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Plasmablastic lymphoma
Med Clin (Barc). 2016;147(9):399–404
www.elsevier.es/medicinaclinica
Review
Plasmablastic lymphoma夽 Rubén Fernández-Álvarez a,∗ , Juan-Manuel Sancho b , Josep-María Ribera b a
Servicio de Hematología, Hospital Universitario de Cabue˜ nes, Gijón, Asturias, Spain Servicio de Hematología Clínica, Institut Català d’Oncologia, Hospital Germans Trias i Pujol, Institut de Recerca contra la Leucèmia Josep Carreras, Universitat Autònoma de Barcelona, Badalona, Barcelona, Spain b
a r t i c l e
i n f o
Article history: Received 1 June 2016 Accepted 13 June 2016 Available online 10 December 2016 Keywords: Plasmablastic lymphoma Human immunodeficiency virus infection MYC Chemotherapy Bortezomib
a b s t r a c t Plasmablastic lymphoma (PBL) is a rare and aggressive subtype of non-Hodgkin lymphoma that commonly occurs in human immunodeficiency virus (HIV)-positive individuals, and affects oral sites. Occasionally, it has been described in HIV-negative patients and involving non-oral sites. Pathologically, PBL is a high-grade B-cell lymphoma that displays the immunophenotype of a terminally differentiated B-lymphocyte with loss of B-cell markers (CD20) and expression of plasma-cell antigens. Epstein–Barr virus infection and MYC rearrangements are frequently observed. Treatment of PBL is challenging because of the lack of established treatment and poor outcomes, with median survival times shorter than one year. In this review, we discuss the clinical and epidemiologic spectrum of PBL as well as its distinct pathological features. Finally, we summarize the currently available approaches for the treatment of patients with PBL. ˜ S.L.U. All rights reserved. © 2016 Elsevier Espana,
Linfoma plasmablástico r e s u m e n Palabras clave: Linfoma plasmablástico Infección por el virus de la inmunodeficiencia humana Oncogén MYC Quimioterapia Bortezomib
El linfoma plasmablástico (LPB) es un subtipo de linfoma no hodgkiniano agresivo y poco frecuente que afecta principalmente a pacientes infectados por el virus de la inmunodeficiencia humana (VIH), en los que tiende a presentarse en la cavidad oral. Ocasionalmente también se describe en pacientes no infectados por el VIH y en localizaciones distintas a la cavidad oral. Desde el punto de vista diagnóstico se caracteriza por expresar un inmunofenotipo de célula B activada que pierde los marcadores típicos de célula B madura (es negativo para CD20) y adquiere los asociados a célula plasmática. Además, es frecuente la presencia de infección por el virus de Epstein-Barr y de reordenamientos del gen MYC, lo que contribuye a su identificación. El abordaje terapéutico de estos pacientes es difícil debido a la poca evidencia disponible y al mal pronóstico observado en todas las series (incluidas las más recientes), ˜ En esta revisión se describe el espectro clínico y con medianas de supervivencia inferiores a un ano. epidemiológico del LPB, así como los aspectos fundamentales para su diagnóstico. Por último, se revisan las diferentes opciones terapéuticas utilizadas y la respuesta a las mismas. ˜ S.L.U. Todos los derechos reservados. © 2016 Elsevier Espana,
Introduction Plasmablastic lymphoma (PBL) was first described in 1997 by Delecluse et al. as an aggressive clinical course lymphoma that occurred in the oral cavity of patients infected with the human
夽 Please cite this article as: Fernández-Álvarez R, Sancho J-M, Ribera J-M. Linfoma plasmablástico. Med Clin (Barc). 2016;147:399–404. ∗ Corresponding author. E-mail address: [email protected] (R. Fernández-Álvarez). ˜ S.L.U. All rights reserved. 2387-0206/© 2016 Elsevier Espana,
immunodeficiency virus (HIV).1 Since its initial description, almost 20 years ago, numerous articles (over 600 entries in PubMed) have expanded its clinical and epidemiological spectrum.2 Today we know that this lymphoma can occur outside the oral cavity, usually in other extranodal sites. Also, although it is mainly associated with HIV infection, it has been described in other immunocompromised conditions (such as transplant recipients) and even in immunocompetent patients.3,4 Epstein–Barr virus (EBV) infection and abnormalities in the MYC gene, have been involved in its pathogenesis, observed in about half of cases. In the current classification of the World Health Organization, PBL is defined as a high
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histological grade Non-Hodgkin lymphoma (NHL), whose neoplastic cells stop expressing markers of lymphocyte B (such as CD20 and CD45) and acquire those associated with plasma cell (such as CD138).5 Diagnosis can be complex because of its overlap with other NHL subtypes and some forms of multiple myeloma.6 Despite advances in the diagnosis of this disease, its prognosis remains poor, with median survival of less than one year.7 There is no standard treatment for these patients and the results with conventional chemotherapy are not satisfactory. Intensive regimens have not demonstrated a survival benefit. A better understanding of the biological characteristics of this lymphoma provides an opportunity to explore the utility of more targeted drugs and improve the prognosis of these patients. The objective of this review is to update clinical, diagnostic and therapeutic aspects of PBL. Epidemiology It is difficult to know the incidence of PBL due to its rarity and the lack of epidemiological studies. Most cases are diagnosed in HIV-infected patients,1 in whom it becomes a defining feature of AIDS. It is estimated that it represents 2–12% of all HIVassociated lymphomas.8,9 Thanks to the implementation of potent antiretroviral therapy (ART), the risk of lymphoma in patients with HIV infection has declined significantly: more than 100 times in the mid-1990s, about 25 times in the late 2000s.10 This trend is observed in all NHL subtypes, except Burkitt’s lymphoma, where it remains stable.11,12 In the German cohort of 291 HIV-associated lymphomas diagnosed between 2005 and 2012, 12% were PBL, while the most frequent subtypes were still lymphoma diffuse large B-cell and Burkitt lymphoma (53 and 35%, respectively).9 In the context of HIV infection, PBL occurs predominantly in young males (median age between 39 and 44 years). At the time of diagnosis, the CD4+ lymphocytes count was between 85 and 206 cells/mm3 , depending on the time period studied (prior to the availability of ART or current), and only a minority of patients show virologic suppression of HIV.13 It is the first manifestation of HIV infection in 5% of cases.14 In recent years, there have been reports of PBL in non-HIVinfected individuals; in the literature, they represent approximately one third of all published on this lymphoma.2 They can occur in patients with other states of immunosuppression, such as transplant recipients. However, in most cases, only old age is identified as immunological deterioration factor.3,4 From the epidemiological point of view, patients with PBL can be divided into three categories according to their immune status: HIV infection, post-transplant and HIV-uninfected.2 These subgroups could be different clinical and biological entities, and some of their characteristics have been compared, such as age at diagnosis, primary site of the lymphoma, EBV positivity and the presence of gene abnormalities MYC (Table 1). Characteristically, PBL in patients without HIV infection occur at older ages (median age 58 years) and tend to be more heterogeneous in their primary site. In addition, there have been reports of PBL that occur as a transformation of indolent lymphoma15 or plasmacytomas.16,17 Pathogeny From an ontogenetic point of view, this tumour derives from a population of activated B cells that are in the process of becoming plasma cells (plasmablasts).18 The pathogenesis of PBL is only partially understood, but includes EBV infection and MYC gene deregulation as important mechanisms.2 Therefore, it shares a lymphomagenesis model which is similar to other HIV-associated lymphomas.19 According to this model, HIV indirectly facilitates
Table 1 Plasmablastic lymphoma characteristics according to HIV infection status.
