Clinicopathological analysis of primary central nervous system lymphoma in patients with or without AIDS

Clinicopathological analysis of primary central nervous system lymphoma in patients with or without AIDS | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinicopathological analysis of primary central nervous system lymphoma in patients with or without AIDS Man Li, Jia-min Chen, En-shan Feng, Xiang-mei Chen, Hai-li Gao, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3824370/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background AIDS-related primary central nervous system lymphoma (AR-PCNSL) differs from immunocompetent-primary central nervous system lymphoma (IC-PCNSL) in certain features. The main objective of this study was to investigate the differences in clinicopathological features between AR-PCNSL and IC-PCNSL. Methods Thirty-seven AR-PCNSL patients and thirty IC-PCNSL patients were included. hematoxylin & eosin staining; immunohistochemical detection using CD20, Bcl-2, Bcl-6, p53, C-MYC, Ki67, and METTL3 antibodies; and Epstein–Barr encoding region (EBER) in situ hybridization were performed. Results All of the observed patients were classified as the DLBCL histological type. AR-PCNSL were younger (37.7 vs. 60.5 years) and had a higher likelihood of being male (86.5% vs. 63.3%) than non-AIDS patients were. Elevated LDH and low sugar content in cerebrospinal fluid (CSF) were more common among AR-PCNSL. The expression levels of METTL3, Bcl-2 and p53 expressions were significantly higher in AR-PCNSL patients than in PCNSL patients without AIDS. In contrast, AR-PCNSL patients exhibited lower levels of Bcl-6 expression. AR-PCNSL patients were more likely to be positive for EBER, accounting for 81.1% of these patients. Furthermore, we also found that the expression of METTL3 was lower in GCB-like DLBCL (n=7) than in ABC-like DLBCL (n=32) in AR-PCNSL ( p =0.041); however, in IC-PCNSL patients, the expression of METTL3 was not significantly different between GCB-like DLBCL and ABC-like DLBCL ( p =0.710). Conclusions Our study of Chinese AR-PCNSL and IC-PCNSL patients revealed new findings, indicating that METTL3, Bcl-2 and p53 were increased in AR-PCNSL patients compared to IC-PCNSL patients and that METTL3 was higher in ABC-like DLBCL patients than in GCB-like DLBCL in AR-PCNSL patients, suggesting a notable distinction in the pathological characteristics between PCNSL patients with or without AIDS. ARDS METTL3 AR-PCNSL IC-PCNSL GCB-like DLBCL ABC-like DLBCL Figures Figure 1 Figure 2 Background Primary central nervous system lymphoma (PCNSL) is a unique and uncommon type of extranodal non-Hodgkin lymphoma that is distinguished by its specific biological features and accounts for approximately 2.4–4.9% of all primary brain tumors [ 1 , 2 ]. In recent years, the incidence of PCNSL has increased, which is partially due to the emergence of AIDS [ 3 ]. After the human body is infected with HIV, the CD4 + T lymphocyte undergoes a progressive decline. In the late stage of the disease, severe immunodeficiency occurs, which is clinically manifested not only by opportunistic infections but also by a significantly increased probability of tumor occurrence [ 4 ]. With the widespread use of highly effective antiretroviral therapy in clinical practice, HIV/AIDS-related lymphoma has become the most common HIV-defining tumor [ 5 ]. AIDS-related primary central nervous system lymphoma (AR-PCNSL) is distinct from immunocompetent primary central nervous system lymphoma (IC-PCNSL) [ 6 ]. Although the tumor manifestations of PCNSL patients with and without AIDS are similar, several distinct features, such as overall survival, prognostic factors, treatment outcomes and tumorigenic mechanisms, still exist because of the immunocompetence of the host [ 7 ]. Patients suffering from AR-PCNSL experience early disease, complex clinical manifestations, disease advancement, and an unfavorable prognosis. A better understanding of the clinicopathological differences between AR-PCNSL and IC-PCNSL would help us identify potential therapeutic targets, develop innovative treatment regimens, and ultimately reduce morbidity and mortality. Despite similar clinical presentations, there have been no comparative studies evaluating the pathological characteristics of AR-PCNSL and IC-PCNSL patients treated at the same institution. The present analysis was retrospectively conducted to examine the clinical characteristics of Chinese AR-PCNSL and IC-PCNSL patients for the first time. Materials and methods Patients and samples This study enrolled 37 patients who were diagnosed with PCNSL with AIDS and 30 patients who were diagnosed with PCNSL without AIDS. Twelve patients were diagnosed with germinal center B-cell (GCB)-like DLBCL, a form of diffuse large B-cell lymphoma (DLBCL), while 55 had activated B-cell (ABC)-like DLBCL, which arises from a different cellular origin. Between January 2008 and December 2021, Beijing Ditan Hospital of Capital Medical University in China admitted all patients. The patients' medical records were collected, and they underwent physical examinations and routine laboratory tests. All patients had central nervous system involvement as their initial symptoms, and the lesions were all located in the intracalvarium. Imaging studies ruled out metastasis of lymphoma from other sites to the CNS. Two independent pathologists evaluated the histological type of each tumor using the 5th edition of the Lymphatic Hematopoietic Tissue Tumor World Health Organization Classification [ 8 ]. All patients were subjected to preoperative laboratory testing, which included assessing the blood CD4 + T-cell count and detecting lactate dehydrogenase (LDH). We also measured protein, sugar, and chloride concentrations in the cerebrospinal fluid (CSF). This study complied with the Helsinki Declaration and was approved by the ethics committee of Beijing Ditan Hospital (DTEC-KY2022-007-02). Immunohistochemical staining and scoring Freshly prepared neutral formalin solution was used to fix the biopsy tissues, and FFPE procedures were used to process them. The tissue sections (4 µm) were placed on positively charged glass slides, and hematoxylin and eosin were used to stain the serial sections. The primary antibodies used for IHC staining, which included CD20, C-MYC, Bcl-2, Bcl-6, p53 and Ki67, were all purchased from Beijing Zhongshan Jinqiao Biotechnology Co., Ltd. The anti-METTL3 antibody (ab195352, 1:1000) was purchased from Abcam (USA). Two neuropathologists separately interpreted the results. The protein expression was scored semiquantitatively based on both the intensity and area of expression. The expression intensity was evaluated on a scale of 0 to 3, with 0 indicating negative staining, 1 indicating weak staining, 2 indicating moderate staining, and 3 indicating strong staining. The expression area was scored on a scale of 0 to 4, with 0 representing less than 5%, 1 representing 6–25%, 2 representing 26–50%, 3 representing 51–75%, and 4 representing greater than 75%. EBER in situ hybridization The Epstein–Barr encoding region (EBER) (catalog PB0589, Leica) probe was used to detect EBERs in FFPE tissues. Sections (4 µm) were stained on an automated stainer (Leica Microsystem catalog # DS9390). The instrument was used for deparaffinizing and retrieving antigens from the sections. Hybridization with an EBV probe was carried out at 37°C for 2 hours. Next, the sections were exposed to anti-fluorescein antibody for 15 minutes, postprimary AP for 15 minutes, polymer AP for 20 minutes, and mixed red (alkaline phosphatase red chromogen) for 10 minutes; finally, the sections were counterstained with hematoxylin for 10 minutes. Positive signals were brownish-yellow and localized within the nuclei. Statistical analysis All the statistical analyses were conducted with IBM SPSS software (version 22.0; IBM Corp., Armonk, NY). Frequencies were used to describe categorical data. Quantitative data are presented as the mean ± standard error. We performed Student’s independent t test or one-way ANOVA to assess the differences in the expression of CD20, C-MYC, Bcl-2, Bcl-6, p53, METTL3, and Ki67 between patients