuberculosis therapy regimen); OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SCC, squamous cell carcinoma; SD, stable disease.

The patient was enrolled in a phase 3 clinical trial conducted in our center (RATIONAL 307) (2). Inclusion criteria for the clinical trial were stage IIIB to IV stage squamous NSCLC without prior therapy history. 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 Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal. Since January 2019, the patient had been receiving the treatment regimen of tislelizumab (200 mg on day 1) combined with albumin-bound paclitaxel (100 mg/m² on days 1, 8, and 15) and carboplatin (AUC5 on day 1) every 3 weeks (Figure 4).

The monitoring CT scan demonstrated that, after three cycles of treatment, the primary lesion had significantly decreased in size compared to baseline (Figure 1B). However, new nodules were detected in the right lung (Figures 1C,4). To clarify the diagnosis, we performed CT-guided lung biopsy in April 2019. During the puncture process, the patient experienced severe coughing, and the subsequent CT scan showed pneumothorax, so we stopped the lung biopsy. Following continuation of the original treatment plan for 4–5 cycles, the patient experienced grade 3 hematological toxicity (neutropenia and thrombocytopenia). After symptomatic management, a repeat percutaneous CT-guided right lung biopsy was conducted in June 2019, revealing epithelioid granulomatous inflammation (Figures 3B,4). Immunohistochemical findings were as follows: CD68 (3+), CD163 (3+), CKpan (epithelial+), TTF-1 (epithelial+), CD20 (focal+), CD30 (focal+), CK5/6 (−), P63 (−). Special stains demonstrated: PAM (−), PAS (−), acid-fast staining (−). Considering the patient’s history of significant granulocytopenia following chemotherapy, and despite the negative tuberculosis polymerase chain reaction (PCR) result in the lung tissue specimen, tuberculosis could not be definitively ruled out. As such, empirical anti-tuberculosis therapy (HRZE) was initiated, which included isoniazid, rifampicin, pyrazinamide and ethambutol (Figure 4).

In August 2019, a follow-up chest CT scan revealed partial resolution of the right lung lesion compared to prior imaging, but new lesions were identified in the left lung with surrounding scattered small nodules (Figure 1D). Subsequently, a percutaneous CT-guided lung biopsy of the new left lung lesion was conducted again. Pathological examination demonstrated granulomatous inflammation with necrosis, along with fibrous tissue proliferation and carbonaceous deposition (Figure 3C). No definitive evidence of malignancy was observed. The patient was ultimately diagnosed with immune-related granulomatous pneumonia (sarcoid-like reaction). In August 2019, prednisone was initiated at a dose of 30 mg/day, and tislelizumab maintenance therapy was continued (Figure 4). In September 2019, follow-up CT imaging demonstrated significant resolution of the nodules (Figure 1E), leading to the discontinuation of anti-tuberculosis medications. From September 2019 to January 2020, tislelizumab monotherapy was maintained for disease control, while the prednisone dosage was gradually tapered. By January 2020, prednisone was fully discontinued (Figure 4). In April 2020, a chest CT follow-up revealed the pulmonary lesions are trending toward stabilization (Figure 1F).

Long-term follow-up of the patient demonstrated a progression-free survival (PFS) of 46 months, which was markedly longer than the median PFS observed in patients with advanced squamous cell carcinoma (Figure 4). By the end of 2022, the patient’s follow-up chest CT scan demonstrated an increase in the size of the lesion compared to the previous examination (Figure 1G). On November 21, 2022, the patient underwent a repeat percutaneous CT-guided lung biopsy, and the pathological results confirmed the diagnosis of squamous cell carcinoma (Figure 3D), resulting in the determination of disease progression. This represents a striking contrast compared to the previous change in the patient’s condition. The sustained administration of immunotherapy appeared to contribute positively to the patient’s overall survival benefit. The patient stick to the treatment of tislelizumab, and anti-angiogenic therapy was added. The latest CT scan was performed in September 2024 (Figures 1H,4).

Discussion

During lung cancer immunotherapy, the differential diagnosis of new pulmonary lesions is critically important. The potential considerations for differential diagnosis may include, but are not limited to, tumor progression, immune-mediated pulmonary adverse events, pulmonary infections induced by specific pathogens, and pseudo-progression following immunotherapy (3). This patient underwent four percutaneous lung biopsies, yielding histological evidence on three occasions. Among these, two pathological assessments ruled out tumor progression. By continuing immunotherapy based on these findings, the patient achieved a prolonged PFS and demonstrated significant improvement in overall survival.

