Clinicopathological features and prognostic factors of AIDS-related lymphoma: a retrospective single-center study in China.

Introduction

In 2023, approximately 40 million people living with human immunodeficiency virus (PLWH), and this number is expected to continue rising [ 1 ]. Prior to the advent of antiretroviral therapy (ART), PLWH faced a risk of developing non-Hodgkin lymphoma (NHL) more than 100 times higher than that of the general population, while the risk of classical Hodgkin lymphoma (HL) was approximately 7 times greater [ 2 , 3 ]. Since the introduction of ART in 1996, its widespread use has significantly extended the lifespan of PLWH; however, acquired immunodeficiency syndrome (AIDS)-related malignancies, particularly lymphoma, remain a substantial health threat [ 4 , 5 ]. Although the incidence of AIDS-related lymphoma (ARL) has declined with the widespread use of ART, ARL still accounts for more than 50% of all AIDS-related malignancies and remains a leading cause of death among PLWH [ 6 , 7 ].

Among PLWH, the most prevalent lymphoma subtypes are diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL), with other forms such as primary effusion lymphoma (PEL) and plasmablastic lymphoma (PBL) also being relatively common [ 8 ]. The complex interplay between human immunodeficiency virus (HIV) infection, immune suppression, and co-infection with Epstein-Barr virus (EBV) is thought to contribute to significant variations in the incidence and prognosis of NHL and HL, as well as differences between various NHL subtypes [ 9 ]. Several key risk factors for NHL have been identified, including low CD4 + T cell count and high HIV viral load [ 10 – 12 ]. Moreover, PLWH generally exhibit poorer outcomes for malignancies compared to their HIV-negative counterparts [ 13 ]. Current treatment guidelines advocate for providing the same therapeutic interventions to PLWH diagnosed with malignancies as those offered to HIV-negative patients [ 14 , 15 ]. In the United States, PLWH are more likely to be diagnosed at advanced stages of malignancy than non-PLWH [ 13 ]. Despite significant progress in understanding the relationship between HIV and lymphoma, most research has focused on specific subtypes or geographic regions, with a lack of large-scale, population-based studies. As one of the countries with the highest number of PLWH globally, China faces a critical need for systematic research to better understand the epidemiology and clinical outcomes of ARL.

Our study retrospectively examines the clinical data of ARL patients treated at our institution, focusing on their initial clinical presentations, immunohistochemical profiles, treatment regimens, and clinical outcomes. The aim is to elucidate the prognostic differences between lymphoma subtypes in PLWH and to identify the key factors influencing lymphoma survival outcomes. These findings may provide valuable insights for early diagnosis, individualized treatment strategies, and prognostic assessment of ARL, while contributing to the broader scientific understanding and clinical management of this devastating disease.

Methods

Study design and participants

This retrospective study analyzed patients diagnosed with ARL at Beijing Youan Hospital, affiliated with Capital Medical University, from January 2017 to November 2024. To ensure diagnostic consistency and accuracy, all cases underwent a comprehensive retrospective pathological review and were independently re-evaluated by two experienced pathologists according to the 2022 WHO classification criteria [ 16 ]. Patients were excluded based on the following criteria: (a) presence of concurrent malignancies; (b) missing treatment data; and (c) incomplete diagnoses or cases that did not meet the established diagnostic criteria. The patient selection process is illustrated in Fig. 1 . A total of 130 lymphoma patients were included in the study, consisting of 51 cases of DLBCL, 56 cases of BL, 8 cases of PBL, 6 cases of T/NK cell lymphoma, and 9 cases of HL. This study was conducted in accordance with the Declaration of Helsinki and approved by our Institutional Review Board (reference number: Jing You Ke Lun Zi < 2020 > 107). Informed consent was waived due to the retrospective nature of the study. All patient data were handled with strict confidentiality and anonymized.

Fig. 1 Flowchart depicting patient selection and exclusion criteria. HL, Hodgkin lymphoma; NHL, non-Hodgkin lymphoma; DLBCL, diffuse large B-cell lymphoma; BL, burkitt lymphoma; PBL, plasmablastic lymphoma

Data collection

Blood samples and tumor tissue specimens were collected from all patients prior to treatment. Data collected included demographic variables (age and sex), HIV-related parameters (duration from HIV infection to lymphoma diagnosis, timing of ART initiation, CD4 + T cell count, and HIV viral load at lymphoma diagnosis), and lymphoma-specific clinical and pathological features. These latter variables comprised cell-of-origin subtype, Eastern Cooperative Oncology Group (ECOG) performance status, serum lactate dehydrogenase (LDH) levels, presence of B symptoms, number and sites of extranodal involvement, bone marrow and central nervous system involvement, Ann Arbor stage, and expression of immunohistochemical markers including Ki-67, MYC, BCL2, MUM1, CD38, and Epstein–Barr virus encoded RNA (EBER). For patients who died during hospitalization, the date of death was retrieved from medical records. For those who survived or died after discharge, the last follow-up date was used as the endpoint for survival data. The primary endpoint of this study was overall survival (OS), defined as the interval from the date of lymphoma diagnosis to death from any cause or to the date of last follow-up for censored patients.

