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DOI: 10.1055/a-2444-3438
Sinonasal Plasmablastic Lymphoma: A Systematic Review
Abstract
Objective Plasmablastic lymphoma (PBL) is a type of non-Hodgkin's B-cell lymphoma associated with human immunodeficiency virus and Epstein–Barr virus, commonly located in the oral cavity or gastrointestinal tract. Sinonasal involvement is rare, and there is no consensus on treatment.
Data Sources Peer-reviewed published articles served as data sources.
Review Methods A systematic review was conducted of the PubMed database for all cases of sinonasal PBL between 1978 and 2023 with the phrase “plasmablastic lymphoma.” Studies not written in English and that did not separate individual cases of sinonasal PBL from aggregated data were excluded. Age, sex, immune status, treatment, and outcomes were collected.
Conclusion PBL is a rare malignancy in the sinonasal region usually treated with chemotherapy. It most commonly occurs in immunocompromised adults but has also been diagnosed in immunocompromised children and in immunocompetent adults. It is aggressive and has a poor prognosis.
Implications for Practice PBL is a recently described entity with few cases of the sinonasal anatomic variant in the literature. Sinonasal PBL was most frequently treated with chemotherapy alone, closely followed by chemoradiation. The most common chemotherapy regimen utilized in the literature is cyclophosphamide, doxorubicin, oncovin/vincristine, and prednisone, which is also the most common chemotherapy regimen in nonsinonasal PBL. A second commonly used regimen is cyclophosphamide, vincristine/oncovin, doxorubicin/adriamycin, and dexamethasone. However, no treatment has emerged as superior to others with regard to survival. Further data are needed to better understand this rare disease.
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Keywords
plasmablastic lymphoma - sinonasal lymphoma - non-Hodgkin's lymphoma - diffuse large B-cell lymphoma - sinonasal neoplasmIntroduction
Plasmablastic lymphoma (PBL) is a rare and highly aggressive form of non-Hodgkin's B-cell lymphoma that was first described in 1997.[1] Typically, PBL is extranodal and is most commonly seen in the oropharyngeal area, followed by the gastrointestinal tract, lymph nodes, and skin.[1] [2] [3] PBL most commonly presents in males and can occur at any age, although it very rarely presents in children.[4] [5] [6] [7] [8] [9] Additionally, PBL is commonly associated with human immunodeficiency virus (HIV) and Epstein–Barr virus (EBV). It presents with an aggressive clinical course, frequent relapse, and poor prognosis.[1] PBL in HIV-positive patients often presents with more advanced disease than in immunocompetent patients.[5] [10] [11] Respective of immune status, median overall survival is generally less than 12 months.[4] [7]
PBL often presents as tumors in extranodal sites, notably in the oral cavity and/or gastrointestinal tract, with immunosuppressed posttransplant patients showing a higher incidence of nodal and skin involvement.[4] Upon PBL presentation, more than 65% of HIV-positive patients, 50% of posttransplant patients, and 25% of seemingly immunocompetent patients demonstrate Ann Arbor stages III and IV.[2] In HIV-positive patients, bone marrow involvement has been shown in up to 40% of patients.[4]
PBL is a rare disease with no widely accepted evidence-based therapies. The most commonly used PBL treatment regimen is a combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).[10] However, guidelines established by the National Comprehensive Cancer Network (NCCN) on AIDS-related B cell lymphomas recommend more aggressive therapy such as dose-adjusted etoposide, vincristine, and doxorubicin with cyclophosphamide and prednisone (DA-EPOCH).[4] [12] [13] Neither CHOP nor more intensive treatment regimens like DA-EPOCH have been demonstrated to be superior over the other when comparing overall survival.[14]
There exists a paucity of PBL cases that are reported in the sinonasal region, and there is no compilation in the literature of sinonasal PBL. Here we gather all reported cases of sinonasal PBL and analyze them as a cohort to present a comprehensive review of this rare disease.
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Methods
A systematic review of the literature was conducted by doing a comprehensive search of PubMed for all cases of sinonasal PBL. The search was performed with the query of “plasmablastic lymphoma,” which returned 928 articles. Exclusion criteria included articles not written in English. Of the 928 studies, 55 assessed PBL in the nasal cavity and/or nasal sinuses. Two studies were excluded for being inaccessible beyond their abstracts, and three studies with 29 cases were excluded as individual data could not be separated from aggregated data. Two studies were excluded because the full-length article was not available in English. After these studies were excluded, 48 studies presenting case reports or case series of sinonasal PBL between the years of 1978 and 2023 resulted in 73 individual cases. From these 48 articles, patient information including age, sex, immune status, treatment regimen, staging, and outcomes were collected. The article selection process is depicted in [Fig. 1].