Frequently in the literature, % Risk factors
Average age, years Over 60, % Sex male:female Positive EBV, % MYC gene abnormalities, % Extranodal presentation, % Primary site, %
Nodal presentation, % Advanced stage, %
HIV positive
HIV negative
70 Low CD4+ lymphocyte counts Absence of prior ART 39 1 4:1 75–80 50–80 95 Oral cavity (48–58) Extraoral (42–48) 5 50–65
30 Advanced age Posttransplant Prior lymphoma transformation 58 56 2–3:1 50–67 40–44 70–90 Oral cavity (16–40) Extraoral (56–84) 10–30 40–60
ART, antiretroviral therapy; EBV, Epstein–Barr virus; HIV, human immunodeficiency virus.
the development of lymphomas, through the participation of several elements: the transforming action of oncogenic viruses (such as EBV and human herpes virus type 8 [HHV-8]), chronic activation of B cells and the acquisition of critical genetic abnormalities (such as MYC gene). Moreover, recent data show that HIV itself could directly contribute to the development of lymphomas.20 By releasing certain proteins (p17 variants), it could support the clonal growth and development of B cells in germinal centres, increasing the risk of acquisition of genetic abnormalities and the onset of lymphomas. The presence of EBV in PBL was demonstrated in 80% of cases, and the proportion is higher in HIV positive cases.3 Various pathogenic mechanisms by which EBV can exert its transforming and oncogenic action have been described. By multiple gene expression is able to prevent apoptosis of B cells, alter the cell cycle regulation and inhibit tumour suppressor genes.21 Like other oncogenic viruses, EBV produces micro-RNA (miRNA), that destroy RNA and interfere with specific protein expression. For example, EBVassociated mi-RNA BHRF-1 inhibits the tumour suppressor gene P53 and miR-BART1 activates BCL2, an anti-apoptotic protein.22 On the other hand, the MYC gene deregulation could allow B cells to escape the plasma cell differentiation program and become plasmablasts. Interestingly, in most PBL cases, Blimp1 protein overexpression is detected, a transcription factor that governs plasma-cell differentiation and in non-neoplastic plasma cells represses MYC2,23 expression. It has been postulated that MYC overexpression, which is constant in PBL, could void the inhibitory effect of Blimp124 and thus promote the transformation of mature B cells in plasmablasts, blocking a greater plasmacytic differentiation. Additionally, MYC gene deregulation allows B cells to avoid physiological apoptosis favoured by Blimp1. Clinical presentation Most patients present with rapidly growing masses, sometimes destructive, affecting extranodal structures, particularly mucous. The most common site is the oral cavity, where masses can be observed in the gums, palate or alveolar mucosa, and sometimes infiltrate the surrounding bone structures (maxillary and mandibular). The preference for the oral cavity is typical of HIV-infected patients, while in uninfected patients the site is more heterogeneous. Approximately half of the cases occur outside the oral cavity, and can affect the gastrointestinal tract (12%), skin and soft tissue (6%), lymph nodes, nasal cavity and sinuses, genitals, central nervous system (CNS) and bone. Bone marrow infiltration is detected in up to 30% of cases, and in these cases the differential diagnosis
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with multiple myeloma is important. Primary nodal presentation is rare, except in transplant patients, in whom a skin involvement has also been observed.3 Approximately two thirds of patients are diagnosed in advanced clinical stages (i.e., stages iii or iv) and almost half have B symptoms. There are hardly any available data on laboratory abnormalities at the time of diagnosis; however, high lactate dehydrogenase (LDH) values have been described in most patients.7
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At genetic level, MYC gene translocations are the most common genetic alteration in PBL. Thanks to fluorescence in situ hybridization (FISH) studies, they are detected in half of the cases, with the immunoglobulin heavy chain IGH29,30 gene being the most frequently translocated. A smaller proportion of cases have MYC gene amplifications. By contrast, BCL2 and BCL629 gene rearrangements have not been detected. It is important to stress that most cases show overexpression of MYC protein, regardless of whether the gene status has been rearranged or not by FISH.30
Diagnosis and evaluation From a clinical standpoint, PBL lesions in the oral cavity may be indistinguishable from other neoplastic lesions, such as carcinoma, melanoma, or other types of lymphoma. Furthermore, PBL can occur in many different sites, outside the oral cavity, therefore, its differential diagnosis ranges from carcinomas to other types of lymphoma or opportunistic infections. As in all lymphomas, its diagnosis should be histological and requires tissue biopsy. Whenever possible, an excisional biopsy of the suspicious lesion will be performed, which will further define its morphology and immunophenotype. At the time of diagnosis, an extension study should be conducted, which is identical to that performed in other NHLs. A TC scan should be available in the initial evaluation. The role of positron emission tomography (PET) is not established in the staging of PBL, although there are cases in the literature confirming its significant fluorodeoxyglucose uptake and potential usefulness.25–27 It should be noted that the lymph nodes that occur in HIV infection may show uptake on PET, so false positives may occur.27 As in other aggressive lymphomas, it is recommended to perform a bone marrow biopsy in the initial evaluation. Given its aggressive nature and the reported cases of CNS infiltration, it is appropriate to perform a lumbar puncture to rule out meningeal infiltration by lymphoma. The PBL is defined as a high histologic grade lymphoma whose neoplastic cells express immunophenotyping of plasma cells in the absence of typical mature B cell markers.5 Its morphology shows diffuse proliferation of cells that resemble immunoblasts, with abundant cytoplasm and central nucleus with prominent nucleoli. Sometimes they acquire greater plasma cell differentiation, with basophilic cytoplasm, perinuclear halo and eccentric nucleus. Characteristically, this tumour has a high proliferative index, as indicated by the high expression of Ki67 (60–90%). Necrosis and cellular debris within the macrophages is frequently observed, which can lead to a “starry sky” pattern. Immunohistochemistry is essential for the diagnosis of PBL. Although, from an ontogenetic point of view, it is a B-cell lymphoma, it does not express typical mature B cell markers (such as CD19, CD20 and PAX5), and only a few cases are positive for CD45 and CD79a. However, it expresses plasmacytic differentiation markers, such as MUM1, CD38 and CD138. In some cases, aberrant CD10 and CD56 expression (absent in normal plasma cells) is detected. There are additional markers (PRDM1/Blimp1 and XBP1s) that are overexpressed in the final B differentiation stages and have proven useful in identifying a plasmablastic immunophenotype.23 However, this finding is only investigational. In most cases, the tumour cells are positive for EBV. Their presence is detected by RNA hybridization techniques (EBER), while immunohistochemical staining for LMP1 (latent membrane protein) is usually negative. In a recent study, positivity for EBV based on EBER expression was more frequent in HIV-infected (75%) and in transplant patients (67%) than in immunocompetent (50%).3 HHV8 is typically absent in this lymphoma. In order to improve the diagnostic ability of PBL in environments with few resources, some minimum immunohistochemical criteria have been proposed, including staining for CD20, CD38 and CD138, as well as Ki67 higher than 60% and EBV expression.28
Differential diagnosis PBL shares immunophenotypic and morphologic features with other plasmablastic differentiation lymphomas and plasma cell neoplasms.6 The similarities with this heterogeneous group of neoplasms can make diagnosis difficult and adversely affect patient treatment. For its distinction, the clinical context, the presence of immunodeficiency and EBV positivity by EBER need to be considered. Table 2 summarizes the data that help distinguish these entities. The most important differential diagnosis must be made with some aggressive and poorly differentiated forms of myeloma (or plasmacytoma), since treatment and prognosis of this entity are very different. The presence of paraprotein, bone disease, hypercalcemia or renal failure favours myeloma diagnosis. By contrast, HIV-infection and EBER positivity favour PBL diagnosis. There is also a heterogeneous group of lymphomas with plasmablastic differentiation that should be included in the differential diagnosis. The ALK+ large B-cell lymphoma can resemble PBL morphologically, as it does not express CD20 either. However, it is not associated with immunodeficiency and EBV is negative. Immunohistochemical staining for ALK is essential to recognize this neoplasm, showing granular expression in the cytoplasm.31 On the other hand, the characteristic absence of HHV8 in PBL allows its differentiation from lymphomas associated to this virus (large B-cell lymphoma associated with multicentric Castleman’s disease and primary effusion lymphoma). Prognosis Characteristically, PBL has an aggressive clinical course and poor prognosis. In the series including more cases, the median survival ranges between 5 and 15 months (Table 3), and it is estimated that only a quarter of patients are cured (overall survival at 5 years lower than 30%).7 These low survival rates contrast with the improvement in the prognosis of HIV-associated lymphomas. Some of the biological characteristics of PBL, as the absence of CD20 expression or the presence of MYC gene rearrangements, could explain this adverse prognosis. HIV infection does not worsen the prognosis of patients, possibly due to the immune reconstitution obtained with ART. In a comparative analysis, the median survival in HIV-infected patients was 10 months, while in non-infected was 11 months.3 However, patients with other immunocompromised states or transplanted are the ones with shorter survival rates (median of 7 months in the same analysis). Another series of 114 cases of PBL in patients without HIV infection demonstrated again the worst prognosis of the transplant subgroup compared to immunocompetent patients (median survival 6.5 vs 36 months, respectively).4 Apparently, there is great survival variability in the series published. For example, in the German cohort of HIV-associated lymphomas, the median survival was only 5 months with an interval ranging from 0 to 76 months.13 Several studies have demonstrated the prognostic role of conventional clinical factors such as stage of disease and general condition.7 However, there
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Table 2 Differential diagnosis of plasmablastic lymphoma. Location
Clinical context
Plasmablastic lymphoma
Extranodal (oral cavity, mucosa)
Multiple myeloma
Bone marrow and extranodal
DLBCL ALK+
Lymph nodes
HHV8-positive large B cell lymphoma
Lymph nodes and spleen
Primary effusion lymphoma
Serous (pleura, pericardium, peritoneum)
Immunophenotypic markers
HIV infection Posttransplant Advanced age Paraprotein Renal disease Bone disease Youth Advanced stages B symptoms Multicentric Castleman disease HIV infection HIV infection Kaposi’s sarcoma Absence of tumour masses
Infection
Positive
Negative
HIV
EBV
HHV8
CD138 MUM1/IRF4 MYC CD138 cIg
CD45 CD20 PAX5 CD20 PAX5
70%
Yes
No
No
No
No
ALK CD4 CD45 CD20+ or − MUM1/IRF4 cIgM CD45 CD330 MUM1/IRF4
CD20 CD30 MYC CD79a CD138
No
No
No
Yes
No
Yes
Yes
Yes
Yes
PAX5 CD20 CD138 Ig
ALK, anaplastic lymphoma kinase; DLBCL, diffuse large B cell lymphoma; EBV, Epstein–Barr virus; HHV8, human herpesvirus type 8; HIV, human immunodeficiency virus.