with and without AIDS, as well as between GCB-like DLBCL and ABC-like DLBCL. Differences were considered to be statistically significant at p values < .05. Results Patient characteristics All the tumors observed were of the DLBCL histological type. According to the Hans model classification, the origin of the germinal center B-cell subtype (germinal center B cell, GCB) accounted for 17.9% (12/67), and the origin of the activated B-cell (ABC) subtype accounted for 82.1% (55/67). AR-PCNSL patients were more likely to be male (86.5% vs. 63.3%, p = .027) or younger (median age 37.7 years vs. 60.5 years, p = .001) and had a greater likelihood of receiving a diagnosis of PCNSL than patients with IC-PCNSL. Among the 67 PCNSL patients, 24 had single lesions, 43 had multiple lesions, 43 had supratentorial lesions, 7 had infratentorial lesions, 16 had supratentorial and infratentorial lesions, and 1 had spinal cord lesions. The location of the tumor was not significantly different between the AR-PCNSL group and the IC-PCNSL group. The related clinical information can be found in Table 1 . Table 1 Demographics and laboratory results of patients with PCNSL. AR-PCNSL (n = 37) IC-PCNSL (n = 30) Total (n = 67) p value Median age 34(14–69) 60 (42–84) 47(14–84) ------ Age (years) 37.7 ± 12.9 60.5 ± 10.9 47.9 ± 16.4 .001* Gender Male 32 (86.5%) 19 (63.3%) 51(76.1%) .027* Female 5 (13.5%) 11 (36.7%) 16(23.9%) Site Supratentorial 27 16 43 .709 Infratentorial 2 5 7 Supra& Infratentorial 7 9 16 Spinal canal 1 0 1 Single/multiple Single 10 14 24 .468 Multiple 27 16 43 LDH (U/L) 295.3 ± 138.3 199.7 ± 74.4 258.8 ± 125.1 .002* CSF protein (mg/dl) 107.9 ± 71.2 106.3 ± 87.8 107.4 ± 74.9 .954 CSF sugar (mmol/l) 3.1 ± 1.1 3.9 ± 1.0 3.4 ± 1.1 .038* CSF chloride (mmol/l) 122.0 ± 5.9 120.8 ± 5.1 121.8 ± 5.5 .422 * p < .05. Laboratory results The average LDH concentration in AR-PCNSL patients was 295.3 ± 138.3 U/L, ranging from 122.3 to 746.1 U/L, and in IC-PCNSL patients, it was 199.7 ± 74.4 U/L, ranging from 112.8 to 444 U/L ( p = .002). CSF sugar levels were different between AR-PCNSL and IC-PCNSL ( p = .038). Moreover, there was no significant difference in CSF protein or CSF glucose levels ( p = .954, p = .422). We also examined the CD4 + T-cell counts in individuals living with AIDS, which yielded an average count of 125.1 ± 205.8 cells/µl (ranging from 2 to 798 cells/µl). It was observed that 89.7% (35 out of 37) of patients had low CD4 + T-cell counts. Pathology characteristics of patients with AR-PCNSL Histology revealed a distinct angiocentric distribution, along with notable features such as large pleomorphic nuclei with an irregularly thick nuclear membrane, prominent nucleoli, abundant mitotic figures, and apoptotic bodies. Many slides also exhibited regions of geographic necrosis. The pathological type was DLBCL, in which neoplastic cells were positive for pan-B-cell markers such as CD20. We found no difference in the expression of C-MYC between AR-PCNSL and IC-PCNSL. In AR-PCNSL, the expression levels of p53 (24 of 39, 64.9%) and Bcl-2 (25 of 37, 67.6%) were greater than those of p53 (7 of 30, 23.3%) and Bcl-2 (7 of 30, 23.3%) in IC-PCNSL patients. Of the 37 AR-PCNSL patients, 86.5% (32/37) had a high Ki-67 index, whereas 76.7% (23/30) had this index in IC-PCNSL. Only 6 AR-PCNSL patients (16.2%) had high expression of Bcl-6, but the percentage of IC-PCNSL with high expression was 73.3% (22/30). EBER-1 was expressed in 81.1% (30 of 37) of the AR-PCNSL samples but was uniformly negative in the IC-PCNSL samples, and the difference was significant ( p = .001). Representative images are shown in Fig. 1 . The clinicopathological features can be found in Table 2 . Table 2 Pathology characteristics of AR-PCNSL and IC-PCNSL. AR-PCNSL (n = 37) IC-PCNSL (n = 30) p value p53 (High expression/Low expression) 24/13 (64.9%) 7/23 (23.3%) .001* Ki-67 (High expression/Low expression) 32/5 (86.5%) 23/7 (76.7%) .498 C-MYC (High expression/Low expression) 11/26 (29.7%) 11/19 (36.7%) .340 Bcl-2 (High expression/Low expression) 25/12 (67.6%) 7/23 (23.3%) .046* Bcl-6 (High expression/Low expression) 6/31 (16.2%) 22/8 (73.3%) .001* EBER (Positive/negative) 30/7 (81.1%) 0/30 (0%) .001* * p < .05 METTL3 expression is elevated in AR-PCNSL patients First, histochemical analysis of METTL3 expression showed that METTL3 expression was significantly greater in AR-PCNSL tumor samples than in IC-PCNSL tumor samples ( p = .001) (Fig. 2 A-C). We further analyzed METTL3 expression in GCB-like DLBCL and ABC-like DLBCL patients from the AR-PCNSL and IC-PCNSL cohorts. METTL3 was expressed at lower levels in GCB-like DLBCL patients than in ABC-like DLBCL patients ( p = .027) in the AR-PCNSL cohort (Fig. 2 D-F), whereas there was no difference in the IC-PCNSL cohort (Fig. 2 G-I). Discussion AIDS-related lymphomas are generally divided into three types: systemic lymphoma, PCNSL, and primary effusion lymphoma [ 9 ]. Unlike systemic lymphoma involving the central nervous system, PCNSL tumors are localized only to the central nervous system and not to other regions. The incidence of PCNSL in individuals infected with human immunodeficiency virus (HIV) ranges from 2–6%, which is 1,000 times greater than that in HIV-negative individuals [ 10 ]. More than 96% of PCNSLs are highly invasive B-cell lymphomas, with DLBCL being the most common subtype, while T-cell and low-grade lymphomas account for 1–4% of PCNSLs [ 11 , 12 ]. In 2004, three antibodies (CD10, Bcl-6, and Mum-1) were utilized by Hans et al. [ 13 ] to label and classify DLBCL into two subtypes: germinal center B-cell-like (referred to as the GCB type) and activated B-cell-like (known as the ABC type). This classification has been extensively employed in clinical practice to determine the source and prognosis of DLBCL tumor cells. Despite the similar clinical presentations of PCNSL with and without AIDS, the etiology and pathological characteristics of AR-PCNSL and IC-PCNSL are completely different. Thus, our study aimed to compare clinicopathological features of patients with PCNSL who were infected or not infected with HIV. In our hospital, we conducted a retrospective study in which the clinical features of 67 patients with PCNSL were evaluated, both with and without HIV infection. All 67 patients with PCNSL had a histological classification of DLBCL. The tumor cells were diffusely distributed in sheets, with a relatively uniform morphology, minimal cytoplasm, round nuclei, uneven distribution of chromatin, and frequent nuclear division. Tumor cells commonly aggregate in Virchow-Robin spaces and may invade the blood vessel walls of the brain or form ‘sleeve-like’ structures. Some tumor tissues exhibit a scattered distribution of phagocytic cells, forming a ‘starry sky’ pattern. PCNSL can occur in any part of the CNS but is most often found in the supratentorial region. The commonly affected areas are the cerebral hemispheres, basal ganglia, and corpus callosum, with some lesions also located on the brain surface. The sites at which the tumor occurred were not significantly different between AR-PCNSL and IC-PCNSL. The age and gender distribution of the patients with AR-PCNSL were in line with previous findings, with younger male patients being more common than younger patients with IC-PCNSL [ 14 ]. AR-PCNSL patients were more likely to have elevated LDH, CSF protein, and CSF chloride levels and lower CSF sugar. This could be because PCNSL patients can disseminate through the cerebrospinal fluid, and AR-PCNSL patients are more prone to spread through the cerebrospinal fluid. Histologically, 25 of the 37 AR-PCNSL patients (67.6%) overexpressed of the protein Bcl-2, which is basically consistent with the literature (40%-81%) [ 15 ]. Among the IC-PCNSL patients, only 23.3% had Bcl-2 overexpression, which was significantly lower than that of the AR-PCNSL patients. This may be because the Bcl-2 protein is a cell apoptosis inhibitor gene and an important pathogenic factor in the development of lymphoma. The Ki67 positivity rate is positively correlated with lymphoma invasiveness and malignancy level [ 16 ]. Our study revealed that 86.5% of the patients had high Ki-67 expression (Ki-67 index > 50%), which is consistent with the literature and indicates rapid growth of tumor cells [ 17 ]. Additionally, Bcl-6 serves as a major regulatory element in the germinal center reaction, controlling B-cell activation, differentiation, cell cycle arrest, and apoptosis. Reis et al. [ 18 ] reported that increased expression of Bcl-6 in patients with PCNSL was associated with an extended period of survival, indicating its predictive value. Therefore, the lower expression of Bcl-6 in AR-PCNSL may indicate a poorer prognosis than in IC-PCNSL. The TP53 gene is one of the most important tumor suppressor genes and regulates the cell cycle, apoptosis, and repair of DNA damage [ 19 ]. Our research revealed that p53 expression was significantly increased in AR-PCNSL. In addition, we conducted EBER in situ hybridization on paraffin tissue specimens taken from all 67 patients and found that 81.1% of the AR-PCNSL patients tested positive for EBER. No patients with IC-PCNSL were found to have EBV. EBV infection in humans could play a significant role in causing immunodeficiency among patients diagnosed with PCNSL. In addition to EBV infection immortalizing normal B cells, infected B cells can also escape suppression by normal T cells, leading to malignant transformation. However, the pathogenesis of PCNSL is still unclear. Current research suggests that changes in epigenetic modifications are closely related to the onset of PCNSL [ 20 ]. Gene chip research has shown that, compared to normal tissue, PCNSL tissue has 194 genes whose DNA is methylated, the most significant difference being observed for genes with multiple CpG-enriched regions and promoter regions [ 21 ]. In eukaryotic cells, m6A modification is highly prevalent and plays a crucial regulatory role in cell differentiation, the stress response, tumor formation, and correlation with virus infection. The abundance of m6A in both viral and host-cell RNA is significantly increased by HIV infection [ 22 ]. This fact motivates further exploration of the involvement of RNA methylation in HIV-1 biology and the mammalian response to viral infection. m6A modification is regulated mainly by complex interactions between methyltransferase complexes, demethylases, and methylation-reading proteins. Some of the members of the methyltransferase complex are METTL3, METTL14, METTL16, Wilms tumor 1-associated protein, RNA binding motif protein 15, and KIAA1429 [ 23 ]. Mounting evidence shows that the abnormal expression and function of METTL3 are closely related to tumor progression. Mechanistically, METTL3 can promote the translation of MYC, Bcl-2 and PTEN mRNAs. METTL3 can also regulate the stability of mRNAs by changing the level of m6A modification [ 24 ]. Therefore, further research on the role and specific molecular mechanism of METTL3 in AR-PCNSL development is highly important, and it is anticipated that AR-PCNSL will offer novel molecular targets for clinical diagnosis and treatment. We found that 84.6% of the AR-PCNSL patients exhibited high METTL3 expression, and in the IC-PCNSL cohort, only 43.4% of the patients exhibited high METTL3 expression. Therefore, we can infer that the HIV virus may cause excessive levels of m6A through promoting the expression of METTL3, leading to changes in the expression of downstream genes, such as Bcl-2, p53, Bcl-6, and Ki67, as well as other genetic abnormalities; dysregulation and release of cytokines; damage to dendritic cells; and/or infection with EB virus, hepatitis C virus, or other viruses. These stimuli lead to rearrangement of immunoglobulin variable genes, ultimately leading to the development of PCNSL in AIDS patients. Therefore, compared to patients with IC-PCNSL, patients with AR-PCNSL have earlier disease onset and a worse prognosis. In addition, AR-PCNSL patients with ABC-like DLBCL were more likely to express METTL3 than were those with GCB-like DLBCL. In IC-PCNSL patients, there were no differences in the expression of METTL3 between ABC-like DLBCL and GCB-like DLBCL. This may indicate that in AR-PCNSL, the expression of METTL3 not only promotes the occurrence and progression of PCNSL but also may be related to the origin of the tumor cells. Earlier studies have reported that compared to ABC-like DLBCL, GCB-like DLBCL has a better prognosis [ 25 ]; therefore, there may be a correlation between the expression of METTL3 and the prognosis of AR-PCNSL. Overall, although the clinical symptoms of AR-PCNSL and IC-PCNSL are similar, the age onset of AR-PCNSL is earlier and it is more prone to occur in males. Similarly, the expression of METTL3, Bcl-2 and p53 was greater in these patients than in IC-PCNSL patients, while the expression of Bcl-6 was lower. Furthermore, among the AR-PCNSL patients, METTL3 was upregulated in ABC-like DLBCL compared with that in GBC-like DLBCL among AR-PCNSL patients. HIV may promote an increase in METTL3 expression and thereby influence the level of DNA methylation, the mRNA stability of cancer-related genes, the expression of oncogenes, cancer cell signaling pathways, and cancer cell apoptosis. Our findings may provide new sights into Chinese PCNSL patients with or without ARDS, which implies that further study is needed to explore novel pathways involved in tumor formation. Abbreviations AIDS Acquired immune deficiency syndrome HIV Human immunodeficiency virus DLBCL(GCB) Germinal center B-cell-like diffuse large B-cell lymphoma DLBCL(ABC) Activated B-cell-like diffuse large B-cell lymphoma PCNSL Primary central nervous system lymphoma AR-PCNSL AIDS-related primary central nervous system lymphoma IC-PCNSL Immunocompetent-primary central nervous system lymphoma EBER Epstein–Barr encoding region LDH Dehydrogenase CSF Cerebrospinal fluid Declarations Acknowledgements The authors are grateful to Liang Zhang and Li-ming Qi for excellent technical assistance. Authors’ contributions ML, JMC and XGZ designed the study protocol; ESF and XMC collected data collection; HLG, ZYM and PW analysed the data; ML and JMC contributed to drafting the manuscript. All the authors have read and agreed to the published version of the manuscript. Funding This work was supported by a grant from the Beijing Medical Management Bureau Cultivation Plan (NO. PX2020070). Data Availability The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request. Competing interests The authors declare no competing interests. Ethics approval and consent to participate This study complied with the Helsinki Declaration and was approved by the ethics committee of Beijing Ditan Hospital (DTEC-KY2022-007-02). Consent for publication Not applicable. Author details 1 Department of Pathology, Capital Medical University Affiliated Beijing Ditan Hospital, NO.8 Jing Shun East Street, Chaoyang District, Beijing 100015, PR China; 2 Department of Neurosurgery, Capital Medical University Affiliated Beijing Ditan Hospital, NO.8 Jing Shun East Street, Chaoyang District, Beijing 100015, PR, China References Radke J, Ishaque N, Koll R, et al. The genomic and transcriptional landscape of primary central nervous system lymphoma. Nat Commun. 2022;13(1):2558. Franca RA, Travaglino A, Varricchio S, et al. 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Structure-based design of inhibitors of the m 6 A-RNA writer enzyme METTL3. ACS Bio Med Chem Au. 2023;3(4):359–70. Camilleri-Broët S, Crinière E, Broët P, et al. A uniform activated B-cell-like immunophenotype might explain the poor prognosis of primary central nervous system lymphomas: analysis of 83 cases. Blood. 2006;107(1):190–6. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3824370","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":264901401,"identity":"7d479978-c2c4-4173-9783-ebf17fc2ccfe","order_by":0,"name":"Man Li","email":"","orcid":"","institution":"Capital Medical University Affiliated Beijing Ditan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Man","middleName":"","lastName":"Li","suffix":""},{"id":264901402,"identity":"c7654431-7fcc-4dcd-b80e-a296f3180b40","order_by":1,"name":"Jia-min Chen","email":"","orcid":"","institution":"Capital Medical University Affiliated Beijing Ditan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jia-min","middleName":"","lastName":"Chen","suffix":""},{"id":264901403,"identity":"8b6fb2f2-d62a-4897-8557-1c4cae1446b8","order_by":2,"name":"En-shan Feng","email":"","orcid":"","institution":"Capital Medical University Affiliated Beijing Ditan Hospital","correspondingAuthor":false,"prefix":"","firstName":"En-shan","middleName":"","lastName":"Feng","suffix":""},{"id":264901404,"identity":"c7b8ef04-e190-471b-a0d2-54eae88747bc","order_by":3,"name":"Xiang-mei Chen","email":"","orcid":"","institution":"Capital Medical University Affiliated Beijing Ditan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiang-mei","middleName":"","lastName":"Chen","suffix":""},{"id":264901405,"identity":"a0543d50-3f06-4d6a-aaa1-691b02ee6d8a","order_by":4,"name":"Hai-li Gao","email":"","orcid":"","institution":"Capital Medical University Affiliated Beijing Ditan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hai-li","middleName":"","lastName":"Gao","suffix":""},{"id":264901406,"identity":"cbefd8c8-05a9-41a8-9a01-1fa1f58371ed","order_by":5,"name":"Zhi-yuan Ma","email":"","orcid":"","institution":"Capital Medical University Affiliated Beijing Ditan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhi-yuan","middleName":"","lastName":"Ma","suffix":""},{"id":264901407,"identity":"641b5ab8-271a-4d70-9c06-3002fdd618e8","order_by":6,"name":"Peng Wang","email":"","orcid":"","institution":"Capital Medical University Affiliated Beijing Ditan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Peng","middleName":"","lastName":"Wang","suffix":""},{"id":264901408,"identity":"471b5833-d0bc-4153-823d-fbede2d65c61","order_by":7,"name":"Xin-gang Zhou","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAo0lEQVRIiWNgGAWjYBAC9nYILUe8Fp7DENqYdC2JDcRrYeYxYOZtO5zedzyB8cPHHCK1MM44czh35pkHzJIztxGhxR6oheFDxeHcDTcS2Jh5idECsoUhweBwugFpWoC2JJCiha0A6Jd0w5lnHjYT5xce9uYNwBCzluc7nnzww0ditDAwcJj/YGBoZmA4QHzUsD8AEnVALQnE6hgFo2AUjIKRBgDM+jJjhQGhlwAAAABJRU5ErkJggg==","orcid":"","institution":"Capital Medical University Affiliated Beijing Ditan Hospital","correspondingAuthor":true,"prefix":"","firstName":"Xin-gang","middleName":"","lastName":"Zhou","suffix":""}],"badges":[],"createdAt":"2023-12-30 15:44:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3824370/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3824370/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":49235647,"identity":"fab077b5-9434-4b62-b358-d92967d7c26d","added_by":"auto","created_at":"2024-01-05 17:51:34","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1881762,"visible":true,"origin":"","legend":"\u003cp\u003ePathology characteristics of AR-PCNSL and IC-PCNSL. He staining of AR-PCNSL (A) and IC-PCNSL (I) revealed a significant B-cell appearance characterized by a thick nuclear envelope and one to more prominent nucleoli. CD20 was expressed by neoplastic cells in AR-PCNSL (B) and IC-PCNSL (J), which indicated that CD20 was a pan-B-cell marker. Representative IHC staining demonstrating the expression of C-MYC in AR-PCNSL patients (C) versus IC-PCNSL patients (K). Overexpression of p53 was more common in AR-PCNSL patients (D) than in IC-PCNSL patients (L). The expression of Bcl-2 was greater in AR-PCNSL (E) than in IC-PCNSL (M). AR-PCNSL (F) patients had lower Bcl-6 expression than did IC-PCNSL patients (N). Nuclear expression of Ki-67 in AR-PCNSL (G) and IC-PCNSL (O). EBER was undetectable in IC-PCNSL patients (H) but was upregulated in AR-PCNSL patients (P) (X400).\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3824370/v1/c24ba88376c3c50693950d71.png"},{"id":49235648,"identity":"428dbce6-d6ae-4065-9b20-8b4f33fe1fc6","added_by":"auto","created_at":"2024-01-05 17:51:34","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1423329,"visible":true,"origin":"","legend":"\u003cp\u003eMETTL3 expression was upregulated in AR-PCNSL and ABC-like DLBCL. Representative IHC staining demonstrated that the expression of METTL3 in AR-PCNSL (A) was greater than that in patients with IC-PCNSL (B). D and E, IHC staining showed that METTL3 expression was significantly upregulated in ABC-like DLBCL (E) compared with GCB-like DLBCL (D). However, there was no difference in the expression of METTL3 between GCB-like DLBCL(G) and ABC-like DLBCL(H) in IC-PCNSL patients (X400). The semiquantitative score of each specimen is shown in 2C, 2F and 2I.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-3824370/v1/a5e6ee8ffbba2a15c4826c51.png"},{"id":51668244,"identity":"d85f1ee3-eb11-40ea-9002-e0c5c8812b44","added_by":"auto","created_at":"2024-02-27 00:14:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3213355,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3824370/v1/055f9598-1595-4223-98fa-c23f7537f865.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinicopathological analysis of primary central nervous system lymphoma in patients with or without AIDS","fulltext":[{"header":"Background","content":"\u003cp\u003ePrimary central nervous system lymphoma (PCNSL) is a unique and uncommon type of extranodal non-Hodgkin lymphoma that is distinguished by its specific biological features and accounts for approximately 2.4\u0026ndash;4.9% of all primary brain tumors [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In recent years, the incidence of PCNSL has increased, which is partially due to the emergence of AIDS [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. After the human body is infected with HIV, the CD4\u003csup\u003e+\u003c/sup\u003eT lymphocyte undergoes a progressive decline. In the late stage of the disease, severe immunodeficiency occurs, which is clinically manifested not only by opportunistic infections but also by a significantly increased probability of tumor occurrence [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. With the widespread use of highly effective antiretroviral therapy in clinical practice, HIV/AIDS-related lymphoma has become the most common HIV-defining tumor [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. AIDS-related primary central nervous system lymphoma (AR-PCNSL) is distinct from immunocompetent primary central nervous system lymphoma (IC-PCNSL) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Although the tumor manifestations of PCNSL patients with and without AIDS are similar, several distinct features, such as overall survival, prognostic factors, treatment outcomes and tumorigenic mechanisms, still exist because of the immunocompetence of the host [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Patients suffering from AR-PCNSL experience early disease, complex clinical manifestations, disease advancement, and an unfavorable prognosis. A better understanding of the clinicopathological differences between AR-PCNSL and IC-PCNSL would help us identify potential therapeutic targets, develop innovative treatment regimens, and ultimately reduce morbidity and mortality.\u003c/p\u003e \u003cp\u003eDespite similar clinical presentations, there have been no comparative studies evaluating the pathological characteristics of AR-PCNSL and IC-PCNSL patients treated at the same institution. The present analysis was retrospectively conducted to examine the clinical characteristics of Chinese AR-PCNSL and IC-PCNSL patients for the first time.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients and samples\u003c/h2\u003e \u003cp\u003eThis study enrolled 37 patients who were diagnosed with PCNSL with AIDS and 30 patients who were diagnosed with PCNSL without AIDS. Twelve patients were diagnosed with germinal center B-cell (GCB)-like DLBCL, a form of diffuse large B-cell lymphoma (DLBCL), while 55 had activated B-cell (ABC)-like DLBCL, which arises from a different cellular origin. Between January 2008 and December 2021, Beijing Ditan Hospital of Capital Medical University in China admitted all patients. The patients' medical records were collected, and they underwent physical examinations and routine laboratory tests. All patients had central nervous system involvement as their initial symptoms, and the lesions were all located in the intracalvarium. Imaging studies ruled out metastasis of lymphoma from other sites to the CNS. Two independent pathologists evaluated the histological type of each tumor using the 5th edition of the Lymphatic Hematopoietic Tissue Tumor World Health Organization Classification [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. All patients were subjected to preoperative laboratory testing, which included assessing the blood CD4\u003csup\u003e+\u003c/sup\u003e T-cell count and detecting lactate dehydrogenase (LDH). We also measured protein, sugar, and chloride concentrations in the cerebrospinal fluid (CSF). This study complied with the Helsinki Declaration and was approved by the ethics committee of Beijing Ditan Hospital (DTEC-KY2022-007-02).