Spontaneous Regression Of A Plasmablastic Lymphoma With Myc Rearrangement

Abstract

Plasmablastic lymphoma (PBL) is an aggressive type of lymphoma and classified as mature B-cell neoplasm with a median overall survival of 6–11 months according to the World Health Organization classification (Swerdlow et al, 2016). It is commonly associated with Epstein–Barr virus (EBV), as most patients have EBV infection (Liu et al, 2012; Swerdlow et al, 2016), but it was first reported as a human immunodeficiency virus (HIV)-related malignancy, affecting the oral cavity of an HIV-positive patient (Delecluse et al, 1997). Other reports showed that PBL could affect various extranodal sites of both HIV-positive and HIV-negative patients, including patients with compromised immune system due to treatment with immunosuppressive medication as well as elderly patients with immunosenescence and no other known immune deficiencies (Castillo et al, 2015; Liu et al, 2015). PBL in elderly, HIV-negative patients (PBL-E) has been commonly considered as a subgroup of PBL, described as a more indolent form with a good prognosis (Igawa et al, 2015). Although the pathogenesis of PBL is not completely understood, MYC gene rearrangements, which are typically found in Burkitt lymphoma and other aggressive lymphomas, such as diffuse large B-cell lymphoma, have been identified as an important factor. The MYC rearrangement, detected in approximately 50% of PBL cases (Castillo et al, 2015), is associated with an unfavourable outcome. We describe a case of a MYC rearranged PBL in an immunocompromised patient due to methotrexate therapy and active EBV infection, which completely regressed without anti-neoplastic treatment after stopping methotrexate treatment. A 69-year-old male was referred to our university hospital for workup of rapid deterioration and abdominal pains. Five years before, the patient was diagnosed with T4, N0, M0 gastric cancer that was treated with neoadjuvant chemotherapy, tumour excision and adjuvant chemotherapy (Al-Batran et al, 2017). Local tumour recurrence was excluded through an esophago-gastro-duodenoscopy 3 months before admission. He also suffered from rheumatoid arthritis, diagnosed 10 years earlier for which he receives treatment with methotrexate 10 mg subcutaneously once every week. Laboratory testing revealed elevated inflammatory markers, with leucocytosis of (22.6 × 109/l) and elevated C-reactive protein (98.3 mg/l). Laboratory results also showed acute kidney failure (creatinine 267 µmol/l), thrombocytopenia (88 × 109/l) and elevated lactate dehydrogenase (LDH; 2500 iu/l – 10×> upper limit of normal). Clinical examination identified a significantly enlarged spleen (4 cm below costal margin) with tenderness. A computed tomography (CT) scan of the thorax and abdomen showed no signs of loco-regional relapse or metastases of the gastric cancer but an enlarged spleen (14 × 9.5 cm) with multiple splenic infarctions. A bone marrow biopsy with aspiration was performed and histopathological evaluation showed diffuse 80% infiltration of large blasts positive for CD138, IgG and EBV positive and negative for CD3, CD20 and CD79a with displacement of haematopoiesis. EBV in situ hybridization demonstrated EBV/EBV-encoded small RNA positivity. The bone marrow smear (Fig 1A) showed approximately 60% infiltration of large cells with basophilic cytoplasm and a nuclear-cytoplasmic ratio of 3:1. Most cells displayed prominent nucleoli and a perinuclear halo reminiscent of plasma cell differentiation. Flow cytometry (Fig 1B) showed a CD38− and CD19-positive population with lambda light chain restriction, accounting for 12% of all events. Cytogenetics, performed by Münchner Leukämielabor GmbH (Munich, Germany) on the bone marrow aspiration showed t(8;14)(q24;q32) in 4 of 24 metaphases, and fluorescence in situ hybridisation showed signals typical for IGH-MYC rearrangement. Due to the association of PBL with HIV and EBV, we performed polymerase chain reactions, excluding HIV infection but detecting 2900 copies/ml of EBV DNA. Because of the poor overall condition, methotrexate was stopped and symptomatic therapy with antibiotics, intravenous fluids and analgesics were given, and the general condition of the patient improved rapidly within 10 days. Pain symptoms ceased, the kidney function recovered and the platelet count and LDH levels normalized. Considering the improving clinical status, we decided to refrain from anti-neoplastic therapy and followed a watch-and wait-strategy. Follow-up bone marrow biopsies were performed 2 and 6 weeks after the initial biopsy. Histological and morphological (Fig 2A) findings showed no evidence of PBL infiltration. The flow cytometric-characterized CD38 and CD19 positive population could not be found in the follow-up aspirations (Fig 2B) and the IGH-MYC rearrangement could no longer be detected. A positron-emission tomography/CT scan, performed 3 weeks after initial presentation, showed no areas of abnormally high glucose uptake. At last follow-up, 12 weeks after diagnosis of the PBL, the patient remained free of complaints, with unremarkable physical examination and normal laboratory results including blood counts and LDH. More than 50% of PBL cases show IGH-MYC rearrangements. So far, there have been very few cases describing spontaneous regression of PBL in the literature. These include HIV-positive patients under highly active antiretroviral therapy (HAART) (Armstrong et al, 2007), HIV-negative patients with no known immune deficiency and patients after reduction of immunosuppressive therapy (Garcia-Noblejas et al, 2013). To our knowledge, this is the first description of an EBV-associated PBL manifestation in the bone marrow with IGH-MYC rearrangement, that spontaneously regressed. Our patient presented multiple risk factors with long-term methotrexate treatment, rheumatoid arthritis, EBV reactivation, advanced age and previous anti-neoplastic treatment. Although the described PBL is related to immunosuppression, its clinical course lacks the aggressivity, fast progression and poor outcome that is typical for PBLs developing under immunosuppression. The detected IGH-MYC translocation is associated with aggressive behaviour in PBL and has been shown to be a negative prognostic factor in patients with PBL (Morscio et al, 2014). MYC is a proto-oncogene, first described in Burkitt lymphoma and its rearrangement and related dysregulation is an important factor in lymphomagenesis. Taking this into account, the spontaneous complete remission of an IGH-MYC-rearranged B-cell malignancy is quite unusual. In conclusion, we report a unique case of EBV-associated PBL with IGH-MYC rearrangement in an HIV-negative patient with immunosuppression due to methotrexate treatment, which, despite the generally bad prognosis, spontaneously regressed after stopping methotrexate treatment without further anti-neoplastic treatment. KY, GA and MB wrote the manuscript. StS, LT, DKM and JTB revised the manuscript. MB, JTB and LT provided bone marrow smear images and flow cytometry data. VL and MS provided clinical data. RMB provided histopathological data. The authors have no conflicts of interest to declare.