Histopathological, immunohistochemical, and EBER in situ hybridization analysis

Hematoxylin and eosin (HE) staining was performed to evaluate the morphological characteristics of the tumors. Immunohistochemical (IHC) analysis was conducted on formalin-fixed and paraffin-embedded (FFPE) tissue samples, using antibodies targeting Ki-67, CD10, BCL6, BCL2, MYC, MUM1, and CD38. The positivity thresholds for CD10, BCL6, MUM1, and CD38 were set at 30%, for MYC at 40%, and for BCL2 at 50%. Ki-67 expression was quantified in 10% increments, with ≥ 80% staining classified as “positive/high.” EBER was detected using the EBV probe in situ hybridization kit (ISH-6021, Zhongshan Golden Bridge Biotechnology Co., Ltd., Beijing, China) according to the manufacturer’s instructions, with positive signals appearing brownishyellow in the cell nucleus.

Terminology definitions

The Ann Arbor staging was determined based on pre-treatment computed tomography (CT) or positron emission tomography/computed tomography (PET/CT) scans of the chest, abdomen, and pelvis, in conjunction with bone marrow biopsy results [ 17 ]. Patients were defined as having B symptoms if they met any of the following criteria: (a) unexplained weight loss of more than 10% of the body weight during the 6 months before initial staging investigation; (b) unexplained, persistent, or recurrent fever with temperatures above 38 °C during the previous month; and (c) recurrent drenching night sweats during the previous month [ 18 ].

Lymphoma chemotherapy

Treatment information for patients was collected from hospital records and pharmacy archives. ARL patients received chemotherapy regimens, including the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) [ 19 ], EPOCH (etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone) [ 20 ], Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) [ 21 ], and the ABVD regimen (Doxorubicin, Bleomycin, Vinblastine, and Dexamethasone) [ 22 ], with some patients also undergoing surgical treatment.

Statistical analysis

Statistical analyses were performed using SPSS version 26.0. For continuous variables, intergroup comparisons were conducted using the Mann-Whitney U test, while categorical variables were analyzed using the chi-square test. Survival curves were generated using the Kaplan-Meier method, and differences between groups were assessed using the log-rank test. Patients who were alive at the last follow-up were censored at that time, while those lost to follow-up were censored at the date of last contact, under the assumption that no further events occurred beyond that point. Univariate and multivariate analyses were performed using the Cox proportional hazards model to calculate hazard ratios (HR) and 95% confidence interval (95% CI). Variables with a P -value < 0.05 in univariate analysis were included in the multivariate model. A two-tailed P -value of < 0.05 was considered statistically significant for all tests.

Results

Patient characteristics

This study included 130 patients, and the baseline HIV-related characteristics are summarized in Table 1 . Among the histologically confirmed cases of ARL, BL and DLBCL were the most prevalent subtypes, accounting for 43.1% and 39.2% of cases, respectively. These was followed by HL at 6.9%, PBL at 6.2%, and T/NK cell lymphoma, which was the least common, comprising 4.6% of the cohort. The median age of the patients was 39 years (range: 17–75), with a male predominance (94.6%). At the time of lymphoma diagnosis, 51.5% of patients had been living with HIV for more than 6 months; however, only 35.4% had received ART for more than 6 months prior to the ARL diagnosis. The median CD4 + T cell count at diagnosis was 140 cells/µl (range: 4–593), with 62.3% of patients presenting with a CD4 + T cell count below 200 cells/µl. Of the 116 patients tested for HIV viral load, 64.7% had detectable levels (≥ 40 copies/µl). Among the 120 patients assessed for EBV viral load, 42.5% had a viral load of ≥ 500 copies/µl. Notably, when comparing DLBCL and BL cases, patients with BL were significantly younger ( P = 0.001), exhibited higher CD4 + T cell count ( P = 0.035), and were more likely to have a detectable HIV viral load ( P = 0.002).

Table 1 Baseline characteristics of patients with AIDS-related lymphoma ( n = 130) All ( n = 130) DLBCL ( n = 51) BL ( n = 56) PBL ( n = 8) T/NK CL( n = 6) HL ( n = 9) P -value Median age (range) (years) 39 (17–75) 46 (22–75) 37 (22–57) 35 (27–59) 36 (17–54) 36 (25–47) 0.001 Gender, n (%) Male 123 (94.6) 48 (94.1) 54 (96.4) 8 (100) 5 (83.3) 8 (88.9) Female 7 (5.4) 3 (5.9) 2 (3.6) 0 (0) 1 (16.7) 1 (11.1) Time from HIV diagnosis to lymphoma (months) 0.802 Median (range) 6 (0-144) 4 (0-144) 2.5 (0-122) 8.5 (1–72) 90 (2-144) 36 (6–96) < 6, n (%) 63 (48.5) 27 (52.9) 31 (55.4) 3 (37.5) 2 (33.3) 0 (0) ≥ 6, n (%) 67 (51.5) 24 (47.1) 25 (44.6) 5 (62.5) 4 (66.7) 9 (100) Time from ART initiation to lymphoma diagnosis (months) 0.343 Median (range) 1 (0-144) 1 (0-144) 0 (0-120) 2 (0–36) 13 (0–60) 36 (6–96) < 6, n (%) 84 (64.6) 34 (66.7) 42 (75.0) 5 (62.5) 3 (50.0) 0 (0) ≥ 6, n (%) 46 (35.4) 17 (33.3) 14 (25) 3 (37.5) 3 (50.0) 9 (100) CD4 + T cell count (cells/ul) 0.035 Median (range) 140 (4-593) 106 (5-535) 144 (9-576) 106 (14–570) 139 (135–593) 353 (4-547) < 200, n (%) 81 (62.3) 39 (76.5) 32 (57.1) 6 (75.0) 2 (33.3) 2 (22.2) ≥ 200, n (%) 49 (37.7) 12 (23.5) 24 (42.9) 2 (25.0) 4 (66.7) 7 (77.8) HIV viral load (copies/ul), n/N (%) 0.002 Median (range) 1566 (0-1170821) 306 (0-1170821) 18,790 (0-996948) 0 (0-1170820) 4773 (0-516305) 0 (0-2831) < 40 41/116 (35.3) 23/50 (46.0) 9/51 (17.6) 4/7 (57.1) 1/3 (33.3) 4/5 (80) ≥ 40 75/116 (64.7) 27/50 (54.1) 42/51 (82.4) 3/7 (42.9) 2/3 (66.7) 1/5 (20) EBV viral load copies/ul, n/N (%) 0.567 Median (range) 0 (0-1.8 × 10 8 ) 0 (0-1.87 × 10 7 ) 0 (0-1.8 × 10 8 ) 2.145 × 10 4 (0-1.18 × 10 6 ) 0 (0-4.22 × 10 3 ) 1.49 × 10 3 (0-1.03 × 10 5 ) < 500 69/120 (57.5) 29/48 (60.4) 33/50 (66.0) 1/8 (12.5) 4/5 (80) 2/9 (22.2) ≥ 500 51/120 (42.5) 19/48 (39.6) 17/50 (34.0) 7/8 (87.5) 1/5 (20) 7/9 (77.8) Abbreviation: NHL, non-Hodgkin lymphoma; DLBCL, diffuse large B-cell lymphoma; BL, Burkitt lymphoma; PBL, plasmablastic lymphoma; T/NK CL, T/NK cell lymphoma; HL, Hodgkin lymphoma; HIV, human immunodeficiency virus; ART, antiretroviral therapy; EBV, Epstein-Barr virus P -values were calculated comparing DLBCL and BL groups and statistically significant P -values are highlighted

Immunohistochemistry

Table 2 summarizes the immunohistochemical characteristics of the various ARL subtypes. Among patients with DLBCL, approximately half (46.9%) were of germinal center B-cell-like (GCB) subtype. Ki-67 expression was notably high, with 76.5% of patients showing ≥ 80% staining. The majority of DLBCL cases were positive for BCL2 (67.3%), MUM1 (73.5%), and CD38 (61.4%), while 43.1% exhibited EBER positivity via in situ hybridization. In BL cases, all patients demonstrated Ki-67 expression ≥ 80%, with high positivity for MYC (85.7%) and CD38 (71.7%), but relatively low expression of BCL2 (16.4%) and MUM1 (37.5%). The EBER positivity rate in BL was 30.4%. Due to the limited number of PBL, T/NK cell lymphoma, and HL cases, the statistical significance of their immunohistochemical findings was limited. Nonetheless, it is noteworthy that nearly all HIV-infected PBL and HL cases were EBER positive. When comparing DLBCL with BL, BL patients had significantly higher rates of Ki-67 ≥ 80% ( P < 0.001) and MYC positivity ( P < 0.001), while BCL2 and MUM1 expression were lower ( P < 0.001).

Table 2 Immunohistochemistry of AIDS-related lymphoma ( n = 130) DLBCL ( n = 51) BL ( n = 56) PBL ( n = 8) T/NK CL( n = 6) HL ( n = 9) P -value COO GCB 23/49 (46.9) - - - - - Non-GCB 26/49 (53.1) - - - - - Ki 67%, n/N < 0.001 < 80 12/51 (23.5) 0/56 (0) 0/8 (0) 1/6 (16.7) 0/9 (0) ≥ 80 39/51 (76.5) 56/56 (100) 8/8 (100) 5/6 (83.3) 9/9 (100) MYC, n (%) < 0.001 < 40 28/51 (54.9) 8/56 (14.3) 0/6 (0) 0 0/2 (0) ≥ 40 23/51 (45.1) 48/56 (85.7) 6/6 (100) 0 2/2 (100) BCL2, n (%) < 0.001 < 50 16/49 (32.7) 46/55 (83.6) 3/5 (60) 1/5(20) 4/4 (100) ≥ 50 33/49 (67.3) 9/55 (16.4) 2/5 (40) 4/5 (80) 0/4 (0) MUM1, n/N (%) < 0.001 < 30 13/49 (26.5) 35/56 (62.5) 2/8 (25.0) 0/4 (0) 0/7 (0) ≥ 30 36/49 (73.5) 21/56 (37.5) 6/8 (75.0) 4/4 (100) 7/7 (100) CD38, n (%) 0.281 < 30 17/44 (38.6) 15/53 (28.3) 1/8 (12.5) 2/3 (76.7) 2/2 (100) ≥ 30 27/51 (61.4) 38/53 (71.7) 7/8 (87.5) 1/3 (33.3) 0/2 (0) EBER, n (%) 0.170 Positive 22/51 (43.1) 17/56 (30.4) 8/8 (100) 3/8 (50) 9/9 (100) Negative 29/51 (56.9) 39/56 (69.6) 0/0 (0) 3/8 (50) 0/0 (0) Abbreviation: DLBCL, diffuse large B-cell lymphoma; BL, Burkitt lymphoma; PBL, plasmablastic lymphoma; T/NK CL, T/NK cell lymphoma; HL, Hodgkin lymphoma; EBER, Epstein-Barr virus-encoded RNA P -values were calculated comparing DLBCL and BL groups and statistically significant P-values are highlighted

Clinical analysis, treatment, and survival outcomes

Table 3 provides a comprehensive summary of the clinical staging, prognosis, treatment, and outcomes of ARL. Most patients in this study were young, with only six DLBCL patients over the age of 60. At diagnosis, poor performance status was commonly observed, particularly among DLBCL patients who had elevated ECOG scores. The majority of patients were diagnosed at Ann Arbor stage III or IV, with extranodal involvement at more than one site. Bone marrow infiltration was observed across all ARL subtypes, with the highest frequencies seen in BL (46.4%) and T/NK cell lymphomas (50%), whereas the incidence in DLBCL was comparatively lower (21.7%). Central nervous system involvement was also documented in patients with DLBCL, BL, and PBL. Additionally, over half of the patients had elevated LDH levels and presented with B symptoms. Compared with DLBCL, BL was characterized by a younger age at diagnosis ( P = 0.026), lower ECOG performance status scores ( P = 0.009), and a significantly higher frequency of bone marrow involvement ( P = 0.007). Additionally, risk stratification was conducted for each lymphoma subtype, categorizing patients into low-, intermediate-, and high-risk categories. The International Prognostic Index (IPI) was used for DLBCL and PBL, while the BL-IPI score was applied to BL. T/NK-cell lymphomas were assessed using the Prognostic Index for T-cell lymphoma (PIT), and HL patients were assessed using the International Prognostic Score (IPS).

Table 3 Clinical staging, prognosis, treatment, and outcomes of AIDS-related lymphoma ( n = 130) DLBCL ( n = 51) BL ( n = 56) PBL ( n = 8) T/NK CL( n = 6) HL ( n = 9) P -value Age (years), n (%) 0.026 < 60 45 (88.2) 56 (100) 8 (100) 6 (100) 9 (100) ≥ 60 6 (11.8) 0 (0) 0 (0) 0 (0) 0 (0) ECOG score, n (%) 0.009 0–1 19 (37.3) 35 (62.5) 4 (50) 5 (83.3) 6 (66.7) ≥ 2 32 (62.7) 21 (37.5) 4 (50) 1 (16.7) 3 (33.3) Ann Arbor stage, n (%) 0.478 I/II 5 (9.8%) 8 (14.3) 1 (12.5) 3 (50) 5 (55.6) III/IV 46 (90.2) 47 (85.7) 7 (87.5) 3 (50) 4 (44.4) Extranodal involved sites, n (%) 0.562 0–1 21 (41.2) 20 (35.7) 1 (12.5) 4 (66.7) 7 (77.8) ≥ 2 30 (58.8) 36 (64.3) 7 (87.5) 2 (33.3) 2 (22.2) LDH, n (%) 0.343 ≤ 1×ULN 17 (33.3) 14 (25) 5 (62.5) 4 (66.7) 7 (77.8) > 1×ULN 34 (66.7) 42 (75) 3 (37.5) 2 (33.3) 2 (22.2) B symptoms, n (%) 0.311 Yes 34 (66.7) 32 (57.1) 4 (50) 5 (83.3) 4 (44.4) No 17 (33.3) 24 (42.9) 4(50) 1 (16.7) 5 (55.6) Bone marrow involvement, n (%) 11 (21.7) 26 (46.4) 3 (37.5) 3 (50) 3 (33.3) 0.007 CNS involvement, n (%) 6 (11.8) 8 (14.3) 1 (12.5) 0 0 0.699 Risk stratification, n (%) - low 1 (2.0) 15 (26.8) 1 (12.5) 3 (50) 5 (55.6) intermediate 47 (92.2) 19 (33.9) 5 (62.5) 2 (33.3) 2 (22.2) high 3 (5.9) 22 (39.3) 2 (25) 1 (16.7) 2 (22.2) Initial chemotherapy regimen for lymphoma, n (%) CHOP 23 (45.1) 18 (32.1) 4 (50) 0 0 EPOCH 21 (41.2) 16 (28.6) 4 (50) 3 (50) 0 Hyper-CVAD 3 (5.9) 10 (17.9) 0 0 0 ABVD 0 0 0 0 7 (77.8) Other regimens 1 (2.0) 5 (8.9) 0 0 0 No regimen 3 (5.9) 7 (12.5) 0 3 (50) 2 (22.2) Regimen with R 42 (82.4) 34 (60.7) 3 (37.5) 0 0 Survival 0.401 Median survival (months) 18 11 28 14 33 2-year OS, (%) 51.7 43.8 58.3 50 85.7 Abbreviation: DLBCL, diffuse large B-cell lymphoma; BL, Burkitt lymphoma; PBL, plasmablastic lymphoma; T/NK CL, T/NK cell lymphoma; HL, Hodgkin lymphoma; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; ULN, upper limit of normal; CNS, central nervous system; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; EPOCH, etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone; Hyper-CVAD, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone; ABVD, Doxorubicin, Bleomycin, Vinblastine, and Dexamethasone; R, Rituximab; OS, overall survival The risk stratification systems for different lymphoma subtypes are as follows: DLBCL and PBL, the International Prognostic Index (IPI) was applied, categorizing patients as low risk (0–1 points), intermediate risk (2–3 points), or high risk (4–5 points); BL, assessed using the BL-IPI, with risk groups defined as low (0 points), intermediate (1 point), and high (≥ 2 points); T/NK-cell lymphomas, stratified according to the Prognostic Index for T-cell lymphoma (PIT) into low (0 points), intermediate (1–2 points), and high-risk (≥ 3 points) groups; HL, the International Prognostic Score (IPS) was used to define low (0–2 points), intermediate (3–4 points), and high-risk (5–7 points) categories P -values were calculated comparing DLBCL and BL groups and statistically significant P -values are highlighted

Regarding treatment, 45.1% of DLBCL patients received the CHOP regimen, 41.2% received EPOCH regimen, and 82.4% were treated with rituximab. Some patients were unable to initiate timely treatment due to rapid disease progression or financial constraints. Among BL patients, 32.1% received CHOP, 28.6% with EPOCH, and 17.9% with Hyper-CVAD, with 60.7% were treated with rituximab. In the PBL cohort, 50% received either CHOP or EPOCH, and 37.5% received rituximab. Among NK/T-cell lymphoma patients, 50% received EPOCH, while the other 50% underwent surgical treatment. The majority of HL patients (77.8%) received the ABVD regimen, with the remaining patients undergoing surgery.

As of the last follow-up on November 31, 2024, 60 patients (46.2%) had died, 69 (53.1%) were alive, and 2 were lost to follow-up. The median follow-up duration was 15 months (range: 1–94 months), and the 2-year OS rate of 50.6% (Fig. 2 a). The 2-year OS rates for DLBCL, BL, PBL, T/NK cell lymphoma, and HL were 51.7%, 43.8%, 58.3%, 50%, and 85.7%, respectively. Notably, HL patients exhibited the most favorable prognosis, while BL patients had the poorest survival outcomes (Fig. 2 b).

Fig. 2 Kaplan-Meier survival curves based on OS. ( a ) Kaplan-Meier estimate of OS for ARL ( n = 130). ( b ) Kaplan-Meier estimate of OS for People Living with HIV with BL ( n = 56), DLBCL ( n = 51), PBL ( n = 8), T/NK CL ( n = 6), and HL ( n = 9). ARL, AIDS-related lymphoma; OS, overall survival; DLBCL, diffuse large B-cell lymphoma; BL, Burkitt lymphoma; PBL, plasmablastic lymphoma; T/NK CL, T/NK Cell lymphoma; HL, Hodgkin lymphoma

Univariate and multivariate analysis of NHL

Univariate analysis identified several factors significantly associated with poor OS, including a CD4 + T cell count < 200 cells/µl ( P = 0.001), presence of B symptoms ( P = 0.037), ECOG score > 1 ( P = 0.001), Ann Arbor stage > 2 ( P = 0.014), extranodal involvement in more than one site ( P < 0.001), and elevated LDH levels ( P < 0.001), and bone marrow involvement ( P = 0.033). Multivariate analysis revealed that a CD4 + T cell count < 200 cells/µl (HR: 2.085, 95% CI: 1.094–3.974, P = 0.026) and elevated LDH levels (HR: 0.378, 95% CI: 0.192–0.746, P = 0.005) were independent prognostic factors for poor survival. Although EPOCH treatment was associated with a trend toward improved prognosis compared with CHOP ( P = 0.057), the difference was not statistically significant. Conversely, a high IPI (score 3–5) was significantly associated with poorer survival outcomes ( P < 0.001) (Table 4 ).

Table 4 Univariate and multivariate analysis of OS in patients with AR-NHL ( n = 121) Univariate analysis Multivariate analysis HR (95% CI) P -value HR (95% CI) P -value Time from HIV diagnosis to lymphoma (months) < 6 mon vs. ≥ 6 mon 0.962 (0.582–1.590) 0.880 Time from ART initiation to lymphoma diagnosis (months) < 6 mon vs. ≥ 6 mon 1.039 (0.609–1.774) 0.888 CD4 + T cell count (cells/µl) < 200 vs. ≥ 200 2.734 (1.480–5.049) 0.001 2.085 (1.094–3.974) 0.026 HIV viral load (copies/ul) < 40 vs. ≥ 40 0.853 (0.487–1.495) 0.579 EBV viral load (copies/ul) < 500 vs. ≥ 500 0.761 (0.450–1.288) 0.309 B symptoms Yes vs. No 0.557 (0.321–0.966) 0.037 1.056 (0.569–1.960) 0.864 Age (years) < 60 vs. ≥ 60 0.845 (0.265–2.699) 0.776 ECOG score < 2 vs. ≥ 2 0.427 (0.254–0.718) 0.001 0.671 (0.378–1.192) 0.174 Ann Arbor stage I/II vs. III/IV 0.280 (0.102–0.773) 0.014 1.002 (0.293–3.426) 0.998 Extranodal involved sites < 2 vs. ≥ 2 0.373 (0.208–0.668) < 0.001 0.609 (0.300-1.236) 0.170 Elevated LDH Yes vs. No 0.295 (0.154–0.568) < 0.001 0.378 (0.192–0.746) 0.005 Bone marrow involvement Yes vs. No 1.735 (1.046–2.877) 0.033 1.194 (0.687–2.073) 0.530 CNS involvement Yes vs. No 0.530 (0.276–1.018) 0.057 IPI score 0-2 vs. 3‐5 4.425 (2.242–8.731) < 0.001 Regimen CHOP vs. EPOCH 0.536 (0.285–1.011) 0.054 KI67% < 80% vs. ≥ 80% 1.244 (0.613–2.525) 0.546 MYC < 40% vs. ≥ 40% 0.719 (0.399–1.295) 0.272 BCL2 < 50% vs. ≥ 50% 0.849 (0.502–1.437) 0.542 MUM1 < 30% vs. ≥ 30% 0.986 (0.586–1.658) 0.957 CD38 < 30% vs. ≥ 30% 1.140 (0.645–2.014) 0.653 EBER Positive vs. Negative 1.007 (0.601–1.687) 0.979 Abbreviation : HR, hazard ratio; CI, confidence interval; HIV, human immunodeficiency virus; ART, antiretroviral therapy; EBV, Epstein-Barr virus; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; IPI, International Prognostic Index; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; EPOCH, etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone; EBER, Epstein-Barr virus-encoded RNA Statistically significant P -values are highlighted

Discussion

HIV infection increases the risk of malignant tumors through multiple mechanisms, including systemic immune impairment, genetic alterations, susceptibility to oncogenic viral, and chronic B-cell activation [ 23 ]. Since the advent of ART in 1996, the immune function of PLWH has significantly improved, leading to prolonged survival [ 24 ]. However, despite substantial immune reconstitution, the effect of ART on the incidence of ARL has been less pronounced.

The distribution of lymphoma subtypes in PLWH differs substantially from that in the general population. In a cohort of 4,115 non-ARL patients, Surabhi et al. reported that HL accounted for 30.35%, and NHL for 69.65%. Among NHL cases, B-cell lymphomas represented 84.08%, while T-cell and NK-cell lymphomas comprised 15.38% [ 25 ]. In contrast, in the present study, BL accounted for 43%, DLBCL for 39%, PBL for 6%, peripheral T/NK-cell lymphoma for 5%, and HL for 7%. Overall, ARL predominantly comprised NHL, with higher frequencies of BL and DLBCL and lower frequencies of other subtypes, highlighting the profound influence of HIV on lymphoma subtype distribution [ 26 ]. The median age in our cohort was relatively young, with only a few patients aged > 60 years, all of whom had DLBCL.

HIV-related factors are critical in the pathogenesis and progression of lymphoma, with differential impacts across subtypes. In this study, 51.5% of patients had been diagnosed with HIV for more than six months prior to lymphoma diagnosis, yet only 35.5% had received ART for more than six months. This is notably lower than previously reported; for instance, one study reported a median 15-year interval between HIV and DLBCL diagnosis, with nearly 80% of patients on ART [ 27 ]. Our findings suggest delayed HIV diagnosis and limited ART exposure, likely due to low awareness, poor access to care, and missed opportunities for early intervention. Notably, many patients were diagnosed with HIV only after presenting with lymphoma-related symptoms. NHL patients showed similar patterns of delayed HIV diagnosis and shorter ART exposure. However, HL patients had a longer duration of HIV infection, with all having been HIV-positive for over six months. Among PLWH, patients with BL were significantly younger ( P < 0.001), had higher CD4 + T cell counts ( P = 0.035), and exhibited higher HIV viral loads ( P = 0.002) compared to those with DLBCL. These observations are consistent with previous findings indicating that AIDS-related BL is more common in individuals with preserved immune function and is strongly associated with cumulative HIV viremia [ 28 , 29 ]. Additionally, most PLWH contract EBV during childhood or adolescence [ 30 ]. Without intervention, EBV coinfection increases lymphoma risk more than 60-fold compared with the general population [ 31 ]. Despite the widespread use of ART, EBV-associated cancers remain prevalent among PLWH [ 32 , 33 ]. In PLWH, the association between different lymphoma types and EBV infection varies: 30-90% of DLBCL (depending on the subtype), 30-60% of BL, 70-80% of PBL, and 100% of HL cases are associated with EBV infection [ 34 ]. In our cohort, PBL and HL showed high EBV positivity (87.5% and 77.8%, respectively), whereas T/NK-cell lymphoma had lower viral loads. Immunohistochemistry confirmed a strong association between EBV and lymphoma in PLWH, with EBER positivity in 100% of HL and 87.5% of PBL cases. These differences suggest that EBV plays a more crucial role in the pathogenesis of lymphoma in PLWH, particularly in HL and PBL.

Ki-67 is a commonly used marker of cellular proliferation [ 35 ]. In the general population, DLBCL exhibits Ki-67 indices ranging from 40 to 90%, while BL approaches 100% [ 36 ]. Our data were consistent with these reports. Notably, there was a significant difference in Ki-67 expression between BL and DLBCL ( P < 0.001), suggesting that Ki-67 may serve as a valuable diagnostic marker for differentiating between these subtypes. Furthermore, compared with the general population, AR-DLBCL showed higher expression rates of MYC (45.1%) and BCL2 (67.3%) [ 37 , 38 ], indicating that ARL is more aggressive, particularly with features characteristic of double-hit or triple-hit lymphomas. We also found high CD38 expression in B-cell NHL, particularly in patients with PBL and BL. CD38 is a transmembrane glycoprotein associated with the GCB subtype and is a marker of mature plasma cells and plasma cell tumours [ 39 ]. In the tumour microenvironment, CD38 + cells may facilitate immune evasion through the release of immunosuppressive mediators [ 40 ]. Interestingly, in PLWH without lymphoma, increased proportion of circulating CD8+/CD38 + T cells are predictive of AIDS progression, CD4 + T cell depletion and higher viral load [ 41 ]. Additionally, co-expression of CD38 and HLA-DR on CD4+/CD45RO + T cells correlates with disease activity, while high CD38 expression on CD4 + T cells, indicative of chronic immune activation, is associated with poor prognosis in advanced HIV infection. Despite these associations, anti-CD38 therapies have not been systematically evaluated in AIDS-related DLBCL, HL or BL. Nevertheless, some studies have reported CD38 expression in all cases of ARL, with expression levels varying by histological subtype [ 42 ]. Daratumumab, a monoclonal antibody targeting CD38 approved for multiple myeloma, has shown promising safety and efficacy in hematologic malignancies and may offer a novel therapeutic approach for ARL, particularly in PBL and BL [ 43 ]. In terms of clinical presentation, similar to previous studies, ARL were often diagnosed at advanced stages, with frequent extranodal involvement and systemic B symptoms [ 44 ].

In terms of treatment, for B-cell NHL, CHOP or EPOCH regimens are standard, often combined with rituximab. Previous studies have indicated EPOCH as a preferred first-line regimen for AR- DLBCL, HHV8-positive DLBCL, and primary effusion lymphoma (PEL), and the 2019 NCCN guidelines recommend it for AIDS-related BL [ 14 ]. These recommendations are supported by phase II trials and meta-analyses demonstrating that EPOCH is more effective than CHOP in ARL [ 45 ]. Our study found that EPOCH treatment was superior to CHOP, although this difference did not reach statistical significance. Rituximab, a CD20-targeted monoclonal antibody, is routinely recommended for B-cell NHL in PLWH, regardless of HIV status [ 46 ]. The introduction of rituximab-based regimens has significantly improved outcomes in developed countries [ 47 ]. However, in China, due to the lack of medical insurance coverage for rituximab, and the higher proportion of low- and middle-income patients in this study, many patients may be unable to afford the cost of the drug due to financial constraints, and some have poor compliance, failing to complete the treatment as recommended. Furthermore, the use of rituximab has been associated with an increased risk of infection-related mortality. Accordingly, careful monitoring for infectious complications is essential throughout the course of treatment, particularly in patients with CD4 + T cell counts below 50 cells/µl [ 48 ]. Current studies have shown that for patients with extranodal T/NK cell lymphoma, those treated with asparaginase (Asp)-containing chemotherapy regimens achieve significantly higher complete remission rates compared to those receiving non-Asp-based regimens [ 49 , 50 ]. However, in our cohort, most patients received anthracycline-based chemotherapy or surgery, potentially introducing treatment-related bias in mortality outcomes.

Large-scale database analyses continue to identify HIV infection as an independent risk factor for lymphoma-related mortality [ 5 ]. In Western countries, survival outcomes for PLWH with lymphoma now approximate those of HIV-negative individuals [ 51 ]. However, outcomes remain significantly poorer in developing regions, including China, particularly for BL patients [ 52 ]. Early retrospective studies indicated worse outcomes for BL compared with DLBCL, even in the ART era [ 53 ]. A later German study, however, reported comparable survival between these subtypes [ 54 ]. In our cohort, BL prognosis was significantly worse, likely due to a higher incidence of bone marrow involvement ( P = 0.007). Given its high proliferative index and aggressiveness, timely initiation of intensive chemotherapy is critical for BL. However, many BL cases in our study were diagnosed during the COVID-19 pandemic, resulting in treatment delays and missed therapeutic windows. Furthermore, despite the need for intensified chemotherapy in BL, limitations in economic and healthcare resources prevented access to these regimens, further compromising outcomes. Nonetheless, outcomes for HL in our cohort were comparable to those reported in HIV-negative populations [ 55 ].

The IPI is the most widely used risk stratification tool for lymphoma. However, its applicability to ARL remains contentious [ 56 ]. While some studies suggest that IPI or age-adjusted IPI (aaIPI) correlates with prognosis in AR-NHL [ 57 – 59 ], others, such as the study by Stefan et al., found no prognostic relevance for ARL [ 60 ]. Our findings support the prognostic utility of the IPI in AR-NHL. Furthermore, Barta et al. proposed the ARL-IPI, incorporating ECOG performance status, LDH levels, disease stage, extranodal site count, and HIV-specific factors such as CD4 + T cell count, HIV viral load, and prior AIDS history. Their analysis demonstrated superior prognostic performance of the ARL-IPI compared with the aaIPI [ 60 ]. In this study, multivariate Cox analysis revealed that CD4 + T cell count < 200 cells/µl (HR: 2.051, 95% CI: 1.078–3.901, P = 0.029) and elevated LDH levels (HR: 0.383, 95% CI: 0.194–0.754, P = 0.005) were independent adverse prognostic factors for OS in patients with AR-NHL.

This study has several limitations. First, its retrospective design introduces potential selection and information biases, limiting generalisability. Second, the small sample size, especially for rare lymphoma subtypes, reduces statistical power. Third, treatment heterogeneity introduces confounding variables; for instance, while the majority of T/NK cell lymphoma patients in our cohort were treated with anthracycline-based regimens or surgery, prevailing treatment practices increasingly favor asparaginase- or gemcitabine-based protocols. The relatively low proportion of BL patients receiving intensified chemotherapy may have further affected efficacy analyses. Additionally, financial barriers limited rituximab use, potentially compromising survival outcomes. Finally, the lack of molecular mechanisms and genomic data limits a comprehensive understanding of the complex relationship between HIV infection and lymphoma development. Future studies integrating molecular biology data will help clarify the underlying mechanisms and provide a basis for precision medicine.

Conclusion

This study provides a comprehensive analysis of the clinicopathological features, prognostic factors, and treatment outcomes of NHL and HL in PLWH. Our findings emphasize that low CD4 + T cell counts and elevated LDH levels are independent adverse prognostic factors for AR-NHL. Additionally, the IPI is effective for prognostic evaluation of AR-NHL. Notably, the EPOCH chemotherapy regimen demonstrated a trend toward improved outcomes compared to CHOP, although this difference did not reach statistical significance. Future research should focus on expanding sample sizes, integrating molecular data, optimizing prognostic scoring systems, and exploring more targeted therapeutic strategies to improve survival and quality of life for patients with ARL.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Acknowledgements

We would like to thank all the patients and their families. A special thanks to the staff of the Department of Infectious Diseases and Immunology, as well as the Pathology Department.

Author contributions

Y.L. and J.C. co-wrote the initial draft of the manuscript and prepared the accompanying figures and tables. Y.G., L.S., Z.Y., and L.M. contributed to the study’s concept and design. J.C. secured the funding. C.G. and Y.Z. provided critical intellectual contributions and supervised the overall process. All authors reviewed and approved the final manuscript.

Funding

This work is supported by the Beijing Research Ward Excellence Program, BRWEP (BRWEP2024W042180111).

Data availability

The data set used and/or analyzed during the current study is available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Beijing Youan Hospital and performed in accordance with the 1975 Declaration of Helsinki. Informed consent was obtained from all individual participants included in the study.

Competing interests

The authors declare no competing interests.

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