Human immunodeficiency virus-negative plasmablastic lymphoma: A comprehensive analysis of 114 cases
- Authors:
- Published online on: February 17, 2015 https://doi.org/10.3892/or.2015.3808
- Pages: 1615-1620
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Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].
Abstract
Introduction
Plasmablastic lymphoma (PBL) was firstly identified as a unique clinicopathological entity by Delecluse et al (1). For a long time, PBL was viewed as a disease exclusively involving the oral sites of human immunodeficiency virus-positive individuals. Recently, more and more cases of PBL in immunocompetent patients have been reported. However, there is little consensus concerning many aspects such as etiology, clinical findings, optimal treatment strategy and prognostic factors of HIV-negative PBL. Furthermore, Castillo et al demonstrated that HIV-negative PBL cases are rather different compared with their counterparts (2). Through an extensive literature search, 114 cases of HIV-negative PBL were described. To our knowledge, this is the most comprehensive analysis concerning PBL in HIV-negative patients. Our study provides a full-scale view and helps to expand our understanding of this unique lymphoma.
Patients and methods
Literature review
An extensive search was carried out in Pubmed using the key words: ‘plasmablastic lymphoma and human immunodeficiency virus-negative or immunocompetent’ in the English language literature. Only cases with definite pathologic diagnosis of PBL and description of no HIV infection were enrolled. A total of 114 cases of HIV-negative PBL were described in case reports or in small sample size case analyses between February 1997 and 2014 (1,3–53).
Data retrieval
Data were retrieved according to characteristics such as age, gender, stage, site, bone marrow involvement, Ki-67 expression, pathological findings, Epstein-Barr virus (EBV) infection, herpesvirus-8 (HHV-8) infection, immunosuppression, treatment strategy (chemotherapy, radiotherapy and surgery), treatment response, survival and prognosis. Chemotherapy included treatment with bortezomib, but excluded treatment merely with steroids. Surgery excluded incisional biopsy. Ki-67 expression with exact values was recruited, and data showing values of 1+, 2+, 3+ and 4+ were excluded. Immunohistochemistry (IHC) with ± was viewed as positive expression. Complete remission (CR) included near CR. The period from diagnosis to death or latest follow-up was considered as overall survival (OS).
Statistical analysis
Cumulative survival was expressed by Kaplan-Meier estimates and compared with the log-rank (Mantel-Cox) test. SPSS 15.0 statistical software was used for data analysis. P-value <0.05 was indicative of a statistically significant result.
Results
Clinical features
HIV-negative PBL occurred in a wide spectrum of patients, aged from 2 to 86 years, with a mean age at diagnosis of 58.90 years. Notably, HIV-negative PBL mostly occurred in the elderly population. As Table I shows, patients older than 60 years accounted for 56.14% of all the cases. PBL was rarely present in young immunocompetent individuals especially children and teenagers (only 3 patients). HIV-negative PBL was more common in males with a male-to-female ratio of 2.29. With respect to clinical stage, stage IV was most common and I was secondary. Although stage IV was noted in 39.22% of the patients, bone marrow involvement was present in only 12.79% patients. As far as the primary site was concerned, the majority was extranodal. The oral cavity, nasal cavity and sinus were 2 most common sites of involvement. A total of 15.79% of the cases involved the gastrointestinal tract.
Etiological analysis
As shown in Table II, EBV infection was common in HIV-negative PBL, involving 58.70% of the patients, while HHV-8 infection was rather rare, being positive in only 4 cases. Immunosuppression status including post-transplantation, immune-related disease and current or previous malignancy was noted in quite a number of patients (28.16%).
Pathological findings
As shown in Table III, plasma cell markers CD38, VS38c, CD138 and MUM1 were expressed universally in PBL without HIV infection. EMA and CD45 were variably expressed, being positive in 59.26 and 40% of the cases, respectively. B-cell marker CD20 was rarely noted (only 1 case +, 4 cases ±). A total of 37.93% of the cases had CD79a expression. Notably, a small number of cases expressed T-cell markers CD3 and CD5; 14.89 and 13.04%, respectively. Furthermore, a high number of patients (21.43%) expressed NK-cell marker CD56. Ki-67 expression was universally high with a mean value of 83%, indicating an aggressive behavior.
Treatment and prognosis
As Table IV demonstrates, 18.52% of the patients underwent surgery. A total of 34.44% of the patients received radiotherapy. A majority of the patients (84.27%) received chemotherapy. The CR, partial remission (PR) and refractory rates were 54.93, 16.90 and 25.35%, respectively.
Prognostic factors of OS
As shown in Fig. 1, the median OS was 19 months. The 1- and 2-year survival rates were 52.3 and 45.3%, respectively.
