Introduction
Plasmablastic lymphoma (PbL) falls under the broad category of diffuse large B-cell lymphoma (DLBCL). This entity was first described in 1997 in a group of 16 patients (15/16 patients being human immunodeficiency virus (HIV) positive), with lesions primarily involving the oral cavity [ 1 ]. It has since been classically associated with HIV-positive patients [ 2 ]. However, despite the high degree of association with HIV, it accounts for only 2.6% of acquired immunodeficiency syndrome (AIDS)-related lymphoma [ 3 ], making it a relatively rare diagnosis. Among these HIV-positive patients with PbL, the involvement of the gastrointestinal (GI) tract is rare (12%), with the majority of the extranodal lesions being in the oral cavity (48%). We hereby describe a case of PbL with extranodal involvement of the anorectal region in this patient with HIV AIDS.
Case presentation
A 55-year-old male, with untreated HIV, presented for evaluation of newly diagnosed plasma cell malignancy. Past medical history was significant for HIV (cluster of differentiation 4 (CD4) cell count at admission - 124), heart failure with reduced ejection fraction (HFrEF) status post implantable cardioverter defibrillator (ICD) placement, atrial fibrillation, and chronic obstructive pulmonary disease (COPD) on 2 liters of oxygen at home.
The patient presented one week ago to an outside hospital with complaints of progressively worsening acute onset of shortness of breath. He had a computed tomography (CT) scan of the chest and abdomen revealing pneumonia, multiple lytic lesions in the ribs, and multiple liver masses. A liver biopsy was performed revealing a plasmacytic infiltrate with an expression of Ki-67 > 90%. The cells were positive for CD138, CD56, Epstein Barr Virus (EBV)-encoded RNA (EBER) and negative for CD3, epithelial membrane antigen (EMA), and CD45. The plasma cell infiltrate was shown to demonstrate kappa clonality. Subsequently, the patient was transferred to our institute for further management and care.
The workup performed at our hospital included - a bone survey that did not reveal any evidence of lytic lesions, a bone marrow biopsy revealing no evidence of multiple myeloma, positron emission tomography (PET)-CT, which showed multiple, low-density, hypermetabolic hepatic masses, and multifocal lytic expansile lesions throughout the axial and appendicular skeleton. Interestingly, there was increased radiotracer uptake within the distal rectum near the anal and rectal junction.
The findings of the colonic lesions on the PET-CT were evaluated for underlying malignancy through a colonoscopy, which revealed a submucosal lesion of 1.5 cm x 1.5 cm, 3 cm from the anal verge with normal overlying mucosa. Subsequent endoscopic ultrasound (EUS) revealed an oval, hypoechoic, and heterogenous mass measuring 3.2 cm x 2.7 cm. The wall of the mass was well-demarcated and smooth. The mass appeared to arise from the muscularis layer (endoscopic ultrasound (EUS) layer 4) raising suspicion for leiomyoma, with an intact muscularis noted along the entire lesion. There was no evidence of adjacent lymphadenopathy.
FNA of the lesion revealed scattered and focal clusters of plasma cells with some crush artifacts (Figure 1 ). The plasma cells were positive for CD138 (Figure 2 ) and negative for pan-Cytokeratin (pan-CK). The EBV in situ hybridization (ISH) stain was positive (Figure 3 ).
Flow cytometric analysis showed cells positive for CD138, CD38 (dim/heterogenous), CD56, and CD81; they were negative for CD45, CD19, and CD20. Kappa and lambda light chain analysis showed kappa restriction. Fluorescence in situ hybridization (FISH) revealed gene rearrangement involving 8q24 (c-MYC) and a gain on 14q32. Human herpes virus (HHV)-8 by polymerase chain reaction (PCR) was negative. At this point, a diagnosis of plasmablastic lymphoma was made.
At the time of hospitalization, the patient was not taking any anti-retroviral medications. His CD4 count was 124. He was started on antiretroviral treatment with emtricitabine, tenofovir, and dolutegravir. He was found to have EBV viremia with 26,000 copies, which progressively increased to 381,000 at the time of discharge. This finding was discussed with the infectious disease team, which determined that no treatment was necessary.
The patient was started on bortezomib, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (bortezomib-CHOP) chemotherapy with good tolerance. He was also considered for daratumumab therapy, as his lymphoma cells were CD38 positive. However, due to insurance-related barriers, there was a delay in adding daratumumab therapy, which was ultimately started later with his fourth cycle of bortezomib-CHOP.
