LYG is a rare clinical disease that predominantly affects middle-aged male (range: 30 to 50 years old). Laboratory results were generally normal[5], and imaging features, such as multiple lamellar and nodular shadows, are similar to those observed in infections or tumors[6]. Therefore, treatment is frequently delayed due to misdiagnosis of the disease. Although the performance of fiberoptic bronchoscopy or CT-guided percutaneous lung aspiration biopsy, there remains a great possibility of inconclusive diagnosis due to factors such as sampling[5].
Our patient was initial diagnosed as tuberculosis (TB) for both immunohistochemistry tests (the fiberoptic bronchoscopic needle aspiration biopsy and the CT-guided fine-needle aspiration biopsy) showed granulomatous inflammation with necrosis, although a negative TB-DNA result. Subsequently, he underwent anti-TB treatment, which, unfortunately, proved to be uneffective.
Based on its pathologic features, PLG has been categorized as a distinct mature B-cell neoplasm in the revision of WHO classification of lymphoid neoplasms in 2016 [7]. The patient’s diagnosis of PLG, grade 3, was established by observing a substantial proportion of large atypical EBV + B cells in the microscopic field[8], according to the criteria proposed by Katzenstein et al. in 2010[9]. Although high expression of P53 protein was detected by immunochemistry, next-generation sequencing (NGS) analysis of the patient's tumor tissue did not show a mutation in the P53 gene.
In 2015, the WHO stipulated that grade 3 PLG disease could be managed akin to diffuse large B-cell lymphoma (DLBCL) [10], with a rituximab-based regimen as a first-line treatment option. Therefore, patients with PLG were presently treated with rituximab-based strategies[11], but the median survival time is disappointingly short, approximately 14 months. The suitability of this treatment approach for PLG remains a topic of controversy.
At present, the etiology and pathogenesis of PLG remain incompletely understood. Numerous studies propose a close association between the disease and EBV infection, highlighting EBV’s capacity to bind to the CD21 receptor on B cells surface, leading to monoclonal proliferation of B lymphocytes, particularly in immunodeficient states[3]. In this case, both bone marrow flow cytometry and the lymphocyte subsets analyses showed a reduced number of T cells, potentially facilitating immune escape by abnormal B cells and their eventually transformation into malignant tumors[12]. As for tumor immune escape, Berger[13] concluded that PD-1, an immune checkpoint belonging to the immunoglobulin B7-CD28 family, plays a negative regulatory role in the human immune response by inhibiting T cell activation, proliferation, and inducing T cell death[13]. Suppression of PD-1 results in a significant reduction in T cells numbers, leading to immune evasion by tumor cells[14]. Therefore, PD-1 blockade can attenuate the inhibitory effect on T cell activation, fostering the activation of the endogenous anti-tumor immune response and providing a novel therapeutic pathway for tumor patients. However, until now, there has been no report on the expression of PD-1/PD-L1 in LYG. The immunohistochemistry findings indicated a high PD-1/PD-L1 expression in our patient. Thus, we initiated a PD-1 inhibitor-based regimen. To date, the patient has undergone 14 months of treatment and remains alive, with an overall survival of 26 months longer than the reported median survival time.
Further research indicates that this upregulation of PD-1 expression may also be associated with mutations or deletions in the p53 gene, an important tumor suppressor. Upregulated p53 mediates cell cycle arrest and apoptosis, eliminating damaged cells[15] when oncogenic signals are present. In contrast, mutated p53 may increase PD-L1 expression by activating various cytokines, leading to the conversion of infiltrating T into depleted CD8 + T cells, counteracting the effects of PD-1 inhibitors[14]. However, our patient showed high P53 expression in immunohistochemistry, while intriguingly, NGS analysis did not reveal any mutation in the P53 gene. Consequently, this observation underscores the necessity for further investigation into the relationship between P53 and PD-1.
PLG is an aggressive disease that has been reported to be in long-term remission without treatment in 14–27% of cases. Conversely, it proves fatal in 63.5% of patients, with a reported median survival time of 14 months[4]. To date, treated with PD-1 inhibitor-based therapy, our patient has received 14 months of treatment and remains alive, with an overall survival of 26 months longer than the median survival time reported. We speculated that the PD-1 inhibitor-based regimen may provide alternative therapeutic option for PLG.