Immunosuppression was a poor prognostic factor of OS. As Fig. 2A demonstrates, patients without immunosuppression had an apparently better OS than their immunosuppression counterpart with a median survival of 36.5 vs. 6.5 months. As far as Ann Arbor stage was concerned, stage I showed an OS advantage over stage IV (P=0.0079, Fig. 2B). EBV negativity was another poor prognostic factor of OS. As Fig. 2C shows, HIV negative PBL patients without EBV infection had a much poorer OS than EBV positive patients (P=0.0046).
Treatment response had a strong association with OS. As shown in Fig. 3, either CR or PR was superior to the refractory group in OS (P<0.0001 and P=0.0066, respectively). Furthermore, the CR group showed an OS benefit when compared with PR (P=0.001).
Univariate analysis (Table V) revealed that age, gender and primary site had no strong relationship with OS. Ann Arbor stage IV, immunosuppression, EBV negativity and refractory to treatment were poor prognostic factors of OS. For stage I patients, the application of radiotherapy did not improve the OS.
Discussion
In 1997, Delecluse et al first described 16 PBL cases (15 HIV-positive and 1 HIV-negative) (1). PBL was once considered as a malignancy that predominantly occurred in HIV-infected individuals. In 2010, Castillo et al analyzed 71 cases of HIV-negative PBL published before August 2009 and first revealed that HIV-negative PBL had distinct clinicopathological features (2). Soon after, Castillo et al (54) and Liu et al (26) reviewed 76 and 79 cases of HIV-negative PBL published before June 2010. In recent years, with increasing awareness of this unique entity, more cases have been reported in diverse sites in patients without HIV infection. Thus, it is necessary for us to retrieve all the cases published to date to get a full-scale understanding of this unique lymphoma.
With respect to clinicopathological features of HIV-negative PBL, Ann Arbor stage I was rather predominant, accounting for 31.37% of the entire enrollment, higher than a previous study by Castillo et al (2) (23%), and similar to a study by Liu et al (26) (32.9%). Furthermore, stage I showed a OS superiority than stage IV (P=0.0079). Primary skin HIV-negative PBL accounted for a smaller proportion, only 6.14%, when compared with a previous study of 12% (54). More patients (18.52%) received surgery. Castillo et al reported that only 4% of the patients underwent surgery (54). CD56 expression in our research was 21.43%, much higher than Castillo et al findings (6%) (2). Furthermore, a portion of HIV-negative PBL expressed T-cell markers such as CD3 (14.89%) and CD5 (13.04%).
Regarding the aspect of etiology, some studies have indicated that PBL is closely related with EBV infection (55). Our study also confirmed that 58.70% cases of HIV-negative PBL exhibited EBV infection. Furthermore, univariate analysis showed that EBV infection was a good prognostic factor of OS (P=0.0046). The concrete mechanism need to be clarified in the future. Furthermore, only 7.55% of patients were HHV-8-positive, indicating that HHV-8 infection has a negligible role in HIV-negative PBL. On the contrary, we found that immunosuppression contributed to 28.16% of the cases including post-transplantation, immune-related disease and current or previous malignancy. Additionally, immunosuppression was a poor prognostic factor for OS. Patients with immunosuppression had a poorer OS with a median survival of 6.5 months while patients without immunosuppression achieved a median survival of 36.5 months. Our data also showed that HIV-negative PBL had a predilection for elderly individuals (patients older than 60 years, 56.14%). This proportion in our research was higher than that noted in the studies of Liu et al (43%) (26) and Castillo et al (49%) (54). Elderly individuals often have immune senescence. Decline in immune function may be critical in the disease evolution of HIV-negative PBL.
Since PBL without HIV infection usually has a poorer response to chemotherapy compared with HIV-positive counterparts (2), there is urgent need to develop novel therapies to improve treatment efficacy. Immunotherapy may be promising.
For stage I patients, we first explored the role of radiotherapy. However, the application of radiotherapy did not improve the OS.
In our research, statistical analysis revealed that treatment response had a defined correlation with OS. Either CR or PR was superior to the refractory group in OS (P<0.0001 and P=0.0066, respectively). Furthermore, the CR group showed an OS benefit when compared to PR (P=0.001). Castillo et al (54) demonstrated that CR to chemotherapy had increased OS when compared with patients without CR. Differently, our data elucidated that not only CR, but PR also could bring an OS benefit. The different treatment response was derived from tumor heterogeneity. Extensive research on the heterogeneity of HIV-negative PBL may find the causes of treatment resistance and contribute to the improvement of OS.
Abbreviations:
|
CR |
complete remission |
|
EBV |
Epstein-Barr virus |
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HHV-8 |
herpesvirus-8 |
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HIV |
human immunodeficiency virus |
|
OS |
overall survival |
|
PBL |
plasmablastic lymphoma |
|
PR |
partial remission |
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