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eImmunohistochemical staining and scoring\u003c/h2\u003e \u003cp\u003eFreshly prepared neutral formalin solution was used to fix the biopsy tissues, and FFPE procedures were used to process them. The tissue sections (4 \u0026micro;m) were placed on positively charged glass slides, and hematoxylin and eosin were used to stain the serial sections. The primary antibodies used for IHC staining, which included CD20, C-MYC, Bcl-2, Bcl-6, p53 and Ki67, were all purchased from Beijing Zhongshan Jinqiao Biotechnology Co., Ltd. The anti-METTL3 antibody (ab195352, 1:1000) was purchased from Abcam (USA). Two neuropathologists separately interpreted the results. The protein expression was scored semiquantitatively based on both the intensity and area of expression. The expression intensity was evaluated on a scale of 0 to 3, with 0 indicating negative staining, 1 indicating weak staining, 2 indicating moderate staining, and 3 indicating strong staining. The expression area was scored on a scale of 0 to 4, with 0 representing less than 5%, 1 representing 6\u0026ndash;25%, 2 representing 26\u0026ndash;50%, 3 representing 51\u0026ndash;75%, and 4 representing greater than 75%.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eEBER in situ hybridization\u003c/h2\u003e \u003cp\u003eThe Epstein\u0026ndash;Barr encoding region (EBER) (catalog PB0589, Leica) probe was used to detect EBERs in FFPE tissues. Sections (4 \u0026micro;m) were stained on an automated stainer (Leica Microsystem catalog # DS9390). The instrument was used for deparaffinizing and retrieving antigens from the sections. Hybridization with an EBV probe was carried out at 37\u0026deg;C for 2 hours. Next, the sections were exposed to anti-fluorescein antibody for 15 minutes, postprimary AP for 15 minutes, polymer AP for 20 minutes, and mixed red (alkaline phosphatase red chromogen) for 10 minutes; finally, the sections were counterstained with hematoxylin for 10 minutes. Positive signals were brownish-yellow and localized within the nuclei.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAll the statistical analyses were conducted with IBM SPSS software (version 22.0; IBM Corp., Armonk, NY). Frequencies were used to describe categorical data. Quantitative data are presented as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard error. We performed Student\u0026rsquo;s independent t test or one-way ANOVA to assess the differences in the expression of CD20, C-MYC, Bcl-2, Bcl-6, p53, METTL3, and Ki67 between patients with and without AIDS, as well as between GCB-like DLBCL and ABC-like DLBCL. Differences were considered to be statistically significant at \u003cem\u003ep\u003c/em\u003e values\u0026thinsp;\u003cem\u003e\u0026lt;\u003c/em\u003e\u0026thinsp;.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eAll the tumors observed were of the DLBCL histological type. According to the Hans model classification, the origin of the germinal center B-cell subtype (germinal center B cell, GCB) accounted for 17.9% (12/67), and the origin of the activated B-cell (ABC) subtype accounted for 82.1% (55/67). AR-PCNSL patients were more likely to be male (86.5% vs. 63.3%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.027) or younger (median age 37.7 years vs. 60.5 years, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.001) and had a greater likelihood of receiving a diagnosis of PCNSL than patients with IC-PCNSL. Among the 67 PCNSL patients, 24 had single lesions, 43 had multiple lesions, 43 had supratentorial lesions, 7 had infratentorial lesions, 16 had supratentorial and infratentorial lesions, and 1 had spinal cord lesions. The location of the tumor was not significantly different between the AR-PCNSL group and the IC-PCNSL group. The related clinical information can be found in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographics and laboratory results of patients with PCNSL.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAR-PCNSL (n\u0026thinsp;=\u0026thinsp;37)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIC-PCNSL (n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;67)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian age\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34(14\u0026ndash;69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60 (42\u0026ndash;84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e47(14\u0026ndash;84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e------\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37.7\u0026thinsp;\u0026plusmn;\u0026thinsp;12.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60.5\u0026thinsp;\u0026plusmn;\u0026thinsp;10.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e47.9\u0026thinsp;\u0026plusmn;\u0026thinsp;16.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (86.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (63.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e51(76.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e.027*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (13.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (36.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16(23.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSite\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSupratentorial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e.709\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfratentorial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSupra\u0026amp;\u003c/p\u003e \u003cp\u003eInfratentorial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpinal canal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSingle/multiple\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSingle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e.468\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultiple\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDH (U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e295.3\u0026thinsp;\u0026plusmn;\u0026thinsp;138.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e199.7\u0026thinsp;\u0026plusmn;\u0026thinsp;74.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e258.8\u0026thinsp;\u0026plusmn;\u0026thinsp;125.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.002*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCSF protein (mg/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e107.9\u0026thinsp;\u0026plusmn;\u0026thinsp;71.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e106.3\u0026thinsp;\u0026plusmn;\u0026thinsp;87.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e107.4\u0026thinsp;\u0026plusmn;\u0026thinsp;74.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.954\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCSF sugar (mmol/l)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.038*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCSF chloride (mmol/l)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e122.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e120.8\u0026thinsp;\u0026plusmn;\u0026thinsp;5.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e121.8\u0026thinsp;\u0026plusmn;\u0026thinsp;5.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.422\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e* \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.05.