Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy by enhancing antitumor immunity. Their primary mechanism involves the blockade of the PD-1/PD-L1 axis, which restores T-cell activation and improves immune recognition and elimination of tumor cells (1). This mechanism has positioned immunotherapy as a promising approach for achieving durable disease control and, in selected settings, may contribute to long-term remission (2, 3).

With the widespread clinical use of ICIs, immune-related adverse events (irAEs) are increasingly recognized, with severity ranging from mild symptoms to life-threatening conditions. Although secondary lymphomas appear to be rare, their potential severity warrants close clinical monitoring. The 2025 Drug Vigilance Summary in the Journal for ImmunoTherapy of Cancer reviewed lymphoma cases reported after ICI exposure and identified a signal involving secondary pulmonary lymphoma (SPL), including invasive B-cell lymphoma. While such pharmacovigilance signals do not establish causality, they underscore the importance of clinical vigilance, particularly when new lymphadenopathy or atypical effusions emerge during or after immunotherapy.

Clinically, diffuse large B-cell lymphoma (DLBCL) often presents with lymphadenopathy or extranodal involvement, which may be misinterpreted as cancer progression, thus posing challenges for early diagnosis and potentially delaying appropriate treatment. The management of such cases may be further complicated by the interruption of immunotherapy due to severe irAEs, which could impact tumor control and influence recurrence risk (4). It is crucial to recognize that these phenomena may be due to an immune dysregulation process rather than direct causality from the immunotherapy itself. This necessitates a cautious approach in the interpretation of new lymphoid findings and highlights the importance of maintaining a high index of suspicion when managing cancer patients undergoing ICI therapy.

A 70-year-old woman presented with a two-month history of mild abdominal discomfort. In August 2022, upper gastrointestinal endoscopy performed at Weifang Sunshine United Hospital revealed mass lesions at the gastroesophageal junction and gastric fundus. Histopathological examination of biopsy specimens confirmed poorly differentiated gastric cardia adenocarcinoma, and Epstein–Barr virus–encoded RNA (EBER) in situ hybridization was negative. The patient was transferred on August 14, 2022, to Weifang People’s Hospital for pathological review, which confirmed moderately to poorly differentiated gastric adenocarcinoma. She subsequently received two cycles of neoadjuvant FOLFOX chemotherapy (oxaliplatin, leucovorin, and 5-fluorouracil).Preoperative evaluation in September 2022 showed negative HIV serology; human herpesvirus 8 (HHV-8) testing was not performed. The patient underwent laparoscopic total gastrectomy with regional lymph node dissection and Roux-en-Y reconstruction. Postoperative histopathology demonstrated diffuse poorly differentiated gastric adenocarcinoma with prominent lymphocytic infiltration and no lymph node metastasis (Figures 1A, B).

In November 2022, postoperative surveillance positron emission tomography/computed tomography (PET/CT) revealed a hypermetabolic nodule in the left abdominal cavity (Figure 2A) and left-sided pleural effusion (Figure 2B), raising suspicion for metastatic lymphadenopathy. From November to December 2022, the patient initiated adjuvant therapy with two cycles of FOLFOX combined with the programmed cell death protein 1 (PD-1) inhibitor sintilimab. In January 2023, diagnostic thoracentesis demonstrated abundant, diffusely distributed, relatively monomorphic atypical lymphoid cells. EBER in situ hybridization showed focal positivity. Given that exfoliative cytology alone was insufficient for definitive diagnosis, B-cell receptor gene rearrangement analysis was performed and revealed monoclonal B-cell rearrangement (Table 1). After multidisciplinary pathological consultation and consideration of prior cytotoxic and immunomodulatory therapy, the findings were interpreted as treatment-associated abnormal B-cell proliferation. Continued antitumor therapy with close surveillance was recommended. Between January and early April 2023, the patient received two intrapleural treatments with reduction of pleural effusion and subsequently completed six additional cycles of FOLFOX combined with sintilimab.

In April 2023, follow-up ultrasonography identified a large right-sided pleural effusion. Repeat cytological analysis (Figures 3A–C), flow cytometry (Figures 3D–G), and external expert consultation favored a diagnosis of diffuse large B-cell lymphoma (DLBCL). PET/CT showed resolution of metabolic activity in the previously noted left abdominal lesion but increased metabolic activity in pleural and pericardial effusions (Figures 2C, D), consistent with malignant effusions. After one additional cycle of the original regimen, the patient was evaluated at Peking University Cancer Hospital on April 28, 2023. Multidisciplinary consultation raised the possibility of concomitant gastric adenocarcinoma and DLBCL; however, repeat tissue biopsy was recommended but not obtained, and the nature of the lymphoid proliferation—reactive, immune-related, or overt lymphoma—remained uncertain. In May 2023, the patient returned to Weifang People’s Hospital. Given the absence of significant metabolic activity in abdominal lymph nodes, resolution of bilateral pleural effusions, and apparent clinical stability of the lymphoproliferative process, she received two cycles of sintilimab maintenance therapy between May and June 2023 following comprehensive reassessment.