are conflicting data on the prognostic significance of age or LDH values. It has been suggested that the international prognostic index adjusted for age could be a useful prognostic tool in these patients.13 There are limited data on the prognostic impact of biological data. The presence of MYC3.7 gene rearrangements and negativity for EBV4,30,32 have correlated with worse outcomes. Treatment There is no consensus on what should be the standard treatment for patients with PBL. Due to the low frequency of lymphoma, the only studies that have examined the efficacy of the
treatments are retrospective in nature. Without treatment, the median survival is only 3–4 months.33 Given the aggressive nature of this lymphoma, the usual practice involves the administration of combination chemotherapy, with a relatively high response rate (up to 77% in a series). However, responses are often transient and patient survival remains short (14 months in the same series), most dying from disease progression.34 A common observation from 2 retrospective studies is that patients who achieve a complete response after chemotherapy show significantly prolonged survival rates.7,34 Historically, the most commonly used chemotherapy regimen in this lymphoma has been cyclophosphamide, adriamycin, vincristine and prednisone (CHOP), with
Table 3 Major studies on plasmablastic lymphoma treatment1. Study (reference)
Period
No.
HIV infection (%)
Age (years)
CD4+ lymphocyte (/mm3 )
Castillo et al.14
1997–2007
53
100
38
178
–
Castillo et al.34
1997–2009
70
100
39
165
–
Castillo et al.7
2000–2010
50
100%
43
206
Ibrahim et al.37
2000–2012
25
100
44
Schommers et al.13
2005–2012
18
100
1994–2013
61
30
30
Loghavi et al.
MYC gene translocation (%)
Treatment
OS (months)
Influence OS
CHOP (51%) EPOCH, CODOX-M/IVAC (25%) CHOP (50%) EPOCH, Hyper-CVAD/MA, CODOX-M/IVAC (23%)
15
–
14
41
CHOP (63%) EPOCH, Hyper-CVAD/MA (37%)
11
87
32
EPOCH (56%) CHOP (20%)
11.6 (2–63)
44
85
–
49
–
67
Response to treatment and staging Intensive regimens with no benefit Response to treatment, stage, ECOG and MYC rearranged Intensive regimens with no benefit Better survival with EPOCH versus CHOP (17 versus 7 months) ECOG, age, LDH, IPI Age, stage and EBV Intensive regimens with no benefit
CHOP (61%) Others (39%) Hyper-CVAD/MA (45%) CHOP (21%), EPOCH (21%)
5 (0–76) 7 (0.3–156)
CHOP, cyclophosphamide, doxorubicin, vincristine and prednisone; CODOX-M/IVAC, cyclophosphamide, doxorubicin, methotrexate, ifosfamide, etoposide, and cytarabine; ECOG, Eastern Cooperative Oncology Group; EPOCH, etoposide, prednisone, vincristine, doxorubicin and cyclophosphamide; Hyper-CVAD/MA, hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate and cytarabine; IPI, International Prognostic Index; LDH, lactate dehydrogenase; PBL, plasmablastic lymphoma; OS, overall survival; EBV: Epstein–Barr virus; HIV, human immunodeficiency virus.
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the previously commented poor results (Table 3). For this reason, the recommendations of scientific groups35 and some reviews2 favour the use of regimens that are more intensive than CHOP, such as etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (EPOCH), cyclophosphamide, doxorubicin, methotrexate, ifosfamide, etoposide, and cytarabine (CODOX-M/IVAC) or hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate and cytarabine (hyper-CVAD/MA). However, it is unclear that more intensive regimens can improve results. In this regard, 2 retrospective studies found no survival benefit with more intensive regimens when compared with CHOP.7,34 In both studies, patients had a short median survival (11 and 14 months respectively), with no difference between the strategy of intensive chemotherapy and CHOP-based chemotherapy. More recently, the infusion regimen DA-EPOCH (dose-adjusted EPOCH) has been proposed as potentially more effective than CHOP in the treatment of HIV-associated lymphomashas.36 In the case of PBL, a retrospective study showed longer survival in patients treated with EPOCH compared with those who received CHOP (17 versus 7 months, p < 0.04).37 In patients infected with HIV, ART is an essential part of PBL treatment. ART addition to chemotherapy improves the prognosis of these patients.38,39 Additionally, favourable responses have been described in cases where the only treatment was ART, though usually not durable.40 Conversely, there are relapses after interruption of ART,41 underscoring its importance in the treatment of these patients. Local or locoregional radiotherapy has been used, without being able to establish its role in the treatment of these patients.2 In fact, in a study of 114 patients, the addition of radiotherapy in localized stages demonstrated no benefit in overall survival.4 Regarding the use of autologous stem cell transplantation (ASCT), isolated cases have been reported with prolonged survival when used in first remission after chemotherapy.42 This procedure could benefit patients with good clinical conditions, especially if the disease is chemosensitive, although there is insufficient data for widespread recommendation. A recent review43 recommended to consider ASCT as first line in the presence of risk factors such as a high international prognostic index or absence of complete response after chemotherapy. The use of prophylaxis against CNS relapse has not been systematically evaluated, but it seems advisable given the frequent extranodal involvement, high proliferative index and the presence of MYC gene rearrangements in many cases.2 New treatments New treatment options need to be incorporated in order to improve the prognosis of these patients. Taking advantage of the immunophenotypical similarity with multiple myeloma, the utility of antimyeloma drugs in the treatment of PBL has been studied. In particular, an emerging therapeutic option is bortezomib, a proteasome inhibitor with activity in myeloma and some NHL subtypes. Bortezomib has activity against diffuse large B-cell lymphoma with non-germinal centre phenotype44 and could also induce lysis of EBV-infected cells,45 which provides a justification for its efficacy in PBL. There is an emerging clinical experience with bortezomib in PBL, with promising results. In limited series of patients, the addition of bortezomib (1.3 mg/m2 administered on days 1, 4, 8 and 11) to different chemotherapy regimens (DAEPOCH, CHOP) has resulted in rapid responses, lasting remissions and prolonged survival.46,47 Other agents with which responses have been described in isolated cases include thalidomide and lenalidomide48,49 or anti-CD30 antibody brentuximab vedotin,50 although neither the dose nor the optimal chemotherapy regimen for combination is established.