Granulomatous inflammation should raise suspicion of tuberculosis or fungal infection. However, the microbiological test results were negative, and the patient showed a significant response to corticosteroid treatment, suggesting that the formation of the new nodules may be closely related to an immune-mediated mechanism (4). In the setting of agranulocytosis, empirical anti-tuberculosis treatment is justified but was ultimately deemed unnecessary. Repeated biopsies excluded malignancy and infectious diseases, confirming the diagnosis of a corticosteroid-sensitive immune-related adverse event (irAE).

ICIs may induce the formation of sarcoidosis-like granulomas through the activation of macrophages (CD68+/CD163+) and the induction of a Th1-type immune response (5). The biphasic pattern characterized by an initial corticosteroid-dependent response followed by self-limiting relapses indicates the presence of dynamic immune regulation during disease progression.

Current studies have shown that ICI-related sarcoidosis has specific clinical features, and its manifestations are often more benign than idiopathic sarcoidosis (6). Therefore, it does not necessarily mean that ICI treatment needs to be stopped (7). Moreover, in the case of Common Terminology Criteria for Adverse Events (CTCAE) grade 1 ICI-related sarcoidosis, continuing ICI use is usually safe. According to the CTCAE grading criteria, the patient exhibits solely imaging abnormalities without apparent clinical symptoms, thereby being classified as CTCAE Grade 1. In light of the dynamic evolution of the lesion, corticosteroid treatment is recommended to effectively control disease progression (8). As the prednisone dosage is relatively low and a gradual tapering regimen is adopted, its influence on the efficacy of immunotherapy is deemed negligible. Therefore, during the course of corticosteroid treatment, it is resolved to maintain the administration of checkpoint inhibitor.

Emerging evidence indicates that tislelizumab is associated with a relatively lower overall incidence of irAEs compared to certain other ICIs, with generally milder severity and a reduced likelihood of specific irAEs, such as endocrine disorders (9). In contrast, several other ICIs have been linked to a higher frequency of severe irAEs, including grade 3 or higher pneumonitis and myocarditis. Consequently, in the context of re-challenge therapy, tislelizumab may offer a favorable risk-benefit profile by preserving robust anti-tumor efficacy while potentially mitigating the occurrence of certain irAEs.

Pathological confirmation should serve as the diagnostic gold standard to avoid unnecessary anti-infection treatment (10). In this case, the patient exhibited a rapid response to prednisone, further supporting an immune-mediated etiology. However, nodule recurrence following corticosteroid discontinuation indicates that some patients may require a more gradual tapering regimen. Furthermore, despite the confirmed diagnosis of granulomatous pneumonia, the patient successfully continued tislelizumab treatment, suggesting that irAEs may not preclude the safe continuation of ICI therapy when corticosteroid control is well maintained.

However, it is crucial to recognize that even when imaging studies demonstrate lesion regression, residual tumor components may persist or coexist within granulomatous lesions. Traditional biopsy modalities have inherent limitations: bronchoscopic biopsy, restricted by sampling depth and scope, frequently fails to reach deeper tissues within granulomas; meanwhile, CT-guided needle biopsies yield relatively small tissue specimens, which may inadequately capture the lesion’s heterogeneity and readily overlook sparsely distributed tumor cells (11).

Accordingly, in cases where routine biopsy results are inconclusive yet clinical suspicion of malignancy remains strong, cryobiopsy stands out as a valuable supplementary method. This technique enables the procurement of larger, histologically intact tissue samples, thereby enhancing the accuracy of identifying tumor components within a granulomatous backdrop and furnishing critical evidence for a definitive diagnosis (12).

Conclusions

This case suggests that tislelizumab may induce granulomatous pulmonary nodules which is sensitive to corticosteroid but may have a brief recurrence after drug withdrawal. Pathological confirmation is crucial for differentiating benign lesions from tumor progression. Patients exhibiting controllable irAEs can safely proceed with ICI treatment under rigorous surveillance.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-598/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-598/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-2025-598/coif). The 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 Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying 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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