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Results
Final analysis of the literature search included 73 individual cases of sinonasal PBL from 48 studies ([Table 1]).[3] [7] [8] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] Age ranged from 6 to 91 years. Five patients were missing sex information, six had no reported immune system status, 41 were without staging information, and nine without treatment status. Individual cases were mostly male 80.9% (55/68). The majority were immunocompetent (42/67, 62.7%). Twenty-six individuals were immunocompromised. In total, 35.8% (24/67) were HIV positive, one of the 67 (1.5%) had been on prolonged steroids for eosinophilic granulomatosis with polyangiitis and chronic rhinosinusitis with polyps, and one (1.5%) was an organ transplant recipient. Of those with staging, 43.8% (14/32) were diagnosed with advanced stage disease, including 40.6% (13/32) who presented with stage IV disease. Of those 13 patients with stage IV disease, two patients had distant metastasis, one to the liver and one to the central nervous system.
Abbreviations: BFM, Berlin–Frankfurt–Munster protocol; CDOP, cyclophosphamide, epirubicin, vindesine, prednisolone; CEOP, cyclophosphamide, etoposide, oncovin/vincristine, and prednisone; CHOP, cyclophosphamide, doxorubicin, oncovin/vincristine, and prednisone; CVAD, cyclophosphamide, vincristine/oncovin, doxorubicin/adriamycin, and dexamethasone; CVD, cyclophosphamide, bortezomib, dexamethasone; DA-EPOCH, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin; DeVIC, dexamethasone, etoposide, ifosfamide, carboplatin; EPOCH, etoposide, prednisone, oncovin/vincristine, cyclophosphamide, and doxorubicin; GEMOX, gemcitabine and oxaliplatin; IMRT, intensity-modulated radiation therapy; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone.
Note: “–" denotes no data reported.
[Table 2] shows the treatment regimens reported in the literature. A total of 84.4% (54/64) received chemotherapy, with 21 patients additionally receiving radiation. Ten (15.6%) underwent surgical resection. Of these 10 patients, two also received chemotherapy (3.1%), another two underwent radiation, and four (6.4%) underwent both chemotherapy and radiation. Five individuals (7.8%) received definitive radiation alone. The most common chemotherapy regimen ([Table 3]) was CHOP, which 37.7% of chemotherapy patients (20/53) received. The second most common chemotherapy regimen was cyclophosphamide, vincristine/oncovin, doxorubicin/adriamycin, and dexamethasone (CVAD), which was given to nine patients (17.0%). EPOCH was another common regimen, and 6 (11.3%) of patients received this. One patient spontaneously regressed without treatment and remained in remission 4 years later.
Abbreviations: BFM, Berlin–Frankfurt–Munster protocol; CDOP, cyclophosphamide, epirubicin, vindesine, prednisolone; CEOP, cyclophosphamide, etoposide, oncovin/vincristine, and prednisone; CHOP, cyclophosphamide, doxorubicin, oncovin/vincristine, and prednisone; CVAD, cyclophosphamide, vincristine/oncovin, doxorubicin/adriamycin, and dexamethasone; CVD, cyclophosphamide, bortezomib, dexamethasone; DA-EPOCH, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin; DeVIC, dexamethasone, etoposide, ifosfamide, carboplatin; EPOCH, etoposide, prednisone, oncovin/vincristine, cyclophosphamide, and doxorubicin; GEMOX, gemcitabine and oxaliplatin.
Of the 13 patients diagnosed with stage IV disease, only four were still alive at time of follow-up. Follow-up ranged from 12 days to 53 months. One patient spontaneously regressed without treatment. Overall, prognosis for all patients varied from death within 12 days (2 patients) to no evidence of disease at 15 years. Overall mortality rate by time of follow-up was 23.0% (14 of 61 patients with a reported follow-up status had expired at time of follow-up). Two of the 73 patients were lost to follow-up, and 10 other individual cases did not comment on follow-up status.
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Discussion
PBL is an aggressive and rare form of lymphoma that most frequently presents in the oropharynx of individuals with HIV and EBV and is characterized by frequent relapse and poor prognosis. PBL is rarely described in the sinonasal region, and the literature is lacking. To our knowledge, this is the largest analysis of the literature and includes 73 cases of sinonasal PBL with individualized data.
