What Is Dark Zone Lymphoma, and Is It Clinically Relevant?
Dark zone lymphoma includes aggressive B-cell lymphomas with shared molecular features. While some respond to escalated treatment, others remain resistant, highlighting the need for targeted approaches to improve outcomes.
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DARK ZONE LYMPHOMA is an umbrella term that encompasses a range of aggressive B-cell lymphomas that share characteristic features with B cells from the dark zone of the germinal center. Although identified by gene expression profiling, approximately half of this group consists of established lymphoma entities that are routinely identified in clinical practice (ie, Burkitt lymphoma [BL] and high-grade B-cell lymphoma with MYC and BCL2 rearrangements [HGBCL-DH-BCL2]), with these patients receiving escalated treatment in many centers. The remaining half of dark zone lymphomas have poor outcomes following standard frontline therapy and require gene expression profiling for identification because they are not currently detected with routine diagnostic tools.
Relating malignant lymphomas to their putative “cell of origin” has formed a fundamental basis of lymphoma classification. The concept of dark zone lymphomas represents a refinement of this framework to identify a subset of tumors that share features common to dark zone B cells.
The dark zone of the germinal center is formed by densely packed B cells that rapidly proliferate and modify their B-cell receptor before transiting to the light zone to test their newly formed antigen-binding capabilities. This testing occurs through interactions with follicular dendritic and T helper cells, which instruct B cells to differentiate and exit the germinal center or recycle to the dark zone to undergo further rounds of proliferation and B-cell receptor tuning, whereas cells failing to receive appropriate signals undergo cell death. As a result of the different functions associated with the dark and light zones, different cellular programs are active in each. Although light zone B cells are dependent on cell-cell interactions for survival, dark zone B cells rely on activation of key pathways to promote limited cycles of independent cell proliferation and survival prior to light zone reentry. In dark zone lymphomas, these pathways are hijacked to sustain autonomous proliferation.
The first molecular link between aggressive B-cell lymphomas and dark zone germinal center B cells was established when a gene signature for BL was found to share significant overlap with genes that are more highly expressed in dark zone B cells vs light zone B cells.1-3 This link was further solidified when a gene signature expressed by HGBCL-DH-BCL2 was similarly shown to share strong overlap with both the BL and dark zone B-cell signatures.4,5 This signature was initially called the “double-hit signature” but was renamed the dark zone signature (DZsig) to reflect how both HGBCL-DH-BCL2– and BL-derived signatures converge on a dark zone–like state. DZsig expression extends beyond these groups to include approximately 10% of diffuse large B-cell lymphomas (DLBCLs) and approximately 50% of HGBCLs, not otherwise specified.
Clinically, dark zone lymphomas share several characteristics, including a higher proportion of advanced-stage disease, bone marrow involvement, and elevated lactate dehydrogenase. They also have a higher incidence of central nervous system (CNS) involvement at diagnosis and a higher risk of CNS relapse, particularly in the BL group. Dark zone lymphomas with DLBCL morphology have poor outcomes following treatment with standard R-CHOP immunochemotherapy (ie, rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone), whether they are HGBCL-DH-BCL2 or not. Although treatment escalation has been shown to improve outcomes in BL and HGBCL-DH-BCL2, it is uncertain how best to overcome the poor prognosis of the remaining dark zone lymphomas. Although there is diversity among dark zone lymphomas, highlighted by specific clinical features inherent to BL (eg, tumor lysis syndrome), we believe targeting the shared molecular vulnerabilities across the broader group is a pathway to improving patient outcomes.
REFERENCES
Victora GD, Dominguez-Sola D, Holmes AB, Deroubaix S, Dalla-Favera R, Nussenzweig MC. Identification of human germinal center light and dark zone cells and their relationship to human B-cell lymphomas. Blood. 2012;120(11):2240-2248. doi:10.1182/blood-2012-03-415380
Hummel M, Bentink S, Berger H, et al. A biologic definition of Burkitt’s lymphoma from transcriptional and genomic profiling. N Engl J Med. 2006;354(23):2419-2430. doi:10.1056/NEJMoa055351
Dave SS, Fu K, Wright GW, et al. Molecular diagnosis of Burkitt’s lymphoma. N Engl J Med. 2006;354(23):2431-2442. doi:10.1056/NEJMoa055759
Ennishi D, Jiang A, Boyle M, et al. Double-hit gene expression signature defines a distinct subgroup of germinal center B-cell-like diffuse large B-cell lymphoma. J Clin Oncol. 2019;37(3):190-201. doi:10.1200/JCO.18.01583
Alduaij W, Collinge B, Ben-Neriah S, et al. Molecular determinants of clinical outcomes in a real-world diffuse large B-cell lymphoma population. Blood. 2023;141(20):2493-2507. doi:10.1182/blood.2022018248
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