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Among the future treatment strategies, there could be new antiviral agents, cellular immunotherapy against EBV, the use of genetically modified T cells which target the CD30 antigen (present in up to 30% of PBL) or drugs that target the MYC2 gene. Likewise, immune control protein expression (PD-1 and PD-L1) in this tumour is a rationale for exploring monoclonal antibodies (antiPD-1) in this disease, often chemotherapy-resistant.32 Conclusions The PBL is an aggressive and rare lymphoma that typically occurs in the oral cavity of HIV-infected patients. In recent years, significant changes have been described in epidemiology and clinical presentation, so that a third of the cases involve patients not infected with HIV and about half occur in different sites outside the oral cavity. From a diagnostic point of view, PBL has a characteristic morphology and immunophenotype. However, its overlap with other types of NHL and some forms of myeloma make it necessary to include a heterogeneous group of neoplasms in the differential diagnosis. Despite progress in its recognition, PBL remains a therapeutic challenge for the clinician. The available evidence on treatment is limited and conventional chemotherapy provides inadequate disease control in most cases. Taking advantage of the enhanced knowledge of the biological characteristics of this lymphoma, it is necessary to explore the utility of more targeted drugs that help improve the prognosis of these patients. Conflict of interests The author declares no conflict of interest. References 1. Delecluse HJ, Anagnostopoulos I, Dallenbach F, Hummel M, Marafioti T, Schneider U, et al. Plasmablastic lymphomas of the oral cavity: a new entity associated with the human immunodeficiency virus infection. Blood. 1997;89:1413–20. 2. Castillo JJ, Bibas M, Miranda RN. The biology and treatment of plasmablastic lymphoma. Blood. 2015;125:2323–30. 3. Morscio J, Dierickx D, Nijs J, Verhoef G, Bitten E, Vanoeteren X, et al. Clinicopathologic comparison of plasmablastic lymphoma in HIV-positive, immunocompetent, and posttransplant patients: single-center series of 25 cases and meta-analysis of 277 reported cases. Am J Surg Pathol. 2014;38:875–86. 4. Liu M, Liu B, Liu B, Wang Q, Ding L, Xia C, et al. Human immunodeficiency virusnegative plasmablastic lymphoma: a comprehensive analysis of 114 cases. Oncol Rep. 2015;33:1615–20. 5. Stein H, Harris N, Campo E. Plasmablastic lymphoma. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. WHO classification of tumours of the haematopoietic and lymphoid tissues. Lyon: IARC; 2008. p. 256–7. 6. Hsi ED, Lorsbach RB, Fend F, Dogan A. Plasmablastic lymphoma and related disorders. Am J Clin Pathol. 2011;136:183–94. 7. Castillo JJ, Furman F, Beltrán BE, Bibas M, Bower M, Chen W, et al. Human immunodeficiency virus-associated plasmablastic lymphoma: poor prognosis in the era of highly active antiretroviral therapy. Cancer. 2012;118:5270–7. 8. Carbone A, Gloghini A. Plasmablastic lymphoma: one or more entities. Am J Hematol. 2008;83:763–4. 9. Schommers P, Hentrich M, Hoffman C, Gillor D, Zoufaly A, Jensen B, et al. Survival of AIDS-related diffuse large B-cell lymphoma, Burkitt lymphoma, and plasmablastic lymphoma in the German HIV Lymphoma Cohort. Br J Haematol. 2015;168:806–10. 10. Shiels MS, Pfeiffer RM, Gail MH, Hall HI, Li J, Chaturvedi AK, et al. Cancer burden in the HIV-infected population in the United States. J Natl Cancer Inst. 2011;103:753–62. 11. Shiels MS, Pfeiffer RM, Hall HI, Li J, Goedert JJ, Morton LM, et al. Proportions of Kaposi sarcoma, selected non-Hodgkin lymphomas, and cervical cancer in the United States occurring in persons with AIDS, 1980–2007. J Am Med Assoc. 2011;305:1450–9. 12. Guech-Ongey M, Simard EP, Anderson WF, Engels EA, Bhatia K, Devesa SS, et al. AIDS-related Burkitt lymphoma in the United States: what do age and CD4 lymphocyte patterns tell us about etiology and/or biology? Blood. 2010;116:5600–4. 13. Schommers P, Wyen C, Hentrich M, Gillor D, Zoufaly A, Jensen B, et al. Poor outcome of HIV-infected patients with plasmablastic lymphoma: results from the German AIDS-related lymphoma cohort study. AIDS. 2013;27:842–5. 14. Castillo JJ, Pantanowitz L, Dezube BJ. HIV-associated plasmablastic lymphoma: lessons learned from 112 published cases. Am J Hematol. 2008;83:804–9.
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15. Martinez D, Valera A, Perez NS, Villegas S, Gonzalez-Farre B, Sole C, et al. Plasmablastic transformation of low-grade B-cell lymphomas: report on 6 cases. Am J Surg Pathol. 2013;37:272–81. 16. Qing X, Sun N, Chang E, French S, Ji P, Yue C. Plasmablastic lymphoma may occur as a high-grade transformation from plasmacytoma. Exp Mol Pathol. 2011;90:85–90. 17. Ambrosio MR, de Falco G, Gozzetti A, Rocca BJ, Amato T, Mourmouras V, et al. Plasmablastic transformation of a pre-existing plasmacytoma: a possible role for reactivation of Epstein–Barr virus infection. Haematologica. 2014;99:e235–7. 18. Tarte K, Zhan F, de Vos J, Klein B, Shaughnessy J Jr. Gene expression profiling of plasma cells and plasmablasts: toward a better understanding of the late stages of B-cell differentiation. Blood. 2003;102:592–600. 19. Gloghini A, Dolcetti R, Carbone A. Lymphomas occurring specifically in HIV-infected patients: from pathogenesis to pathology. Semin Cancer Biol. 2013;23:457–67. 20. Dolcetti R, Gloghini A, Caruso A, Carbone A. A lymphomagenic role for HIV beyond immune suppression? Blood. 2016;127:1403–9. 21. Grywalska E, Rolinsky J. Epstein–Barr virus-associated lymphomas. Semin Oncol. 2015;42:291–303. 22. Pfeffer S, Voinnet O. Viruses, microRNAs and cancer. Oncogene. 2006;25:6211–9. 23. Montes-Moreno S, Gonzalez-Medina AR, Rodriguez-Pinilla SM, Maestre L, Sanchez-Verde L, Roncador G, et al. Aggressive large B-cell lymphoma with plasma cell differentiation: immunohistochemical characterization of plasmablastic lymphoma and diffuse large B-cell lymphoma with partial plasmablastic phenotype. Haematologica. 2010;95:1342–9. 24. Ott G, Rosenwald A, Campo E. Understanding MYC-driven aggressive B-cell lymphoma: pathogenesis and classification. Blood. 2013;122:3884–91. 25. Schichman SA, McClure R, Schaefer RF, Mehta P. HIV and plasmablastic lymphoma manifesting in sinus, testicles, and bones: a further expansion of the disease spectrum. Am J Hematol. 2004;77:291–5. 26. Hausermann P, Khanna N, Buess M, Itin PH, Battegay M, Dirnhofer S, et al. Cutaneous plasmablastic lymphoma in an HIV-positive male: an unrecognized cutaneous manifestation. Dermatology. 2004;208:287–90. 27. Makis W, Ciarallo A, Lisbona R. Plasmablastic lymphoma of the oral cavity in an HIV-positive patient: staging with 18F-FDG PET/CT. Acta Radiol. 2011;52:970–2. 28. Kane S, Khurana A, Parulkar G, Shet T, Prabhash K, Nair R, et al. Minimum diagnostic criteria for plasmablastic lymphoma of oral/sinonasal region encountered in a tertiary cancer hospital of a developing country. J Oral Pathol Med. 2009;38:138–44. 29. Valera A, Balgué O, Colomo L, Martínez A, Delabie J, Taddesse-Heath L, et al. IG/MYC rearrangements are the main cytogenetic alteration in plasmablastic lymphomas. Am J Surg Pathol. 2010;34:1686–94. 30. Loghavi S, Alayed K, Aladily TN, Zuo Z, Ng SB, Tang G, et al. Stage, age, and EBV status impact outcomes of plasmablastic lymphoma patients: a clinicopathologic analysis of 61 patients. J Hematol Oncol. 2015;8:65. 31. Delsol G, Campo E, Gascoyne RD. ALK-positive large B-cell lymphoma. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. WHO classification of tumours of the haematopoietic and lymphoid tissues. Lyon: IARC; 2008. p. 245–6. 32. Laurent C, Fabiani B, Do C, Tchernonog E, Cartron G, Gravelle P, et al. Immunecheckpoint expression in Epstein-Barr virus positive and negative plasmablastic lymphoma: a clinical and pathological study in 82 patients. Haematologica. 2016;101:976–84. 33. Castillo JJ, Winer ES, Stachurski D, Perez K, Jabbour M, Milani C, et al. Clinical and pathological differences between human immunodeficiency virus-positive and human immunodeficiency virus-negative patients with plasmablastic lymphoma. Leuk Lymphoma. 2010;51:2047–53.