As PBL is a rare disease, and even rarer in the sinonasal region, there is no widely accepted evidence-based treatment of PBL. From this systematic review, the most common treatment used for sinonasal PBL was chemotherapy, with the most common regimen being CHOP. This regimen has been documented as the most widely used treatment regimen for PBL regardless of site of involvement.[2] Castillo et al found that in HIV-positive patients undergoing CHOP, overall response rate was 77%, but overall survival was still low at 14 months, with the high mortality of PBL attributed to a high relapse rate, chemotherapy-resistant disease, and concomitant infections.[60] The NCCN therefore recommends a more intensive treatment approach, specifically suggesting DA-EPOCH, for AIDS-related B cell lymphomas according to their guidelines.[2] [13] However, as shown in previous studies by Castillo et al,[10] [60] and Dodero et al,[61] neither CHOP nor more intensive treatment like DA-EPOCH have been shown to definitively increase overall survival when compared with the other. Various clinical trials are being conducted to assess for treatment efficacy of large B-cell lymphomas such as PBL. Clinical trial NCT05389423 is studying DA-EPOCH with pomalidomide with or without rituximab for HIV-associated lymphomas, including PBL. The use of DA-EPOCH in combination with daratumumab, a monoclonal antibody that targets CD38-expressing cells, which are present in high levels in PBL, is being studied through clinical trial NCT04139304. Other clinical trials include NCT04676360 testing belantamab mafodotin in relapsed or refractory PBL, and NCT04915248 on the use of a combination of daratumumab, dexamethasone, and bortezomib for relapsed or refractory PBL. Results for these clinical trials are pending.
Immunocompromised status, including that measured by HIV status, affects PBL prognosis. Counterintuitively, despite HIV being highly associated with the development of PBL, the possible reversibility of immune system compromise through antiretroviral therapy (ART) may allow HIV-positive patients to have more favorable outcomes. Chemotherapy has been found to generate a better response in HIV-positive patients compared with HIV-negative patients, possibly attributed to the effect of ART on strengthening the immune system.[11] Indeed, having a higher CD4 count is a favorable prognostic factor in PBL,[40] whereas immunosuppression is a negative prognostic factor in HIV-negative individuals.[50] Better survival in EBV-positive and HIV-positive patients has been noted compared with EBV-negative and HIV-negative patients, possibly attributed to a similar mechanism in which initiation of ART allows better virological control.[7] However, this is controversial as Florindez et al[62] concluded that HIV status had no effect on survival in PBL. Morscio et al[7] found no significant difference in the incidence of PBL before and after the initiation of ART, implying that HIV, as a cause of immunosuppression, is still implicated in the development of PBL.
Regardless of HIV status, prognosis of PBL remains poor with a median overall survival < 12 months, and those with HIV initially present with more advanced disease.[2] [4] In our study, almost half of sinonasal PBL patients presented with advanced stage disease, which is slightly lower than but still on par with that seen in the literature,[10] [11] [62] and remains consistent with aggressive disease. In patients with limited-stage (stage I or II) PBL in the head and neck region, the use of involved site radiotherapy may impart a survival benefit.[21] [41] However, despite the achievement of complete remission with PBL treatment, most patients experience relapse of disease with a median progression-free survival period of 6 months.[12]
A limitation of this study stems from its retrospective nature, the limited number of sinonasal region cases of PBL in the literature, and the variation in reporting of these individual cases. These factors collectively diminish the power of the study. Additionally, though 55 studies were identified that described sinonasal PBL, some abstracts could not be accessed and others did not differentiate individualized data from aggregate data, limiting the validity and generalizability of our findings. Furthermore, there are no published randomized controlled trials of treatment regimens for PBL, much less that specifically targeting the sinonasal region.
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Implications for Practice
PBL is a rare malignancy in the sinonasal region associated with immunosuppression, marked by diverse treatment approaches and high mortality. In fact, the most common stage at presentation was stage IV, demonstrating its aggressive course and late diagnosis. This review reveals the most common treatments used, but no regimen has been found to best treat sinonasal PBL. Most cases are treated with chemotherapy alone, followed by chemoradiation. The NCCN recommends DA-EPOCH for AIDS-related B cell lymphomas. However, the most common chemotherapy regimen utilized in the literature for sinonasal PBL is consistent with the most common chemotherapy used in PBL: CHOP. The second most commonly prescribed chemotherapy regimen is CVAD. Additional research is needed to determine optimal treatment for sinonasal PBL, but the rarity of this condition poses a challenging undertaking for treatment and control of disease.
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Conflict of Interest
None declared.
Authors' Contributions
S.C. contributed to study design, data acquisition and interpretation, and manuscript writing; H.C. was involved in data acquisition and interpretation as well as manuscript writing; S.S. participated in data acquisition and interpretation along with manuscript writing; and M.W. contributed to study design, data acquisition and interpretation, and manuscript writing.
Previous Presentation
This article was presented at the AAO-HNSF 2023 Annual Meeting & OTO Experience, Nashville, Tennessee, September 30–October 4, 2023.
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Publikationsverlauf
Eingereicht: 01. September 2024
Angenommen: 08. Oktober 2024
Artikel online veröffentlicht:
13. November 2024
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References
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