Continual follow-up of the patient revealed that the patient had achieved complete remission about five months after initiation of treatment. He remained in remission for five months after which he was found to have a relapse involving a mass in the chest located between the aorta and pulmonary vein. A biopsy was performed, which confirmed the relapse. He was subsequently started on salvage therapy with bortezomib, dexamethasone, cisplatin, cyclophosphamide, and etoposide. Adriamycin was not used due to HFrEF with an ejection fraction of 20%. Follow-up PET-CT after the first cycle of salvage chemotherapy showed considerable response with complete resolution of his chest mass. He was planned for a total of six cycles of chemotherapy; however, at his fifth cycle and 10 months after his initial relapse, his repeat PET-CT showed a relapse of the disease at the same site as before. Due to the poor functional status, the patient was not considered a candidate for further chemotherapy and was transitioned to comfort measures through palliative care management.
Discussion
HIV and AIDS have been known to be associated with a number of lymphoproliferative disorders [ 4 ]. Among these, non-Hodgkin lymphomas (NHLs) contribute to a majority of AIDS-defining malignancies. Most of these NHLs arise systemically with extranodal involvement such as that of the gastrointestinal tract. The most common histologic subtypes of AIDS-NHL include Burkitt’s lymphoma and DLBCL with other rare subtypes including primary effusion lymphoma, anaplastic lymphoma kinase (ALK)-positive DLBCL, plasmablastic lymphoma, and HHV-8-related DLBCL [ 5 ].
PbL is classically described among patients with HIV, with a predominance among males [ 2 ]. However, over the years, it is known to be seen in immunocompetent and organ transplant patients as well [ 2 ]. The median age of diagnosis is around 50 years, with an earlier age of onset seen among the HIV-positive subgroup [ 3 , 4 ]. Most cases present in an advanced stage of the illness, Ann Arbor stage 3 or 4; however, this Ann Arbor staging in cases of PbL has not shown any prognostic correlation [ 2 , 4 ]. The diagnosis of PbL carries a guarded prognosis with a median survival time of 6-19 months with no clear difference among the HIV-positive and HIV-negative populations. The most common presentation is extra-nodal involvement, with the most common site being the oral cavity (44%), followed by the gastrointestinal (14%), and skin (7%) [ 6 ]. However, it is interesting to note that patients with HIV-negative PbL showed a higher gastrointestinal involvement (21%) as compared to HIV-positive PbL (12%) [ 6 ]. They also showed lower rates of oral involvement (40% versus 48%) and lower rates of EBV positivity (46% versus 82%) as compared to those with HIV-positive PbL [ 7 , 8 ]. HIV-negative PbL also presented with B symptoms and frequent bone marrow involvement [ 9 ].
While gastrointestinal (GI) involvement in PbL is seen in 14 % of cases, the diagnosis can be challenging due to the morphologic similarities with other malignancies with plasmablastic features such as Burkitt’s lymphoma, plasmablastic plasma cell myeloma, other types of CD20-negative DLBCL (such as primary effusion lymphoma, ALK-positive DLBCL) and other HHV-8-positive large B-cell lymphoma [ 6 , 10 , 11 ]. PbL differs from DLBCL in that it is negative for immunophenotypic markers such as CD20 and CD45 [ 1 ]. While PbL closely matches the immunophenotype of a plasmablastic plasma cell myeloma, there is the absence of significant bone marrow involvement, a monoclonal protein identified in the serum, and close association of PbL with EBV [ 12 ] versus a plasmablastic plasma cell myeloma, which is found to carry the virus in only 6.7% of the cases [ 13 ].
Hence, the accurate identification and diagnosis of a PbL require a thorough immunophenotypic workup.
The classic immunophenotypic markers seen in PbL include positivity for CD38, CD138, MYC, IRF, and MUM1 with variable expression of CD45, CD30, EMA, and CD79a [ 3 ]. There is, usually an absence of the pan B-cell markers of CD20 and PAX 5 [ 3 ]. They also usually have a Ki-67 index > 90% demonstrating hyperproliferation [ 14 ].
Comparative studies have shown no differences in survival among HIV-positive PbL and HIV-negative PbL [ 2 ]. However, those among HIV-negative PbL who are immunosuppressed have been shown to have significantly poor median survival (six months) as opposed to those without immunosuppression (13 months) [ 7 ]. The use of highly active antiretroviral therapy (HAART) therapy in patients with HIV-positive PbL has shown better survival in some studies; however, other studies have shown no difference [ 6 , 8 ]. Patients with MYC gene rearrangements have shown poor outcomes and shorter overall survival [ 9 ]. The impact of EBV positivity and viral load on outcomes is unclear, with some studies showing an association of a better prognosis among the EBV-positive subgroup with others showing no difference [ 2 , 9 ].
The treatment of PbL is not clearly defined. Without any chemotherapy, the median survival is about three months [ 15 ]. The overall response rate with chemotherapy has shown to be about 77% with a median survival of 14 months and five-year survival of 31% [ 8 ]. Given the poor response to CHOP and CHOP-related regimens in these patients, the National Comprehensive Cancer Network (NCCN) guidelines favor the more intensive regimen - EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride), hyper-CVAD (cyclophosphamide, vincristine, adriamycin, and dexamethasone), and CODOX/M-IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate, and high-dose cytarabine). However, these intensive regimens have not shown any statistically significant survival benefit over CHOP/CHOP-related regimens [ 8 ].