34. Castillo JJ, Winer ES, Stachurski D, Perez K, Jabbour M, Milani C, et al. Prognostic factors in chemotherapy-treated patients with HIV-associated plasmablastic lymphoma. Oncologist. 2010;15:293–9. 35. National Comprehensive Cancer Network. NCCN guidelines version 4.2014. AIDS-related B-cell lymphomas. Available from: http://www.nccn.org [consulted 07.05.16]. 36. Barta SK, Xue X, Wang D, Tamari R, Lee JY, Mounier N, et al. Treatment factors affecting outcomes in HIV-associated non-Hodgkin lymphomas: a pooled analysis of 1546 patients. Blood. 2013;122:3251–62. 37. Ibrahim IF, Shapiro GA, Naina HVK. Treatment of HIV-associated plasmablastic lymphoma: a single-center experience with 25 patients. J Clin Oncol. 2014;32 Suppl. Abstract 8583. 38. Antinori A, Cingolani A, Alba L, Ammassari A, Serraino D, Ciancio BC, et al. Better response to chemotherapy and prolonged survival in AIDS-related lymphomas responding to highly active antiretroviral therapy. AIDS. 2001;15:1483–91. 39. Guan B, Zhang X, Ma H, Zhou H, Zhou X. A meta-analysis of highly active antiretroviral therapy for treatment of plasmablastic lymphoma. Hematol Oncol Stem Cell Ther. 2010;3:7–12. 40. Lester R, Li C, Phillips P, Shenkier TN, Gascoyne RD, Galbraith PF, et al. Improved outcome of human immunodeficiency virus-associated plasmablastic lymphoma of the oral cavity in the era of highly active antiretroviral therapy: a report of two cases. Lek Lymphoma. 2004;45:1881–5. 41. Francischini E, Martins FM, Braz-Silva PH, Magalhaes MH, Ortega KL. HIVassociated oral plasmablastic lymphoma and role of adherence to highly active antiretroviral therapy. Int J STD AIDS. 2010;21:68–70. 42. Cattaneo C, Re A, Ungari M, Peli A, Casari S, Castelnuovo F, et al. Plasmablastic lymphoma among human immunodeficiency virus-positive patients: results of a single center’s experience. Leuk Lymphoma. 2015;56:267–79. 43. Al-Malki MM, Castillo JJ, Sloan JM, Re A. Hematopoietic cell transplantation for plasmablastic lymphoma: a review. Biol Blood Marrow Transpl. 2014;20:1877–84. 44. Dunleavy K, Pittaluga S, Czuczman MS, Dave SS, Wright G, Grant N, et al. Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood. 2009;113:6069–76. 45. Reid EG. Bortezomib-induced Epstein–Barr virus and Kaposi sarcoma herpesvirus lytic gene expression: oncolytic strategies. Curr Opin Oncol. 2011;23:482–7. 46. Castillo JJ, Reagan JL, Sikov WM, Winer ES. Bortezomib in combination with infusional dose-adjusted EPOCH for the treatment of plasmablastic lymphoma. Br J Haematol. 2015;169:352–5. 47. Fernandez-Alvarez R, Gonzalez-Rodriguez AP, Rubio-Castro A, Gonzalez ME, Payer AR, Alonso-Garcia A, et al. Bortezomib plus CHOP for the treatment of HIV-associated plasmablastic lymphoma: clinical experience in three patients. Leuk Lymphoma. 2016;57:463–1466. 48. Bibas M, Grisetti S, Alba L, Picchi G, del Nonno F, Antinori A. Patient with HIV-associated plasmablastic lymphoma responding to bortezomib alone and in combination with dexamethasone, gemcitabine, oxaliplastin, cytarabine, and pegfilgrastim chemotherapy and lenalidomide alone. J Clin Oncol. 2010;28:e704–8. 49. Cao C, Liu T, Zhu H, Wang L, Kai S, Xiang B. Bortezomib-contained chemotherapy and thalidomide combined with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) play promising roles in plasmablastic lymphoma: a case report and literature review. Clin Lymphoma Myeloma Leuk. 2014;14:e145–50. 50. Holderness BM, Malhotra S, Levy NB, Danilov AV. Brentuximab vedotin demonstrates activity in a patient with plasmablastic lymphoma arising from a background of chronic lymphocytic leukemia. J Clin Oncol. 2013;31:e197–9.
www.elsevier.es/medicinaclinica
Review
Plasmablastic lymphoma夽 Rubén Fernández-Álvarez a,∗ , Juan-Manuel Sancho b , Josep-María Ribera b a
Servicio de Hematología, Hospital Universitario de Cabue˜ nes, Gijón, Asturias, Spain Servicio de Hematología Clínica, Institut Català d’Oncologia, Hospital Germans Trias i Pujol, Institut de Recerca contra la Leucèmia Josep Carreras, Universitat Autònoma de Barcelona, Badalona, Barcelona, Spain b
a r t i c l e
i n f o
Article history: Received 1 June 2016 Accepted 13 June 2016 Available online 10 December 2016 Keywords: Plasmablastic lymphoma Human immunodeficiency virus infection MYC Chemotherapy Bortezomib
a b s t r a c t Plasmablastic lymphoma (PBL) is a rare and aggressive subtype of non-Hodgkin lymphoma that commonly occurs in human immunodeficiency virus (HIV)-positive individuals, and affects oral sites. Occasionally, it has been described in HIV-negative patients and involving non-oral sites. Pathologically, PBL is a high-grade B-cell lymphoma that displays the immunophenotype of a terminally differentiated B-lymphocyte with loss of B-cell markers (CD20) and expression of plasma-cell antigens. Epstein–Barr virus infection and MYC rearrangements are frequently observed. Treatment of PBL is challenging because of the lack of established treatment and poor outcomes, with median survival times shorter than one year. In this review, we discuss the clinical and epidemiologic spectrum of PBL as well as its distinct pathological features. Finally, we summarize the currently available approaches for the treatment of patients with PBL. ˜ S.L.U. All rights reserved. © 2016 Elsevier Espana,
Linfoma plasmablástico r e s u m e n Palabras clave: Linfoma plasmablástico Infección por el virus de la inmunodeficiencia humana Oncogén MYC Quimioterapia Bortezomib
El linfoma plasmablástico (LPB) es un subtipo de linfoma no hodgkiniano agresivo y poco frecuente que afecta principalmente a pacientes infectados por el virus de la inmunodeficiencia humana (VIH), en los que tiende a presentarse en la cavidad oral. Ocasionalmente también se describe en pacientes no infectados por el VIH y en localizaciones distintas a la cavidad oral. Desde el punto de vista diagnóstico se caracteriza por expresar un inmunofenotipo de célula B activada que pierde los marcadores típicos de célula B madura (es negativo para CD20) y adquiere los asociados a célula plasmática. Además, es frecuente la presencia de infección por el virus de Epstein-Barr y de reordenamientos del gen MYC, lo que contribuye a su identificación. El abordaje terapéutico de estos pacientes es difícil debido a la poca evidencia disponible y al mal pronóstico observado en todas las series (incluidas las más recientes), ˜ En esta revisión se describe el espectro clínico y con medianas de supervivencia inferiores a un ano. epidemiológico del LPB, así como los aspectos fundamentales para su diagnóstico. Por último, se revisan las diferentes opciones terapéuticas utilizadas y la respuesta a las mismas. ˜ S.L.U. Todos los derechos reservados. © 2016 Elsevier Espana,
Introduction Plasmablastic lymphoma (PBL) was first described in 1997 by Delecluse et al. as an aggressive clinical course lymphoma that occurred in the oral cavity of patients infected with the human
夽 Please cite this article as: Fernández-Álvarez R, Sancho J-M, Ribera J-M. Linfoma plasmablástico. Med Clin (Barc). 2016;147:399–404. ∗ Corresponding author. E-mail address: [email protected] (R. Fernández-Álvarez). ˜ S.L.U. All rights reserved. 2387-0206/© 2016 Elsevier Espana,
immunodeficiency virus (HIV).1 Since its initial description, almost 20 years ago, numerous articles (over 600 entries in PubMed) have expanded its clinical and epidemiological spectrum.2 Today we know that this lymphoma can occur outside the oral cavity, usually in other extranodal sites. Also, although it is mainly associated with HIV infection, it has been described in other immunocompromised conditions (such as transplant recipients) and even in immunocompetent patients.3,4 Epstein–Barr virus (EBV) infection and abnormalities in the MYC gene, have been involved in its pathogenesis, observed in about half of cases. In the current classification of the World Health Organization, PBL is defined as a high