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eLaboratory results\u003c/h2\u003e \u003cp\u003eThe average LDH concentration in AR-PCNSL patients was 295.3\u0026thinsp;\u0026plusmn;\u0026thinsp;138.3 U/L, ranging from 122.3 to 746.1 U/L, and in IC-PCNSL patients, it was 199.7\u0026thinsp;\u0026plusmn;\u0026thinsp;74.4 U/L, ranging from 112.8 to 444 U/L (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.002). CSF sugar levels were different between AR-PCNSL and IC-PCNSL (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.038). Moreover, there was no significant difference in CSF protein or CSF glucose levels (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.954, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.422). We also examined the CD4\u003csup\u003e+\u003c/sup\u003e T-cell counts in individuals living with AIDS, which yielded an average count of 125.1\u0026thinsp;\u0026plusmn;\u0026thinsp;205.8 cells/\u0026micro;l (ranging from 2 to 798 cells/\u0026micro;l). It was observed that 89.7% (35 out of 37) of patients had low CD4\u003csup\u003e+\u003c/sup\u003e T-cell counts.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003ePathology characteristics of patients with AR-PCNSL\u003c/h2\u003e \u003cp\u003eHistology revealed a distinct angiocentric distribution, along with notable features such as large pleomorphic nuclei with an irregularly thick nuclear membrane, prominent nucleoli, abundant mitotic figures, and apoptotic bodies. Many slides also exhibited regions of geographic necrosis. The pathological type was DLBCL, in which neoplastic cells were positive for pan-B-cell markers such as CD20. We found no difference in the expression of C-MYC between AR-PCNSL and IC-PCNSL. In AR-PCNSL, the expression levels of p53 (24 of 39, 64.9%) and Bcl-2 (25 of 37, 67.6%) were greater than those of p53 (7 of 30, 23.3%) and Bcl-2 (7 of 30, 23.3%) in IC-PCNSL patients. Of the 37 AR-PCNSL patients, 86.5% (32/37) had a high Ki-67 index, whereas 76.7% (23/30) had this index in IC-PCNSL. Only 6 AR-PCNSL patients (16.2%) had high expression of Bcl-6, but the percentage of IC-PCNSL with high expression was 73.3% (22/30). EBER-1 was expressed in 81.1% (30 of 37) of the AR-PCNSL samples but was uniformly negative in the IC-PCNSL samples, and the difference was significant (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.001). Representative images are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The clinicopathological features can be found in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePathology characteristics of AR-PCNSL and IC-PCNSL.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAR-PCNSL (n\u0026thinsp;=\u0026thinsp;37)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIC-PCNSL (n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ep53 (High expression/Low expression)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24/13\u003c/p\u003e \u003cp\u003e(64.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7/23\u003c/p\u003e \u003cp\u003e(23.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKi-67 (High expression/Low expression)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32/5\u003c/p\u003e \u003cp\u003e(86.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23/7\u003c/p\u003e \u003cp\u003e(76.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.498\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-MYC (High expression/Low expression)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11/26\u003c/p\u003e \u003cp\u003e(29.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11/19\u003c/p\u003e \u003cp\u003e(36.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.340\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBcl-2 (High expression/Low expression)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25/12\u003c/p\u003e \u003cp\u003e(67.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7/23\u003c/p\u003e \u003cp\u003e(23.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.046*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBcl-6 (High expression/Low expression)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6/31\u003c/p\u003e \u003cp\u003e(16.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22/8\u003c/p\u003e \u003cp\u003e(73.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEBER (Positive/negative)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30/7\u003c/p\u003e \u003cp\u003e(81.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0/30\u003c/p\u003e \u003cp\u003e(0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e*\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.05\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eMETTL3 expression is elevated in AR-PCNSL patients\u003c/h2\u003e \u003cp\u003eFirst, histochemical analysis of METTL3 expression showed that METTL3 expression was significantly greater in AR-PCNSL tumor samples than in IC-PCNSL tumor samples (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA-C). We further analyzed METTL3 expression in GCB-like DLBCL and ABC-like DLBCL patients from the AR-PCNSL and IC-PCNSL cohorts. METTL3 was expressed at lower levels in GCB-like DLBCL patients than in ABC-like DLBCL patients (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.027) in the AR-PCNSL cohort (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD-F), whereas there was no difference in the IC-PCNSL cohort (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eG-I).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eAIDS-related lymphomas are generally divided into three types: systemic lymphoma, PCNSL, and primary effusion lymphoma [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Unlike systemic lymphoma involving the central nervous system, PCNSL tumors are localized only to the central nervous system and not to other regions. The incidence of PCNSL in individuals infected with human immunodeficiency virus (HIV) ranges from 2\u0026ndash;6%, which is 1,000 times greater than that in HIV-negative individuals [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. More than 96% of PCNSLs are highly invasive B-cell lymphomas, with DLBCL being the most common subtype, while T-cell and low-grade lymphomas account for 1\u0026ndash;4% of PCNSLs [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In 2004, three antibodies (CD10, Bcl-6, and Mum-1) were utilized by Hans et al. [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] to label and classify DLBCL into two subtypes: germinal center B-cell-like (referred to as the GCB type) and activated B-cell-like (known as the ABC type). This classification has been extensively employed in clinical practice to determine the source and prognosis of DLBCL tumor cells. Despite the similar clinical presentations of PCNSL with and without AIDS, the etiology and pathological characteristics of AR-PCNSL and IC-PCNSL are completely different. Thus, our study aimed to compare clinicopathological features of patients with PCNSL who were infected or not infected with HIV.\u003c/p\u003e \u003cp\u003eIn our hospital, we conducted a retrospective study in which the clinical features of 67 patients with PCNSL were evaluated, both with and without HIV infection. All 67 patients with PCNSL had a histological classification of DLBCL. The tumor cells were diffusely distributed in sheets, with a relatively uniform morphology, minimal cytoplasm, round nuclei, uneven distribution of chromatin, and frequent nuclear division. Tumor cells commonly aggregate in Virchow-Robin spaces and may invade the blood vessel walls of the brain or form \u0026lsquo;sleeve-like\u0026rsquo; structures. Some tumor tissues exhibit a scattered distribution of phagocytic cells, forming a \u0026lsquo;starry sky\u0026rsquo; pattern. PCNSL can occur in any part of the CNS but is most often found in the supratentorial region. The commonly affected areas are the cerebral hemispheres, basal ganglia, and corpus callosum, with some lesions also located on the brain surface. The sites at which the tumor occurred were not significantly different between AR-PCNSL and IC-PCNSL. The age and gender distribution of the patients with AR-PCNSL were in line with previous findings, with younger male patients being more common than younger patients with IC-PCNSL [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. AR-PCNSL patients were more likely to have elevated LDH, CSF protein, and CSF chloride levels and lower CSF sugar. This could be because PCNSL patients can disseminate through the cerebrospinal fluid, and AR-PCNSL patients are more prone to spread through the cerebrospinal fluid.