Bortezomib has been shown to have some benefits in patients with PbL. This is thought to be due to the similar characteristics that PbL shares with plasmablastic plasma cell myeloma [ 16 ]. It has been used either as a single agent or in a combination with the CHOP/ EPOCH regimen [ 9 ].
Conclusions
Plasmablastic lymphoma is an aggressive B-cell lymphoma with a guarded prognosis. It most commonly presents with extranodal involvement. Although rare, extra-nodal spread to the GI tract can be a presenting feature, and it must be distinguished from other lymphomas with plasmablastic features. Given the rarity of this disease and its aggressive course, a timely and accurate diagnosis of PbL is extremely crucial in determining the prognosis and tailoring the management of the disease.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
References
1 Plasmablastic lymphomas of the oral cavity: a new entity associated with the human immunodeficiency virus infection Blood Delecluse HJ Anagnostopoulos I Dallenbach F 1413 1420 89 1997 9028965
2 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 Morscio J Dierickx D Nijs J 875 886 38 2014 24832164 10.1097/PAS.0000000000000234
3 Plasmablastic lymphoma WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues 321 322 Lyon, France IARC Press https://publications.iarc.fr/Book-And-Report-Series/Who-Classification-Of-Tumours/WHO-Classification-Of-Tumours-Of-Haematopoietic-And-Lymphoid-Tissues-2017
4 HIV-associated plasmablastic lymphoma: lessons learned from 112 published cases Am J Hematol Castillo J Pantanowitz L Dezube BJ 804 809 83 2008 18756521 10.1002/ajh.21250
5 Gastrointestinal malignancies in HIV-infected or immunosuppressed patients: pathologic features and review of the literature Adv Anat Pathol Ho-Yen C Chang F van der Walt J Lucas S 431 443 14 2007 18049132 10.1097/PAP.0b013e31815946d9
6 The biology and treatment of plasmablastic lymphoma Blood Castillo JJ Bibas M Miranda RN 2323 2330 125 2015 25636338 10.1182/blood-2014-10-567479
7 Human immunodeficiency virus (HIV)-negative plasmablastic lymphoma: a single institutional experience and literature review Leuk Res Liu JJ Zhang L Ayala E 1571 1577 35 2011 21752466 10.1016/j.leukres.2011.06.023
8 Plasmablastic lymphoma: a systematic review ScientificWorldJournal Castillo JJ Reagan JL 687 696 11 2011 21442146 10.1100/tsw.2011.59 PMC5720057
9 Plasmablastic lymphoma: current perspectives Blood Lymphat Cancer Lopez A Abrisqueta P 63 70 8 2018 31360094 10.2147/BLCTT.S142814 PMC6467349
10 CD20-negative diffuse large B cell lymphoma: a comprehensive analysis of 695 cases Tumour Biol Li J Zhao S Wang J Chen J Wen W Zhang Q 3619 3637 37 2016 26459310 10.1007/s13277-015-4205-5
11 Manifestations of gastrointestinal plasmablastic lymphoma: a case series with literature review World J Gastroenterol Luria L Nguyen J Zhou J 11894 11903 20 2014 25206297 10.3748/wjg.v20.i33.11894 PMC4155383
12 Plasmablastic lymphomas and plasmablastic plasma cell myelomas have nearly identical immunophenotypic profiles Mod Pathol Vega F Chang CC Medeiros LJ 806 815 18 2005 15578069 10.1038/modpathol.3800355
13 Epstein-Barr virus in B-cell non-Hodgkin's lymphomas: unexpected infection patterns and different infection incidence in low- and high-grade types J Pathol Hummel M Anagnostopoulos I Korbjuhn P Stein H 263 271 175 1995 7745495 10.1002/path.1711750303
14 CD20-negative diffuse large B-cell lymphomas: biology and emerging therapeutic options Expert Rev Hematol Castillo JJ Chavez JC Hernandez-Ilizaliturri FJ Montes-Moreno S 343 354 8 2015 25641215 10.1586/17474086.2015.1007862
15 Clinical and pathological differences between human immunodeficiency virus-positive and human immunodeficiency virus-negative patients with plasmablastic lymphoma Leuk Lymphoma Castillo JJ Winer ES Stachurski D 2047 2053 51 2010 20919850 10.3109/10428194.2010.516040
16 Plasmablastic lymphoma: are more intensive regimens needed? Leuk Res Castillo JJ 1547 1548 35 2011 21788074 10.1016/j.leukres.2011.06.036