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histological grade Non-Hodgkin lymphoma (NHL), whose neoplastic cells stop expressing markers of lymphocyte B (such as CD20 and CD45) and acquire those associated with plasma cell (such as CD138).5 Diagnosis can be complex because of its overlap with other NHL subtypes and some forms of multiple myeloma.6 Despite advances in the diagnosis of this disease, its prognosis remains poor, with median survival of less than one year.7 There is no standard treatment for these patients and the results with conventional chemotherapy are not satisfactory. Intensive regimens have not demonstrated a survival benefit. A better understanding of the biological characteristics of this lymphoma provides an opportunity to explore the utility of more targeted drugs and improve the prognosis of these patients. The objective of this review is to update clinical, diagnostic and therapeutic aspects of PBL. Epidemiology It is difficult to know the incidence of PBL due to its rarity and the lack of epidemiological studies. Most cases are diagnosed in HIV-infected patients,1 in whom it becomes a defining feature of AIDS. It is estimated that it represents 2–12% of all HIVassociated lymphomas.8,9 Thanks to the implementation of potent antiretroviral therapy (ART), the risk of lymphoma in patients with HIV infection has declined significantly: more than 100 times in the mid-1990s, about 25 times in the late 2000s.10 This trend is observed in all NHL subtypes, except Burkitt’s lymphoma, where it remains stable.11,12 In the German cohort of 291 HIV-associated lymphomas diagnosed between 2005 and 2012, 12% were PBL, while the most frequent subtypes were still lymphoma diffuse large B-cell and Burkitt lymphoma (53 and 35%, respectively).9 In the context of HIV infection, PBL occurs predominantly in young males (median age between 39 and 44 years). At the time of diagnosis, the CD4+ lymphocytes count was between 85 and 206 cells/mm3 , depending on the time period studied (prior to the availability of ART or current), and only a minority of patients show virologic suppression of HIV.13 It is the first manifestation of HIV infection in 5% of cases.14 In recent years, there have been reports of PBL in non-HIVinfected individuals; in the literature, they represent approximately one third of all published on this lymphoma.2 They can occur in patients with other states of immunosuppression, such as transplant recipients. However, in most cases, only old age is identified as immunological deterioration factor.3,4 From the epidemiological point of view, patients with PBL can be divided into three categories according to their immune status: HIV infection, post-transplant and HIV-uninfected.2 These subgroups could be different clinical and biological entities, and some of their characteristics have been compared, such as age at diagnosis, primary site of the lymphoma, EBV positivity and the presence of gene abnormalities MYC (Table 1). Characteristically, PBL in patients without HIV infection occur at older ages (median age 58 years) and tend to be more heterogeneous in their primary site. In addition, there have been reports of PBL that occur as a transformation of indolent lymphoma15 or plasmacytomas.16,17 Pathogeny From an ontogenetic point of view, this tumour derives from a population of activated B cells that are in the process of becoming plasma cells (plasmablasts).18 The pathogenesis of PBL is only partially understood, but includes EBV infection and MYC gene deregulation as important mechanisms.2 Therefore, it shares a lymphomagenesis model which is similar to other HIV-associated lymphomas.19 According to this model, HIV indirectly facilitates
Table 1 Plasmablastic lymphoma characteristics according to HIV infection status.
Frequently in the literature, % Risk factors
Average age, years Over 60, % Sex male:female Positive EBV, % MYC gene abnormalities, % Extranodal presentation, % Primary site, %
Nodal presentation, % Advanced stage, %
HIV positive
HIV negative
70 Low CD4+ lymphocyte counts Absence of prior ART 39 1 4:1 75–80 50–80 95 Oral cavity (48–58) Extraoral (42–48) 5 50–65
30 Advanced age Posttransplant Prior lymphoma transformation 58 56 2–3:1 50–67 40–44 70–90 Oral cavity (16–40) Extraoral (56–84) 10–30 40–60
ART, antiretroviral therapy; EBV, Epstein–Barr virus; HIV, human immunodeficiency virus.
the development of lymphomas, through the participation of several elements: the transforming action of oncogenic viruses (such as EBV and human herpes virus type 8 [HHV-8]), chronic activation of B cells and the acquisition of critical genetic abnormalities (such as MYC gene). Moreover, recent data show that HIV itself could directly contribute to the development of lymphomas.20 By releasing certain proteins (p17 variants), it could support the clonal growth and development of B cells in germinal centres, increasing the risk of acquisition of genetic abnormalities and the onset of lymphomas. The presence of EBV in PBL was demonstrated in 80% of cases, and the proportion is higher in HIV positive cases.3 Various pathogenic mechanisms by which EBV can exert its transforming and oncogenic action have been described. By multiple gene expression is able to prevent apoptosis of B cells, alter the cell cycle regulation and inhibit tumour suppressor genes.21 Like other oncogenic viruses, EBV produces micro-RNA (miRNA), that destroy RNA and interfere with specific protein expression. For example, EBVassociated mi-RNA BHRF-1 inhibits the tumour suppressor gene P53 and miR-BART1 activates BCL2, an anti-apoptotic protein.22 On the other hand, the MYC gene deregulation could allow B cells to escape the plasma cell differentiation program and become plasmablasts. Interestingly, in most PBL cases, Blimp1 protein overexpression is detected, a transcription factor that governs plasma-cell differentiation and in non-neoplastic plasma cells represses MYC2,23 expression. It has been postulated that MYC overexpression, which is constant in PBL, could void the inhibitory effect of Blimp124 and thus promote the transformation of mature B cells in plasmablasts, blocking a greater plasmacytic differentiation. Additionally, MYC gene deregulation allows B cells to avoid physiological apoptosis favoured by Blimp1. Clinical presentation Most patients present with rapidly growing masses, sometimes destructive, affecting extranodal structures, particularly mucous. The most common site is the oral cavity, where masses can be observed in the gums, palate or alveolar mucosa, and sometimes infiltrate the surrounding bone structures (maxillary and mandibular). The preference for the oral cavity is typical of HIV-infected patients, while in uninfected patients the site is more heterogeneous. Approximately half of the cases occur outside the oral cavity, and can affect the gastrointestinal tract (12%), skin and soft tissue (6%), lymph nodes, nasal cavity and sinuses, genitals, central nervous system (CNS) and bone. Bone marrow infiltration is detected in up to 30% of cases, and in these cases the differential diagnosis
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with multiple myeloma is important. Primary nodal presentation is rare, except in transplant patients, in whom a skin involvement has also been observed.3 Approximately two thirds of patients are diagnosed in advanced clinical stages (i.e., stages iii or iv) and almost half have B symptoms. There are hardly any available data on laboratory abnormalities at the time of diagnosis; however, high lactate dehydrogenase (LDH) values have been described in most patients.7
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At genetic level, MYC gene translocations are the most common genetic alteration in PBL. Thanks to fluorescence in situ hybridization (FISH) studies, they are detected in half of the cases, with the immunoglobulin heavy chain IGH29,30 gene being the most frequently translocated. A smaller proportion of cases have MYC gene amplifications. By contrast, BCL2 and BCL629 gene rearrangements have not been detected. It is important to stress that most cases show overexpression of MYC protein, regardless of whether the gene status has been rearranged or not by FISH.30
Diagnosis and evaluation From a clinical standpoint, PBL lesions in the oral cavity may be indistinguishable from other neoplastic lesions, such as carcinoma, melanoma, or other types of lymphoma. Furthermore, PBL can occur in many different sites, outside the oral cavity, therefore, its differential diagnosis ranges from carcinomas to other types of lymphoma or opportunistic infections. As in all lymphomas, its diagnosis should be histological and requires tissue biopsy. Whenever possible, an excisional biopsy of the suspicious lesion will be performed, which will further define its morphology and immunophenotype. At the time of diagnosis, an extension study should be conducted, which is identical to that performed in other NHLs. A TC scan should be available in the initial evaluation. The role of positron emission tomography (PET) is not established in the staging of PBL, although there are cases in the literature confirming its significant fluorodeoxyglucose uptake and potential usefulness.25–27 It should be noted that the lymph nodes that occur in HIV infection may show uptake on PET, so false positives may occur.27 As in other aggressive lymphomas, it is recommended to perform a bone marrow biopsy in the initial evaluation. Given its aggressive nature and the reported cases of CNS infiltration, it is appropriate to perform a lumbar puncture to rule out meningeal infiltration by lymphoma. The PBL is defined as a high histologic grade lymphoma whose neoplastic cells express immunophenotyping of plasma cells in the absence of typical mature B