In July 2023, the patient was readmitted with chest tightness and dyspnea. Imaging revealed recurrent pleural and pericardial effusions. Pericardial fluid cytology demonstrated numerous morphologically uniform atypical lymphoid cells (Figure 3H). Integrating immunohistochemical findings (Figures 3I–S) with longitudinal clinical data, a definitive diagnosis of DLBCL was established. According to the Ann Arbor staging system, the disease was classified as stage III, with elevated lactate dehydrogenase (341 U/L). From July to November 2023, the patient received six cycles of R-CHOP chemotherapy. Post-treatment PET/CT demonstrated complete resolution of pleural, pericardial, and pelvic effusions. However, new hypermetabolic lesions were detected in the right colon (Figure 2E) and distal esophageal anastomosis (Figure 2F), raising concern for recurrent or metastatic gastric adenocarcinoma. The patient continued sintilimab maintenance therapy until February 2024 and received two cycles of oral tegafur, which was discontinued due to severe gastrointestinal toxicity.

In November 2024, the patient was rehospitalized with bilateral lower extremity edema and progressive dysphagia. In December 2024, biopsies of retroperitoneal lymph nodes and ascitic fluid were performed. Lymph node histopathology demonstrated lymphoid proliferation with broad immunophenotypic positivity (Figures 4A–L). Ascitic fluid cytology confirmed malignant lymphoid cells (Figures 4M–Q), and PET/CT revealed disseminated hypermetabolic lesions (Figure 2G). DLBCL demonstrated a double-expressor phenotype by immunohistochemistry, with MYC and BCL2 overexpressed in ~65% and ~80% of tumor cells, respectively; FISH for MYC, BCL2, and BCL6 rearrangements was not performed. The patient received one cycle of R-CHOP chemotherapy.

In January 2025, the patient was readmitted due to disease progression. Although a repeat biopsy was recommended, the family declined; the patient subsequently received an additional cycle of R-CHOP chemotherapy before discharge. On January 20, 2025, the patient was hospitalized again for treatment-related myelosuppression—manifested primarily as leukopenia and thrombocytopenia—complicated by pulmonary infection, Aspergillus fumigatus infection, and influenza A. Following targeted anti-infective therapy at Sunshine Fusion Hospital, the patient’s condition improved, allowing discharge. In February 2025, due to further disease progression, the patient was readmitted and treated with two cycles of polatuzumab vedotin combined with rituximab and bendamustine (Pola+BR). On April 11, 2025, the patient succumbed to acute respiratory failure secondary to a pulmonary infection (Figure 1C).

This case report describes a rare clinical scenario in which diffuse large B-cell lymphoma (DLBCL) was diagnosed in a patient with gastric adenocarcinoma during postoperative treatment, including immune checkpoint inhibitor (ICI) therapy. While ICIs have shown significant efficacy in various malignancies, their increasing use has been accompanied by the recognition of rare or unexpected immune-associated events, particularly in less common oncological settings, as noted in a recent systematic review of ICIs in rare tumors (5). Hematologic complications, including sporadic reports of lymphoma occurring temporally with ICI exposure, have raised growing attention (6, 7).

In the present patient, pleural effusion developed during postoperative treatment with FOLFOX chemotherapy combined with the PD-1 inhibitor sintilimab. Cytological examination of the pleural fluid revealed atypical lymphoid cells, with occasional Epstein–Barr virus (EBV)–encoded RNA (EBER)-positive cells identified. These findings suggest the presence of immune perturbation during therapy; however, they do not, in isolation, establish a definitive diagnosis of lymphoma at that time. Immunophenotyping, flow cytometry, and clonality studies were not performed on the pleural effusion specimen, precluding a definitive distinction between a reactive lymphoid process and an evolving lymphoproliferative disorder. Given the effusion-driven presentation, the differential diagnosis should have explicitly included HHV-8–associated primary effusion lymphoma (PEL), HHV-8–negative, EBV-positive effusion-based large B-cell lymphoma in older adults, and other aggressive B-cell lymphomas presenting with serous effusions. Importantly, HIV testing was negative and HHV-8 status was not assessed, which limits precise classification according to WHO/ICC criteria. Early pleural fluid findings must therefore be interpreted with caution, and diagnostic uncertainty at that time must be acknowledged.

