MYC status in HIV‐associated plasmablastic lymphoma: dual‐colour CISH, FISH and immunohistochemistry

Abstract

Aims We utilised chromogenic and fluorescence in‐situ hybridisation (CISH and FISH) to evaluate MYC gene copy numbers and rearrangements within HIV‐associated plasmablastic lymphomas (PBLs). Thereafter, clinicopathological features were explored retrospectively. Methods and results Sixty‐seven (n = 67) patients were included and the HIV seropositive status was confirmed in 98% (63 of 64) with a median viral load of 55 587 (IQR 273 582) copies/ml and median CD4 count of 170 (IQR 249) cells/µl. The mean age was 41 ± 10.1 years and females comprised 54%. PBL was documented predominantly at extra‐oronasal topographic regions. Starry‐sky (SS) appearance was evident in 33% in association with monomorphic morphology (P‐value 0.02). c‐MYC protein was expressed in 81% and latent EBV infection was detected in 90%. EBER ISH‐positive status and MYC rearrangement occurred in 67% of HIV PBL. MYC aberrations included MYC rearrangement (70%), low‐level increase in MYC gene copy numbers (43%), concurrent MYC rearrangement and increased MYC gene copy numbers (49%) as well as low‐level chromosome 8 polysomy (6%). MYC aberrations in HIV PBLs were significantly associated with SS appearance (P ‐0.01), monomorphic morphology (P ‐ 0.03), c‐MYC protein expression ≥40% (P ‐ 0.03) and mortality (P ‐ 0.03). There was advanced stage (Ann Arbor III/IV) at presentation (77%) and the median overall survival for HIV PBL was 75 days (95% CI 14–136). Conclusion Majority of the HIV‐associated PBL tumours harbour MYC aberrations. Due to the persistently inferior survival outcome of HIV‐associated PBL in the era of antiviral treatment, targeted and/or intensified therapy of oncogenic MYC may need to be explored in future.

Plasmablastic lymphoma: An update

“…Up to 70% of PBL cases show MYC protein overexpression due to MYC translocations or amplifications (Figure 2). 4 A higher proportion (up to 87%) of MYC rearrangements in PBL have been reported in a separate study 9 . MYC usually translocates to immunoglobulin genes, particularly the immunoglobin heavy chain (IgH) gene on chromosome 14q32 5 .…”

EBV-Driven Lymphoproliferative Disorders and Lymphomas of the Gastrointestinal Tract: A Spectrum of Entities with a Common Denominator (Part 2)

“…PBL is predominantly an extra-nodal disease, with a predilection for the oral cavity in HIV-positive individuals, with the GIT being the second most common site. Other extra-nodal sites such as the skin, bone, genitourinary tract, sino-nasal tract, central nervous system (CNS), liver, lung and orbits are more rarely reported [ 8 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ].…”

“…MYC amplification and deletion are also detected in 11% and 4% of PBL cases, respectively [ 49 ]. MYC rearrangement usually occurs in association with a positive EBER status, CD10 expression and PRDM1 gene mutation and in the absence of mutations in the MYC promoter region [ 37 , 49 , 50 ]. Mutations in the PRDM1 gene, encoding for the BLIMP1 protein often expressed by PBL, has been found in some cases, and it acts as an MYC regulator [ 51 ].…”

“…Further possible therapeutic options include target therapy with the anti-CD30 Brentuximab Vedotin, immunomodulatory drugs such as Bortezomib and Lenalidomide, and autologous hematopoietic stem cell transplantation (auto-HSCT) [ 49 , 54 , 55 , 56 , 57 ]. In HIV-positive patients, a combination of highly active anti-retroviral therapy (HAART) and chemotherapy is used [ 50 ]. The majority of HIV-associated PBL harbor MYC abnormalities; therefore, targeted therapies of oncogenic MYC are considered a potential treatment worthy of evaluation [ 50 ].…”

“…In HIV-positive patients, a combination of highly active anti-retroviral therapy (HAART) and chemotherapy is used [ 50 ]. The majority of HIV-associated PBL harbor MYC abnormalities; therefore, targeted therapies of oncogenic MYC are considered a potential treatment worthy of evaluation [ 50 ]. Both EBV-positive and EBV-negative PBLs show high levels of immune checkpoint protein (PD-1 and PD-L1) expression by the tumor cells and the macrophages of the microenvironment.…”