\u003c/p\u003e \u003cp\u003eHistologically, 25 of the 37 AR-PCNSL patients (67.6%) overexpressed of the protein Bcl-2, which is basically consistent with the literature (40%-81%) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Among the IC-PCNSL patients, only 23.3% had Bcl-2 overexpression, which was significantly lower than that of the AR-PCNSL patients. This may be because the Bcl-2 protein is a cell apoptosis inhibitor gene and an important pathogenic factor in the development of lymphoma. The Ki67 positivity rate is positively correlated with lymphoma invasiveness and malignancy level [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Our study revealed that 86.5% of the patients had high Ki-67 expression (Ki-67 index\u0026thinsp;\u0026gt;\u0026thinsp;50%), which is consistent with the literature and indicates rapid growth of tumor cells [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Additionally, Bcl-6 serves as a major regulatory element in the germinal center reaction, controlling B-cell activation, differentiation, cell cycle arrest, and apoptosis. Reis et al. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] reported that increased expression of Bcl-6 in patients with PCNSL was associated with an extended period of survival, indicating its predictive value. Therefore, the lower expression of Bcl-6 in AR-PCNSL may indicate a poorer prognosis than in IC-PCNSL. The TP53 gene is one of the most important tumor suppressor genes and regulates the cell cycle, apoptosis, and repair of DNA damage [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Our research revealed that p53 expression was significantly increased in AR-PCNSL. In addition, we conducted EBER in situ hybridization on paraffin tissue specimens taken from all 67 patients and found that 81.1% of the AR-PCNSL patients tested positive for EBER. No patients with IC-PCNSL were found to have EBV. EBV infection in humans could play a significant role in causing immunodeficiency among patients diagnosed with PCNSL. In addition to EBV infection immortalizing normal B cells, infected B cells can also escape suppression by normal T cells, leading to malignant transformation.\u003c/p\u003e \u003cp\u003eHowever, the pathogenesis of PCNSL is still unclear. Current research suggests that changes in epigenetic modifications are closely related to the onset of PCNSL [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Gene chip research has shown that, compared to normal tissue, PCNSL tissue has 194 genes whose DNA is methylated, the most significant difference being observed for genes with multiple CpG-enriched regions and promoter regions [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In eukaryotic cells, m6A modification is highly prevalent and plays a crucial regulatory role in cell differentiation, the stress response, tumor formation, and correlation with virus infection. The abundance of m6A in both viral and host-cell RNA is significantly increased by HIV infection [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. This fact motivates further exploration of the involvement of RNA methylation in HIV-1 biology and the mammalian response to viral infection. m6A modification is regulated mainly by complex interactions between methyltransferase complexes, demethylases, and methylation-reading proteins. Some of the members of the methyltransferase complex are METTL3, METTL14, METTL16, Wilms tumor 1-associated protein, RNA binding motif protein 15, and KIAA1429 [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Mounting evidence shows that the abnormal expression and function of METTL3 are closely related to tumor progression. Mechanistically, METTL3 can promote the translation of MYC, Bcl-2 and PTEN mRNAs. METTL3 can also regulate the stability of mRNAs by changing the level of m6A modification [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Therefore, further research on the role and specific molecular mechanism of METTL3 in AR-PCNSL development is highly important, and it is anticipated that AR-PCNSL will offer novel molecular targets for clinical diagnosis and treatment. We found that 84.6% of the AR-PCNSL patients exhibited high METTL3 expression, and in the IC-PCNSL cohort, only 43.4% of the patients exhibited high METTL3 expression. Therefore, we can infer that the HIV virus may cause excessive levels of m6A through promoting the expression of METTL3, leading to changes in the expression of downstream genes, such as Bcl-2, p53, Bcl-6, and Ki67, as well as other genetic abnormalities; dysregulation and release of cytokines; damage to dendritic cells; and/or infection with EB virus, hepatitis C virus, or other viruses. These stimuli lead to rearrangement of immunoglobulin variable genes, ultimately leading to the development of PCNSL in AIDS patients. Therefore, compared to patients with IC-PCNSL, patients with AR-PCNSL have earlier disease onset and a worse prognosis.\u003c/p\u003e \u003cp\u003eIn addition, AR-PCNSL patients with ABC-like DLBCL were more likely to express METTL3 than were those with GCB-like DLBCL. In IC-PCNSL patients, there were no differences in the expression of METTL3 between ABC-like DLBCL and GCB-like DLBCL. This may indicate that in AR-PCNSL, the expression of METTL3 not only promotes the occurrence and progression of PCNSL but also may be related to the origin of the tumor cells. Earlier studies have reported that compared to ABC-like DLBCL, GCB-like DLBCL has a better prognosis [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]; therefore, there may be a correlation between the expression of METTL3 and the prognosis of AR-PCNSL.\u003c/p\u003e \u003cp\u003eOverall, although the clinical symptoms of AR-PCNSL and IC-PCNSL are similar, the age onset of AR-PCNSL is earlier and it is more prone to occur in males. Similarly, the expression of METTL3, Bcl-2 and p53 was greater in these patients than in IC-PCNSL patients, while the expression of Bcl-6 was lower. Furthermore, among the AR-PCNSL patients, METTL3 was upregulated in ABC-like DLBCL compared with that in GBC-like DLBCL among AR-PCNSL patients. HIV may promote an increase in METTL3 expression and thereby influence the level of DNA methylation, the mRNA stability of cancer-related genes, the expression of oncogenes, cancer cell signaling pathways, and cancer cell apoptosis. Our findings may provide new sights into Chinese PCNSL patients with or without ARDS, which implies that further study is needed to explore novel pathways involved in tumor formation.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAIDS \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Acquired immune deficiency syndrome\u003c/p\u003e\n\u003cp\u003eHIV \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Human immunodeficiency virus\u2028\u003c/p\u003e\n\u003cp\u003eDLBCL(GCB) \u0026nbsp; \u0026nbsp; \u0026nbsp;Germinal center B-cell-like diffuse large B-cell lymphoma\u003c/p\u003e\n\u003cp\u003eDLBCL(ABC) \u0026nbsp; \u0026nbsp; \u0026nbsp; Activated B-cell-like diffuse large B-cell lymphoma\u003c/p\u003e\n\u003cp\u003ePCNSL \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Primary central nervous system lymphoma\u003c/p\u003e\n\u003cp\u003eAR-PCNSL \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; AIDS-related primary central nervous system lymphoma\u003c/p\u003e\n\u003cp\u003eIC-PCNSL \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Immunocompetent-primary central nervous system lymphoma\u003c/p\u003e\n\u003cp\u003eEBER \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Epstein\u0026ndash;Barr encoding region\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLDH \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Dehydrogenase\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCSF \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Cerebrospinal fluid\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are grateful to Liang Zhang and Li-ming Qi for excellent technical assistance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eML, JMC and XGZ designed the study protocol; ESF and XMC collected data collection; HLG,\u0026nbsp;ZYM and PW\u0026nbsp;analysed the data; ML and JMC contributed to drafting the manuscript. All the authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by a grant from the Beijing Medical Management Bureau Cultivation Plan (NO. PX2020070).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study complied with the Helsinki Declaration and was approved by the ethics committee of Beijing Ditan Hospital (DTEC-KY2022-007-02).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u0026nbsp;\u003c/sup\u003eDepartment of Pathology, Capital Medical University Affiliated Beijing Ditan Hospital, NO.8 Jing Shun East Street, Chaoyang District, Beijing 100015, PR China;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e2\u0026nbsp;\u003c/sup\u003eDepartment of Neurosurgery, Capital Medical University Affiliated Beijing Ditan Hospital, NO.8\u0026nbsp;Jing Shun East Street, Chaoyang District,\u0026nbsp;Beijing 100015, PR, China\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRadke J, Ishaque N, Koll R, et al. 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The 5th edition of the world health organization classification of haematolymphoid tumours: lymphoid neoplasms. Leukemia. 2022;36(7):1720\u0026ndash;48.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDlamini Z, Mbele M, Makhafola TJ, et al. HIV-associated cancer biomarkers: a requirement for early diagnosis. Int J Mol Sci. 2021;22(15):8127.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarta SK, Samuel MS, Xue X, et al. Changes in the influence of lymphoma- and HIV-specific factors on outcomes in AIDS-related non-Hodgkin lymphoma. Ann Oncol. 2015;26(5):958\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGandhi MK, Hoang T, Law SC, et al. EBV-associated primary CNS lymphoma occurring after immunosuppression is a distinct immunobiological entity. Blood. 2021;137(11):1468\u0026ndash;77.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCastelli R, Schiavon R, Preti C, et al. HIV-related lymphoproliferative diseases in the era of combination antiretroviral therapy. Cardiovasc Hematol Disord Drug Targets. 2020;20(3):175\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103(1):275\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBayraktar S, Bayraktar UD, Ramos JC, et al. Primary CNS lymphoma in HIV positive and negative patients: comparison of clinical characteristics, outcome and prognostic factors. J Neurooncol. 2011;101(2):257\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGe L, Lu S, Xu L, et al. MYC, BCL2, and BCL6 expression as prognostic indicators in primary central nervous system lymphoma: a systematic review and meta-analysis. Clin Neurol Neurosurg. 2021;208:106838.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHend A, Asker EN, Khorshed MR, Ahmed et al. Prognostic Values of MicroRNA-21 and Ki-67 in Diffuse Large B-Cell Lymphoma Patients. Egypt Experience Clin Lab. 2021;67(7).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang Z, Liu E, Zhang D, et al. The expression and clinical significance of PLK1/p-PLK1 protein in NK/T cell Lymphoma. Diagn Pathol. 2023;18(1):129.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReis DGC, Levy D, Lage L, et al. New genetic prognostic biomarkers in primary central nervous system lymphoma (PCNSL). Brain Behav. 2021;11(4):e02061.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSergey Tsymbal A, Refeld V, Zatsepin, et al. The p53 protein is a suppressor of Atox1 copper chaperon in tumor cells under genotoxic effects. PLoS ONE. 2023;18(12):e0295944.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLebrun L, Allard-Demoustiez S, Salmon I. Pathology and new insights in central nervous system lymphomas. Curr Opin Oncol. 2023;35(5):347\u0026ndash;56.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDowns BM, Ding W, Cope LM, et al. Methylated markers accurately distinguish primary central nervous system lymphomas (PCNSL) from other CNS tumors. Clin Epigenetics. 2021;13(1):104.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLichinchi G, Gao S, Saletore Y, et al. Dynamics of the human and viral m\u003csup\u003e6\u003c/sup\u003eA RNA methylomes during HIV-1 infection of T cells. Nat Microbiol. 2016;1:16011.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJiang X, Liu B, Nie Z, et al. The role of m6A modification in the biological functions and diseases. Signal Transduct Target Ther. 2021;6(1):74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBedi RK, Huang D, Li Y, et al. Structure-based design of inhibitors of the m\u003csup\u003e6\u003c/sup\u003eA-RNA writer enzyme METTL3. ACS Bio Med Chem Au. 2023;3(4):359\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCamilleri-Bro\u0026euml;t S, Crini\u0026egrave;re E, Bro\u0026euml;t P, et al. A uniform activated B-cell-like immunophenotype might explain the poor prognosis of primary central nervous system lymphomas: analysis of 83 cases. Blood. 2006;107(1):190\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"ARDS, METTL3, AR-PCNSL, IC-PCNSL, GCB-like DLBCL, ABC-like DLBCL","lastPublishedDoi":"10.21203/rs.3.rs-3824370/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3824370/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground \u003c/strong\u003eAIDS-related primary central nervous system lymphoma (AR-PCNSL) differs from immunocompetent-primary central nervous system lymphoma (IC-PCNSL) in certain features.\u003cstrong\u003e \u003c/strong\u003eThe main objective of this study was to investigate the differences in clinicopathological features between AR-PCNSL and IC-PCNSL.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods \u003c/strong\u003eThirty-seven AR-PCNSL patients and thirty IC-PCNSL patients were included. hematoxylin \u0026amp; eosin staining; immunohistochemical detection using CD20, Bcl-2, Bcl-6, p53, C-MYC, Ki67, and METTL3 antibodies; and Epstein–Barr encoding region (EBER) in situ hybridization were performed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults \u003c/strong\u003eAll of the observed patients were classified as the DLBCL histological type. AR-PCNSL were younger (37.7 vs. 60.5 years) and had a higher likelihood of being male (86.5% vs. 63.3%) than non-AIDS patients were. Elevated LDH and low sugar content in cerebrospinal fluid (CSF) were more common among AR-PCNSL. The expression levels of METTL3, Bcl-2 and p53 expressions were significantly higher in AR-PCNSL patients than in PCNSL patients without AIDS. In contrast, AR-PCNSL patients exhibited lower levels of Bcl-6 expression. AR-PCNSL patients were more likely to be positive for EBER, accounting for 81.1% of these patients. Furthermore, we also found that the expression of METTL3 was lower in GCB-like DLBCL (n=7) than in ABC-like DLBCL (n=32) in AR-PCNSL (\u003cem\u003ep\u003c/em\u003e=0.041); however, in IC-PCNSL patients, the expression of METTL3 was not significantly different between GCB-like DLBCL and ABC-like DLBCL (\u003cem\u003ep\u003c/em\u003e=0.710).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e Our study of Chinese AR-PCNSL and IC-PCNSL patients revealed new findings, indicating that METTL3, Bcl-2 and p53 were increased in AR-PCNSL patients compared to IC-PCNSL patients and that METTL3 was higher in ABC-like DLBCL patients than in GCB-like DLBCL in AR-PCNSL patients, suggesting a notable distinction in the pathological characteristics between PCNSL patients with or without AIDS.\u003c/p\u003e","manuscriptTitle":"Clinicopathological analysis of primary central nervous system lymphoma in patients with or without AIDS","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-05 17:51:29","doi":"10.21203/rs.3.rs-3824370/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5d3cc13d-9678-4fc9-901b-df46978f73e6","owner":[],"postedDate":"January 5th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-02-27T00:06:09+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-05 17:51:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3824370","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3824370","identity":"rs-3824370","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}