On March 10–12 2017, the EHA-SWG meeting on Rare Lymphomas took place in Barcelona, Spain, and was jointly chaired by Prof. Martin Dreyling, from Klinikum der Universität München, Germany, and Prof. Maire José Kersten, from the Academic Medical Center, Amsterdam, The Netherlands.
The talk began by explaining that immunodeficiency-related Lymphoproliferative Disorders (LPDs) make up a heterogeneous group; ranging from self-limiting hyperplasias to aggressive lymphomas. The WHO classification of immunodeficiency-related LPDs (2008 and 2016) is structured around 4 major categories, based on the immunodeficiency setting/background in which they arise: Post-Transplant Lymphoproliferative Disorders (PTLDs), lymphomas associated with Human Immunodeficiency Virus (HIV) infection, LPDs associated with primary immune disorders, and other iatrogenic immunodeficiency-associated LPDs.
It has been previously reported that immunosuppression for solid organ transplantation increases risk of LPD. Crane et al. (Oncotarget 2015) identified all PTLDs diagnosed over a 28-year time frame at their institution (total = 174 total, PCNS = 29) and all similar cases captured in the United Network for Organ Sharing-Organ Procurement and Transplant Network (UNOS-OPTN) data file.
- Between 1986 and 1997, no PCNS cases were diagnosed
- PCNS cases made up 37% of PTLDs diagnosed between 2011–2014
- PCNS disease was more frequently associated with renal vs other organ transplant, EBV, large B-cell morphology, and Mycophenolate Mofetil (MMF) when compared to PTLD that did not have CNS involvement
- Calcineurin inhibitors were protective against PCNS disease when given alone or in combination with MMF
- Multivariate analysis of UNOS-OPTN dataset found that MMF and lack of calcineurin inhibitor usage were independently associated with risk for development of PCNS PTLD
- These results carry significant implications for the transplant therapy, particularly in the introduction of new therapeutic strategies which lack calcineurin inhibitor usage
D. De Jong then went on to state that PCNSL bears similarities to ABC-DLBCL, such as:
- Recurrent mutations in MYD88 and CD79B
- Both frequently exhibit genomic instability and near-uniform, often biallelic, CDKN2A loss
- Rare TP53 mutations
- Both display near-uniform oncogenic Toll-Like Receptor (TLR) signaling due to MYD88 mutation and/or NFKBIZ amplification
- Frequent concurrent B-Cell Receptor (BCR) activation and deregulation of BCL6
- PCNSLs and PTLs often have 9p24.1/PD-L1/PD-L2 copy number alterations and additional translocations of these loci
However, PCNSL does differ from ABC-DLBCL by its overall genetic profile:
It was also explained that constitutive TLR and BCR signaling are major mechanisms of PCNSL: NFKBIZ gain on chromosome 3 occurs in 40–60% of cases and functional studies highlight NFKBIZ as a functional signaling mechanism. D. de Jong also went on to say that translocations in MYC and BCL2 are extremely rare in PCNSL. Translocations do occur with BCL6 in 17–47% of cases, pairing with Ig- and non-Ig partners. It was also stated that constitutive activation of PD-1 and PD-ligand signaling is a key mechanism of immune evasion in PCNSL.
Moreover, D. de Jong stated that loss of β2M and HLA-I are not specific to PCNSL. HLA expression is lost in >50% of PCNSL cases. Moreover, PCNSL-tumor-Ig have a restricted IgV-spectrum and recognize self-antigens expressed in glial cells. VH-mutation pattern reveals extensive signs of somatic hypermutation with signs of antigen selection.