cell markers.5 Its morphology shows diffuse proliferation of cells that resemble immunoblasts, with abundant cytoplasm and central nucleus with prominent nucleoli. Sometimes they acquire greater plasma cell differentiation, with basophilic cytoplasm, perinuclear halo and eccentric nucleus. Characteristically, this tumour has a high proliferative index, as indicated by the high expression of Ki67 (60–90%). Necrosis and cellular debris within the macrophages is frequently observed, which can lead to a “starry sky” pattern. Immunohistochemistry is essential for the diagnosis of PBL. Although, from an ontogenetic point of view, it is a B-cell lymphoma, it does not express typical mature B cell markers (such as CD19, CD20 and PAX5), and only a few cases are positive for CD45 and CD79a. However, it expresses plasmacytic differentiation markers, such as MUM1, CD38 and CD138. In some cases, aberrant CD10 and CD56 expression (absent in normal plasma cells) is detected. There are additional markers (PRDM1/Blimp1 and XBP1s) that are overexpressed in the final B differentiation stages and have proven useful in identifying a plasmablastic immunophenotype.23 However, this finding is only investigational. In most cases, the tumour cells are positive for EBV. Their presence is detected by RNA hybridization techniques (EBER), while immunohistochemical staining for LMP1 (latent membrane protein) is usually negative. In a recent study, positivity for EBV based on EBER expression was more frequent in HIV-infected (75%) and in transplant patients (67%) than in immunocompetent (50%).3 HHV8 is typically absent in this lymphoma. In order to improve the diagnostic ability of PBL in environments with few resources, some minimum immunohistochemical criteria have been proposed, including staining for CD20, CD38 and CD138, as well as Ki67 higher than 60% and EBV expression.28
Differential diagnosis PBL shares immunophenotypic and morphologic features with other plasmablastic differentiation lymphomas and plasma cell neoplasms.6 The similarities with this heterogeneous group of neoplasms can make diagnosis difficult and adversely affect patient treatment. For its distinction, the clinical context, the presence of immunodeficiency and EBV positivity by EBER need to be considered. Table 2 summarizes the data that help distinguish these entities. The most important differential diagnosis must be made with some aggressive and poorly differentiated forms of myeloma (or plasmacytoma), since treatment and prognosis of this entity are very different. The presence of paraprotein, bone disease, hypercalcemia or renal failure favours myeloma diagnosis. By contrast, HIV-infection and EBER positivity favour PBL diagnosis. There is also a heterogeneous group of lymphomas with plasmablastic differentiation that should be included in the differential diagnosis. The ALK+ large B-cell lymphoma can resemble PBL morphologically, as it does not express CD20 either. However, it is not associated with immunodeficiency and EBV is negative. Immunohistochemical staining for ALK is essential to recognize this neoplasm, showing granular expression in the cytoplasm.31 On the other hand, the characteristic absence of HHV8 in PBL allows its differentiation from lymphomas associated to this virus (large B-cell lymphoma associated with multicentric Castleman’s disease and primary effusion lymphoma). Prognosis Characteristically, PBL has an aggressive clinical course and poor prognosis. In the series including more cases, the median survival ranges between 5 and 15 months (Table 3), and it is estimated that only a quarter of patients are cured (overall survival at 5 years lower than 30%).7 These low survival rates contrast with the improvement in the prognosis of HIV-associated lymphomas. Some of the biological characteristics of PBL, as the absence of CD20 expression or the presence of MYC gene rearrangements, could explain this adverse prognosis. HIV infection does not worsen the prognosis of patients, possibly due to the immune reconstitution obtained with ART. In a comparative analysis, the median survival in HIV-infected patients was 10 months, while in non-infected was 11 months.3 However, patients with other immunocompromised states or transplanted are the ones with shorter survival rates (median of 7 months in the same analysis). Another series of 114 cases of PBL in patients without HIV infection demonstrated again the worst prognosis of the transplant subgroup compared to immunocompetent patients (median survival 6.5 vs 36 months, respectively).4 Apparently, there is great survival variability in the series published. For example, in the German cohort of HIV-associated lymphomas, the median survival was only 5 months with an interval ranging from 0 to 76 months.13 Several studies have demonstrated the prognostic role of conventional clinical factors such as stage of disease and general condition.7 However, there
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Table 2 Differential diagnosis of plasmablastic lymphoma. Location
Clinical context
Plasmablastic lymphoma
Extranodal (oral cavity, mucosa)
Multiple myeloma
Bone marrow and extranodal
DLBCL ALK+
Lymph nodes
HHV8-positive large B cell lymphoma
Lymph nodes and spleen
Primary effusion lymphoma
Serous (pleura, pericardium, peritoneum)
Immunophenotypic markers
HIV infection Posttransplant Advanced age Paraprotein Renal disease Bone disease Youth Advanced stages B symptoms Multicentric Castleman disease HIV infection HIV infection Kaposi’s sarcoma Absence of tumour masses
Infection
Positive
Negative
HIV
EBV
HHV8
CD138 MUM1/IRF4 MYC CD138 cIg
CD45 CD20 PAX5 CD20 PAX5
70%
Yes
No
No
No
No
ALK CD4 CD45 CD20+ or − MUM1/IRF4 cIgM CD45 CD330 MUM1/IRF4
CD20 CD30 MYC CD79a CD138
No
No
No
Yes
No
Yes
Yes
Yes
Yes
PAX5 CD20 CD138 Ig
ALK, anaplastic lymphoma kinase; DLBCL, diffuse large B cell lymphoma; EBV, Epstein–Barr virus; HHV8, human herpesvirus type 8; HIV, human immunodeficiency virus.
are conflicting data on the prognostic significance of age or LDH values. It has been suggested that the international prognostic index adjusted for age could be a useful prognostic tool in these patients.13 There are limited data on the prognostic impact of biological data. The presence of MYC3.7 gene rearrangements and negativity for EBV4,30,32 have correlated with worse outcomes. Treatment There is no consensus on what should be the standard treatment for patients with PBL. Due to the low frequency of lymphoma, the only studies that have examined the efficacy of the
treatments are retrospective in nature. Without treatment, the median survival is only 3–4 months.33 Given the aggressive nature of this lymphoma, the usual practice involves the administration of combination chemotherapy, with a relatively high response rate (up to 77% in a series). However, responses are often transient and patient survival remains short (14 months in the same series), most dying from disease progression.34 A common observation from 2 retrospective studies is that patients who achieve a complete response after chemotherapy show significantly prolonged survival rates.7,34 Historically, the most commonly used chemotherapy regimen in this lymphoma has been cyclophosphamide, adriamycin, vincristine and prednisone (CHOP), with
Table 3 Major studies on plasmablastic lymphoma treatment1. Study (reference)
Period
No.
HIV infection (%)
Age (years)
CD4+ lymphocyte (/mm3 )
Castillo et al.14
1997–2007
53
100
38
178
–
Castillo et al.34
1997–2009
70
100
39
165
–
Castillo et al.7
2000–2010
50
100%
43
206
Ibrahim et al.37
2000–2012
25
100
44
Schommers et al.13
2005–2012
18
100
1994–2013
61
30
30
Loghavi et al.
MYC gene translocation (%)
Treatment
OS (months)
Influence OS
CHOP (51%) EPOCH, CODOX-M/IVAC (25%) CHOP (50%) EPOCH, Hyper-CVAD/MA, CODOX-M/IVAC (23%)
15
–
14
41
CHOP (63%) EPOCH, Hyper-CVAD/MA (37%)
11
87
32
EPOCH (56%) CHOP (20%)
11.6 (2–63)
44
85
–
49
–
67
Response to treatment and staging Intensive regimens with no benefit Response to treatment, stage, ECOG and MYC rearranged Intensive regimens with no benefit Better survival with EPOCH versus CHOP (17 versus 7 months) ECOG, age, LDH, IPI Age, stage and EBV Intensive regimens with no benefit
CHOP (61%) Others (39%) Hyper-CVAD/MA (45%) CHOP (21%), EPOCH (21%)
5 (0–76) 7 (0.3–156)
CHOP, cyclophosphamide, doxorubicin, vincristine and prednisone; CODOX-M/IVAC, cyclophosphamide, doxorubicin, methotrexate, ifosfamide, etoposide, and cytarabine; ECOG, Eastern Cooperative Oncology Group; EPOCH, etoposide, prednisone, vincristine, doxorubicin and cyclophosphamide; Hyper-CVAD/MA, hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate and cytarabine; IPI, International Prognostic Index; LDH, lactate dehydrogenase; PBL, plasmablastic lymphoma; OS, overall survival; EBV: Epstein–Barr virus; HIV, human immunodeficiency virus.