A major limitation of this case is the absence of comprehensive baseline systemic staging prior to the initiation of sintilimab therapy. Whole-body PET/CT or contrast-enhanced CT imaging performed before immunotherapy was not available for review. As a result, the possibility of a pre-existing occult or indolent lymphoproliferative disorder cannot be excluded. This limitation directly affects the interpretation of causality, raising the alternative possibility that immunotherapy and/or chemotherapy may have unmasked or accelerated the clinical manifestation of an underlying process, rather than inducing de novo lymphomagenesis. Notably, postoperative PET/CT identified a solitary FDG-avid lymph node, which was not biopsied and was initially interpreted as metastatic gastric adenocarcinoma. Retrospective reassessment suggests that this lesion may alternatively represent early lymphomatous involvement. The FDG uptake patterns of lymphoma and gastric cancer metastases may overlap, and in the absence of histopathological confirmation, definitive attribution of this hypermetabolic lymph node is not possible. The subsequent development of pathologically confirmed DLBCL supports the possibility that this PET/CT abnormality reflected an early or subclinical lymphoproliferative process.

Gastric cancer, with approximately 90% of cases being gastric adenocarcinoma (8), is common worldwide, while DLBCL arises from complex dysregulation of B-cell development and differentiation (9). Genetic alterations involving MYC, BCL2, and BCL6 (10–12), as well as aberrant activation of signaling pathways such as NF-κB and PI3K/Akt (13), are critical in lymphomagenesis. Based on existing literature, we propose several hypothetical mechanisms through which PD-1 blockade–associated immune modulation could contribute to aberrant B-cell activation in susceptible individuals (Figure 1D). These mechanisms are speculative and are presented to illustrate biological plausibility rather than to imply causation based on this single case.

Secondary DLBCL arising in patients with gastric cancer appears to be uncommon. Immune checkpoint inhibitors enhance T-cell activity by disrupting PD-1/PD-L1 interactions, but in some individuals, this immune activation may be accompanied by dysregulated immune responses (14). Cytokines such as IL-21, IL-4, IL-10, IFN-γ, and TNF-α, which are influenced by T-cell activation, may indirectly affect B-cell proliferation and survival (15–18). In addition, PD-1 signaling plays a role in regulating B-cell homeostasis and antibody quality, and its blockade may perturb these processes (19). Altered follicular helper T-cell (Tfh) localization and function under PD-1 inhibition may further influence B-cell activation (20).

However, chemotherapy-related immune perturbation represents a significant alternative explanation. Oxaliplatin- and fluoropyrimidine-based regimens can induce lymphodepletion, alter antigen presentation, and disrupt immune homeostasis during immune reconstitution (21). Such changes may transiently create a permissive environment for lymphoproliferation, independent of or synergistic with immune checkpoint inhibition. Therefore, the emergence of DLBCL in this patient cannot be attributed solely to PD-1 blockade.

EBV-associated lymphoproliferative processes constitute another plausible explanation. EBV plays a well-established role in the pathogenesis of certain lymphoid malignancies (22).Although preoperative gastric biopsy specimens were negative for EBER, the detection of occasional EBER-positive cells in pleural effusion cytology may reflect EBV reactivation, infected bystander cells, or low-level EBV-associated lymphoproliferation. In the absence of comprehensive EBV evaluation of diagnostic lymphoma tissue, including EBER in situ hybridization on tissue or cell-block specimens and/or EBV DNA analysis, EBV-related mechanisms cannot be definitively excluded (23).

In summary, this case illustrates a temporal association between PD-1 inhibitor–based therapy and the subsequent diagnosis of DLBCL in a patient with gastric adenocarcinoma. However, given the absence of baseline systemic staging, overlapping PET/CT findings, early diagnostic uncertainty in pleural effusion cytology, and the potential contributions of chemotherapy-related immune alteration and EBV-associated processes, a direct causal relationship cannot be established. This report underscores the importance of comprehensive baseline evaluation and careful longitudinal assessment in patients receiving immunotherapy, particularly when atypical lymphoid findings emerge during treatment.

This case highlights the importance of vigilant monitoring of immune responses in patients treated with immune checkpoint inhibitors. In particular, the development of pleural effusion, new-onset lymphadenopathy, or systemic symptoms such as chest tightness should raise clinical suspicion for secondary lymphoma. Multidisciplinary collaboration, integrating pathological and immunological assessments, is essential for the timely recognition and management of immune-related adverse events. Although immune checkpoint inhibitors have demonstrated substantial therapeutic benefit in oncology, the potential risk of immune-mediated complications, including secondary diffuse large B-cell lymphoma (DLBCL), warrants careful and sustained attention.