Non-Hodgkin’s Lymphoma Causes and Pathology

Most NHL cancers are associated with chromosomal abnormalities, originating within a single cell, with subsequent cells carrying the identical variation.³ As such, lymphomas arise at different stages of B-cell differentiation (Figure 1). Application of gene expression profiling helps to distinguish between histologically indistinguishable molecular subtypes. For instance, using DNA microarrays, one can distinguish between activated B-cell-like DLBCL, germinal center (GC) DLBCL, and primary mediastinal B-cell lymphomas, allowing for the selection of different treatments for each lymphoma type.² In case of follicular lymphoma (FL), around 90% of patients have t(14;18) translocation which is the initiating event in the pathogenesis, resulting in deregulated expression of BCL2.⁵ Development of FL requires secondary genetic alterations and measuring the gene expression of the two microenvironmental signatures, lymphoma and normal immune cells, or immune-response 1 and immune-response 2, can be used to predict diagnosis.² In the case of mantle cell lymphomas, deregulation of cell cycle control and DNA damage is responsible for the pathogenesis.²

Figure 1: Simplified scheme of pathogenesis of B-cell Non-Hodgkin’s Lymphomas arising from non-malignant lymphoid tissue²

A summary of non-Hodgkin’s lymphoma causes and the pathology of the various recurrent genomic and molecular biomarkers that are involved in B-cell lymphomas like DLBCL is presented in Figure 2.¹ There is data in the literature on the prognostic effects of various genetic abnormalities in proteins including MYC, BCL2, BCL6, TP53, etc. Specific biomarkers are also expressed at each stage of B-cell development and differentiation, and these have been used to develop unique anti-CD antibodies for the treatment of specific lymphomas. For example, expression of CD20 is largely restricted to B-cells, to certain stages of B-cell development (CD20 is not expressed by a pro-B cell, differentiated plasmablasts, or plasma cells), and is detected in approximately 95% of all B-cell malignancies.4 This makes it a good target for cancer immunotherapy, and currently, there are several anti-CD20 drugs such as rituximab, obinutuzumab, and ofatumumab to treat NHL cancers. Table 1 outlines various microenvironment-related non-Hodgkin’s lymphoma and pathology biomarkers in lymphoma prognosis that can be used to predict the clinical outcome of patients.

Figure 2: Diagnostic and prognostic biomarkers for lymphoma diagnosis and treatment¹

Table 1: Microenvironment-related biomarkers for lymphoma prognosis¹

Biomarkers	Location of expression	Lymphomas involved	Approach	Prognosis
CD117	Mast cells	cHL, DLBCL	IHC	Poor prognosis in cHL; favorable prognosis in DLBCL
Granzyme B	Cytotoxic T-cells	cHL and ALCL	IHC	Unfavorable prognosis
CD68/CD163	Macrophages	cHL, FL, DLBCL	IHC	Poor prognosis in cHL and FL favorable outcome in DLBCL treated with chemo
FOXP3	Treg cells	HL, FL, NKTCL	IHC	Favorable outcome in NKTCL, controversial in DLBCL
PD-1	Tumor infiltrating cells	HL, FL, DLBCL	IHC	Controversial
CD21	Follicular dendritic cells	cHL	IHC	Unfavorable outcome
EBV	Tumor cells	cHL and DLBCL	ISH	Controversial
CD8B1, CD3D, CTSL, CD26, and SH2D1A	Cytotoxic T-cells	Cytotoxic T-cells	GEP	Sustain aggressive phenotype
ITGAV, FoxC1, and CX3CR1	Stroma	DLBCL	GEP	Sustain aggressive phenotype
STAT1 and ALDH1A1	Macrophages	cHL	GEP and IHC	Constitutional symptoms, relapse, adverse outcomes
LY2 and STAT1	Tissue monocytes and activated macrophages	cHL	RT-PCR	Favorable outcome
Fibronectin, MMP9, SPARC, and CTGF	Extracellular matrix and monocytes	DLBCL	IHC and GEP	Favorable outcome
KDR, SPARCL1, CXCL12, CD34, and CD31	Endothelial cells and angio-related components	DLBCL	IHC and GEP	Adverse outcome

ALCL, anaplastic large cell lymphoma; cHL, classic Hodgkin lymphoma; DLBCL, diffuse large B-cell lymphoma;
IHC, immunohistochemistry; EBV, Epstein-Barr virus; FL, follicular lymphoma; FOXP3, forkhead box protein 3;
GEP, gene expression profile; HL, Hodgkin’s lymphoma; ISH, in situ hybridization; NKTCL, natural killer/T-cell lymphoma;
PD1, programmed cell death 1; RT-RCR, PCR with reverse transcription.

References

Sun R, Medeiros LJ, Young KH. Diagnostic and predictive markers for lymphoma diagnosis and treatment in the era of precision medicine. Mod Pathol. 2016;29:1118-1142. https://doi.org/10.1038/modpathol.2016.92
Nogai H, Dörken B, and Lenz G. Pathogenesis of non-Hodgkin’s lymphoma. J Clin Oncol. 2011;29:1803-1811. https://doi.org/10.1200/JCO.2010.33.3252
Fisher RI and Oken MM. Clinical Practice guidelines: Non-Hodgkin’s lymphomas. Cleve Clin J Med. 1995;62(suppl 1):SI-6–SI-42. https://www.ccjm.org/content/ccjom/62/1_suppl_1/SI-6.full.pdf
Forsthuber TG, Cimbora DM, Ratchford JN, Katz E, Stüve O. B cell-based therapies in CNS autoimmunity: Differentiating CD19 and CD20 as therapeutic targets. Ther Adv Neurol Disord. 2018;11:1756286418761697. https://doi.org/10.1177/1756286418761697
National Comprehensive Cancer Network^®. NCCN Clinical Practice Guidelines in Oncology. B-Cell Lymphomas. Version 5.2022. July 12, 2022. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf