In a previous study, despite the effective use of cART, the standardized incidence ratio of NHL in PLWH compared to the general population was 11.5, making lymphoma one of the leading causes of death among PLWH [15]. The mechanisms underlying the high incidence of lymphomas in individuals with HIV infection include HIV-induced immune suppression, genetic abnormalities, cytokine dysregulation, chronic antigen stimulation, and concurrent infections with γ-herpesviruses (EBV and KSHV), alongside dysregulated immune responses controlling these viruses [16]. Particularly noteworthy is the observation that ARL exhibit a higher frequency of genetic mutations compared to non-HIV-infected individuals [17]. HGBL-11q is a recently described high-grade mature B-cell neoplasm characterized by gain in the 11q23.2-11q23.3 region and loss in the 11q24.1-qter region, but lack of MYC translocation and the presence of 11q aberration. Due to its rarity, reports on HGBL-11q in PLWH are limited. Literature reports indicated that 43% of post-transplant Burkitt lymphoma cases and 60% of post-transplant EBV-negative Burkitt lymphoma cases had 11q abnormalities, suggesting a possible association of such tumors with transplantation and immune deficiency [5]. Because lymphoma is one of the main risk factors for PLWH, we evaluated the incidence and clinicopathological characteristics of HGBL-11q in PLWH. In this study, we retrospectively analyzed the clinicopathological features of 10 AR-HGBL-11q cases at our institution and compared them with 7 previously reported cases to better understand this distinct lymphoma entity in PLWH. The incidence of AR-HGBL-11q in our AIDS-related aggressive B-cell lymphoma cohort was 10.4% (10/96), which was slightly higher than the prevalence of 7.96% (9/113) in the HIV-negative population [18]. Most of our patients had a long history of HIV infection, with a median duration of 38 months, which was consistent with previous reports [8,9,10,11,12,13,14]. AR-HGBL-11q primarily affects young to middle-aged men, with a median age of 35 years in our series, younger than the median age of 49.5 years reported for the general population [19]. All our patients were male, and a similar male predominance was observed in the literature [18].

AR-HGBL-11q tends to be present at an advanced stage with frequent extranodal involvement. In our cohort, 60% of patients were diagnosed with stage IV disease with extranodal involvement, most commonly affecting the gastrointestinal tract, followed by the liver and spleen. In contrast, the majority of HIV-negative HGBL-11q patients are in stage I/II [20]. B symptoms and bulky disease were observed in 40% and 50% of the patients. Elevated serum LDH levels were common (70%). However, none of our patients had central nervous system or bone marrow involvement at presentation. Morphologically, AR-HGBL-11q exhibits features reminiscent of BL, DLBCL, and HGBL, NOS. In our series, 60% of cases showed classical BL morphology, 20% resembled DLBCL, and 20% were classified as HGBL, NOS. Notably, all cases featured a peculiar pattern of prominent apoptotic bodies or coarse apoptotic debris, which is uncommon in other aggressive B-cell lymphomas, consistent with the characteristics of HIV-negative HGBL-11q [19]. Additionally, eosinophils can be present in B-cell lymphomas, and their quantity contributes to lymphoma classification [21]. However, analysis of eosinophil count in tissues from HGBL-11q cases has not been reported. In our observation of the histomorphology of AR-HGBL-11q, we found that 90% (9/10) of cases exhibited an increase in eosinophils in tumor background under the microscope. These distinct morphological features may provide clues to the diagnosis of HGBL-11q. In clinical practice, for the final diagnosis of the last AR-HGBL-11q case, we relied on the summarized histological features of the previous 9 cases-prominent apoptotic debris, along with eosinophils in tumor background, and thereby considered the case as AR-HGBL-11q. Subsequently, FISH testing was conducted to confirm the diagnosis, which validated the importance of the particular morphology in the diagnosis of this rare type of B-cell lymphoma.

The immunophenotype of AR-HGBL-11q was characterized by a high frequency of the GCB phenotype (90% in our cohort) according to the Hans algorithm, which is consistent with previous reports [12]. CD10 and BCL6 were expressed in 70% and 90% of cases, respectively. Interestingly, the expression of LMO2, a germinal center marker, was observed in 60% of our cases, higher than the reported rate of 38% in HIV-negative HGBL-11q [22]. Another interesting finding is the significant decrease in the expression of lymphocyte-enhancing factor-binding factor 1 (LEF1), as revealed by proteomic and transcriptomic of HGBL-11q [23]. Immunohistochemical detection of LEF1 has not previously been performed in HGBL-11q. To address this research gap, we conducted immunohistochemical analysis of LEF1 in AR-HGBL-11q screened cases. The results showed that LEF1 was weakly positive in only 20% of the cases. Furthermore, the expression of MUM1 has a negative impact on the prognosis of HIV-related BL [11]. Grzegorz et al.‘s study showed that MUM1 is generally negative in HGBL-11q of HIV-negative individuals [24]. However, in our cohort, 30% (3/10) of cases were positive for MUM1, which may support the view that AR-HGBL-11q has a worse prognosis than non-HIV-infected individuals. These findings suggest that AR-HGBL-11q may have a unique immunophenotypic profile compared with its HIV-negative counterpart.

EBV infection is rare in HGBL-11q, with no positive cases reported in the literature [25]. In our series, one case (10%) was EBER-positive and expressed EBNA2, indicating a EBV-latency infection type III, which suggested low immunity. The patient’s CD4 + T cell count was very low (only 4 cells/µL), the lowest of the 10 cases in our study, and his EBV serum was positive. This finding expands the spectrum of EBV-associated HGBL-11q and highlights the need for routine EBER testing for this type of lymphoma, especially in the HIV setting. FISH analysis confirmed the absence of MYC rearrangement and presence of 11q aberrations in all AR-HGBL-11q cases. The characteristic 11q aberration pattern, featuring proximal gains and telomeric losses, was observed in 60% and 100% of our cases, respectively. This complex aberration pattern is considered a defining feature of HGBL-11q and is crucial for its diagnosis [26].

To further characterize AR-HGBL-11q, we conducted a comparative analysis of 11 cases of ARL from our institution, which lacked both MYC rearrangement and 11q aberration and were referred to as MYC/11q-ARL. Our investigation revealed distinct clinicopathological features that distinguished AR-HGBL-11q from MYC/11q-ARL. Notably, AR-HGBL-11q exhibited a significantly higher frequency of coarse apoptotic debris (P < 0.001) and eosinophils (P = 0.002), higher expression of LMO2 (P = 0.080), and lower frequencies of LEF1 (P = 0.080), BCL2 (P = 0.007), MUM1 (P = 0.004), and EBER positivity (P = 0.027) compared to MYC/11q-ARL. These distinct features suggest that AR-HGBL-11q represents a unique subgroup of ARL with characteristic morphological, immunophenotypic, and molecular profiles.

Regarding treatment and prognosis, 80% of our patients received EPOCH as the first-line regimen, and all but 2 achieved complete remission. Anti-CD20 antibody therapy has been proven effective in treating ARL and is typically used in combination with chemotherapy to enhance treatment efficacy, which was also widely used among our patients [27]. However, other targeted inhibitors, such as BTK and PI3K inhibitors, have been less reported in the treatment of ARL and are still in the research phase. The use of immune checkpoint inhibitors such as PD-1 and PD-L1 inhibitors may increase the risk of immune-related adverse events, necessitating careful evaluation for their application in PLWH [28]. Currently, there are no reports on the use of targeted therapies and immune therapies, such as BTK inhibitors or PI3K inhibitors, specifically for AR-HGBL-11q patients. Future studies are expected to explore whether these treatment modalities can further improve patient survival and quality of life, particularly in patients who have become resistant to conventional treatments or have relapsed. Nevertheless, treatment decisions for ARL should comprehensively consider the immune status and the impact of ART to ensure treatment safety and efficacy. The estimated 2-year overall survival rate was 79%, less favorable compared to the over 90% survival rate reported for HIV-negative HGBL-11q [12, 29]. Compared with MYC/11q-ARL, AR-HGBL-11q showed a trend towards better survival, however, the difference was not statistically significant (P = 0.15), possibly due to the limited sample size.

Our study had several limitations. First, although our AR-HGBL-11q cohort study is relatively large compared to previous studies, the number of cases remains relatively small, limiting the statistical power and generalizability of our findings. Future studies will require a larger sample size to validate our results. Second, to summarize the clinical and pathological characteristics of this rare entity, we analyzed cases collected from different institutions’ literature and further compared global MYC/11q-ARL cases. Thus, there may be bias in this information. Third, due to the retrospective nature of case identification and the majority of samples from live tissue examinations, despite the fact that FISH analysis is a common molecular technique, next-generation sequencing can provide more comprehensive genetic features and insights into potential therapeutic targets, which is necessary for further research.