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the previously commented poor results (Table 3). For this reason, the recommendations of scientific groups35 and some reviews2 favour the use of regimens that are more intensive than CHOP, such as etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (EPOCH), cyclophosphamide, doxorubicin, methotrexate, ifosfamide, etoposide, and cytarabine (CODOX-M/IVAC) or hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate and cytarabine (hyper-CVAD/MA). However, it is unclear that more intensive regimens can improve results. In this regard, 2 retrospective studies found no survival benefit with more intensive regimens when compared with CHOP.7,34 In both studies, patients had a short median survival (11 and 14 months respectively), with no difference between the strategy of intensive chemotherapy and CHOP-based chemotherapy. More recently, the infusion regimen DA-EPOCH (dose-adjusted EPOCH) has been proposed as potentially more effective than CHOP in the treatment of HIV-associated lymphomashas.36 In the case of PBL, a retrospective study showed longer survival in patients treated with EPOCH compared with those who received CHOP (17 versus 7 months, p < 0.04).37 In patients infected with HIV, ART is an essential part of PBL treatment. ART addition to chemotherapy improves the prognosis of these patients.38,39 Additionally, favourable responses have been described in cases where the only treatment was ART, though usually not durable.40 Conversely, there are relapses after interruption of ART,41 underscoring its importance in the treatment of these patients. Local or locoregional radiotherapy has been used, without being able to establish its role in the treatment of these patients.2 In fact, in a study of 114 patients, the addition of radiotherapy in localized stages demonstrated no benefit in overall survival.4 Regarding the use of autologous stem cell transplantation (ASCT), isolated cases have been reported with prolonged survival when used in first remission after chemotherapy.42 This procedure could benefit patients with good clinical conditions, especially if the disease is chemosensitive, although there is insufficient data for widespread recommendation. A recent review43 recommended to consider ASCT as first line in the presence of risk factors such as a high international prognostic index or absence of complete response after chemotherapy. The use of prophylaxis against CNS relapse has not been systematically evaluated, but it seems advisable given the frequent extranodal involvement, high proliferative index and the presence of MYC gene rearrangements in many cases.2 New treatments New treatment options need to be incorporated in order to improve the prognosis of these patients. Taking advantage of the immunophenotypical similarity with multiple myeloma, the utility of antimyeloma drugs in the treatment of PBL has been studied. In particular, an emerging therapeutic option is bortezomib, a proteasome inhibitor with activity in myeloma and some NHL subtypes. Bortezomib has activity against diffuse large B-cell lymphoma with non-germinal centre phenotype44 and could also induce lysis of EBV-infected cells,45 which provides a justification for its efficacy in PBL. There is an emerging clinical experience with bortezomib in PBL, with promising results. In limited series of patients, the addition of bortezomib (1.3 mg/m2 administered on days 1, 4, 8 and 11) to different chemotherapy regimens (DAEPOCH, CHOP) has resulted in rapid responses, lasting remissions and prolonged survival.46,47 Other agents with which responses have been described in isolated cases include thalidomide and lenalidomide48,49 or anti-CD30 antibody brentuximab vedotin,50 although neither the dose nor the optimal chemotherapy regimen for combination is established.
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Among the future treatment strategies, there could be new antiviral agents, cellular immunotherapy against EBV, the use of genetically modified T cells which target the CD30 antigen (present in up to 30% of PBL) or drugs that target the MYC2 gene. Likewise, immune control protein expression (PD-1 and PD-L1) in this tumour is a rationale for exploring monoclonal antibodies (antiPD-1) in this disease, often chemotherapy-resistant.32 Conclusions The PBL is an aggressive and rare lymphoma that typically occurs in the oral cavity of HIV-infected patients. In recent years, significant changes have been described in epidemiology and clinical presentation, so that a third of the cases involve patients not infected with HIV and about half occur in different sites outside the oral cavity. From a diagnostic point of view, PBL has a characteristic morphology and immunophenotype. However, its overlap with other types of NHL and some forms of myeloma make it necessary to include a heterogeneous group of neoplasms in the differential diagnosis. Despite progress in its recognition, PBL remains a therapeutic challenge for the clinician. The available evidence on treatment is limited and conventional chemotherapy provides inadequate disease control in most cases. Taking advantage of the enhanced knowledge of the biological characteristics of this lymphoma, it is necessary to explore the utility of more targeted drugs that help improve the prognosis of these patients. Conflict of interests The author declares no conflict of interest. References 1. Delecluse HJ, Anagnostopoulos I, Dallenbach F, Hummel M, Marafioti T, Schneider U, et al. Plasmablastic lymphomas of the oral cavity: a new entity associated with the human immunodeficiency virus infection. Blood. 1997;89:1413–20. 2. Castillo JJ, Bibas M, Miranda RN. The biology and treatment of plasmablastic lymphoma. Blood. 2015;125:2323–30. 3. Morscio J, Dierickx D, Nijs J, Verhoef G, Bitten E, Vanoeteren X, et al. Clinicopathologic comparison of plasmablastic lymphoma in HIV-positive, immunocompetent, and posttransplant patients: single-center series of 25 cases and meta-analysis of 277 reported cases. Am J Surg Pathol. 2014;38:875–86. 4. Liu M, Liu B, Liu B, Wang Q, Ding L, Xia C, et al. Human immunodeficiency virusnegative plasmablastic lymphoma: a comprehensive analysis of 114 cases. Oncol Rep. 2015;33:1615–20. 5. Stein H, Harris N, Campo E. Plasmablastic lymphoma. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. WHO classification of tumours of the haematopoietic and lymphoid tissues. Lyon: IARC; 2008. p. 256–7. 6. Hsi ED, Lorsbach RB, Fend F, Dogan A. Plasmablastic lymphoma and related disorders. Am J Clin Pathol. 2011;136:183–94. 7. Castillo JJ, Furman F, Beltrán BE, Bibas M, Bower M, Chen W, et al. Human immunodeficiency virus-associated plasmablastic lymphoma: poor prognosis in the era of highly active antiretroviral therapy. Cancer. 2012;118:5270–7. 8. Carbone A, Gloghini A. Plasmablastic lymphoma: one or more entities. Am J Hematol. 2008;83:763–4. 9. Schommers P, Hentrich M, Hoffman C, Gillor D, Zoufaly A, Jensen B, et al. Survival of AIDS-related diffuse large B-cell lymphoma, Burkitt lymphoma, and plasmablastic lymphoma in the German HIV Lymphoma Cohort. Br J Haematol. 2015;168:806–10. 10. Shiels MS, Pfeiffer RM, Gail MH, Hall HI, Li J, Chaturvedi AK, et al. Cancer burden in the HIV-infected population in the United States. J Natl Cancer Inst. 2011;103:753–62. 11. Shiels MS, Pfeiffer RM, Hall HI, Li J, Goedert JJ, Morton LM, et al. Proportions of Kaposi sarcoma, selected non-Hodgkin lymphomas, and cervical cancer in the United States occurring in persons with AIDS, 1980–2007. J Am Med Assoc. 2011;305:1450–9. 12. Guech-Ongey M, Simard EP, Anderson WF, Engels EA, Bhatia K, Devesa SS, et al. AIDS-related Burkitt lymphoma in the United States: what do age and CD4 lymphocyte patterns tell us about etiology and/or biology? Blood. 2010;116:5600–4. 13. Schommers P, Wyen C, Hentrich M, Gillor D, Zoufaly A, Jensen B, et al. Poor outcome of HIV-infected patients with plasmablastic lymphoma: results from the German AIDS-related lymphoma cohort study. AIDS. 2013;27:842–5. 14. Castillo JJ, Pantanowitz L, Dezube BJ. HIV-associated plasmablastic lymphoma: lessons learned from 112 published cases. Am J Hematol. 2008;83:804–9.
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