Cell of Origin - COO
According to the 2016 WHO classification, diagnosis of all cases of DLBCL, NOS should include COO, (GCB vs. ABC or non-GCB, if an IHC algorithm is used), because of their different molecular features, biologic behavior, prognosis and treatment.
The starting point in a discussion about prognostic variables in Diffuse Large B-cell lymphoma is the observation that some patients can be cured and others cannot. Several studies have investigated the biologic underpinnings for these different outcomes. A pioneering genetic evaluation of diffuse large B-cell lymphoma (DLBCL), published by Alizadeh and colleagues in 2000, showed 2 subtypes: germinal center and non–germinal center (also known as activated B-cell/ABC).
This distinction is important because better outcomes are seen in patients with the germinal-center subtype than with the non–germinal-center subtype. We therefore now have a “cell-of-origin” model showing that there are at least 2 genetic biologic types of DLBCL that might explain prognosis and could perhaps be targeted differently. This insight has led to recent trials that test new treatments in one genetic subtype vs the other. We are hopefully very close to understanding whether these 2 subtypes of DLBCL should be treated differently.[15]
The most challenging profile to detect in routine practice is “cell of origin.” The gold standard for identifying germinal-centre DLBCL vs. non–germinal-centre DLBCL was first defined as gene-expression profiling patterns in frozen tumor material. However, gene-expression profiling is not routinely available nor is it considered a standard test. The most common approach is immunohistochemistry using different algorithms, such as the Hans, Choi or Tally algorithms, [9, 10] to determine whether a lymphoma is germinal-centre DLBCL or non–germinal-centre DLBCL. Compared with the gold standard of gene expression profiling in frozen material, there is an error rate of approximately 20% with immunohistochemical algorithms shown below.
The present study has used the Hans/Choi Algorithms to determine the Cell of Origin.[9,10]
Double-expressor lymphoma
The presence of both the MYC and BCL2 rearrangements defines double-hit lymphoma (DHL). This phenotype is very proliferative and drug-resistant, and it is associated with a poor prognosis. Another variant of double-hit lymphoma is co-rearrangement of MYC and the BCL6 gene. Rarely, all 3 genes—BCL2, MYC, and BCL6—are simultaneously rearranged in a phenotype termed triple-hit lymphoma (THL). Both double-hit and triple-hit lymphomas have a poor prognosis with standard treatment.[6,7]
Immunohistochemical staining to identify protein expression of MYC also showed that there are lymphomas in which MYC and BCL2 genes are overexpressed at a protein level, without the genetic rearrangements. This profile has been referred to as the “double-expressor” phenotype in DLBCL in the revised 2016 World Health Organization (WHO) classification of lymphoid neoplasms. The WHO classification defines overexpression as greater than 40% c-MYC-expressing cells and greater than 50% BCL2-expressing cells by IHC. As shown in a study by Hu and colleagues, patients with double-expressor DLBCL have worse outcomes than patients in whom these proteins are not overexpressed; in general, only one-third of patients have long-term disease control with R-CHOP.[16]
Double-hit lymphoma is relatively uncommon, occurring in approximately 5% to 7% of patients with DLBCL. However Dual-expressor lymphomas may be present in as many as one-third of patients with DLBCL and serve to identify a significant subset of cases with a worse prognosis.
Patients who have the double-hit rearrangement usually have protein overexpression, and therefore have the double-expressor phenotype. However, the converse is not always true: dual-expressor protein overexpression is not always associated with an underlying double-hit rearrangement. Complicating the picture is that most double-hit lymphomas occur in the setting of a germinal-centre DLBCL, whereas most double-expressor lymphomas occur in non–germinal-centre DLBCL as demonstrated in this study which shows a strong correlation between the Double Expressor phenotype and the Non-GCB Cell of Origin subtype by IHC.
The double-hit lymphomas can be detected with fluorescence in situ hybridization (FISH) or standard cytogenetic analysis. The double-expressor lymphomas are diagnosed by immunohistochemistry.
The double-expresser phenotype was not given a unique category, but was recognized by the WHO as a poor prognostic sign within DLBCL.
When patients with aggressive B-cell lymphomas relapse or become refractory to therapy, standard options are limited. For patients unable to undergo transplant, or for those who relapse after a stem cell transplant, the median survival is approximately 6 months. Despite the many trials that have tried to improve upon this dismal statistic, there are no breakthroughs at this time. Chimeric antigen receptor (CAR) T-cell therapy is exciting. This treatment is still in the early phases of research and associated with toxicity, but it is promising for patients with aggressive B-cell lymphomas that do not respond to other therapies. There are also a number of new biologic and targeted agents that are promising, and finding which patients may respond to a particular treatment is a high priority.[17]