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Diffuse large B-cell lymphoma

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Title: Diffuse large B-cell lymphoma  
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Diffuse large B-cell lymphoma

Diffuse large B cell lymphoma
Micrograph of a diffuse large B cell lymphoma. Field stain
Classification and external resources
Specialty Hematology and oncology
ICD-10 C83.3
ICD-O M9680/3
eMedicine article/202969
MeSH D016403

Diffuse large B-cell lymphoma (DLBCL or DLBL) is a cancer of B cells, a type of white blood cell responsible for producing antibodies. It is the most common type of non-Hodgkin lymphoma among adults,[1] with an annual incidence of 7–8 cases per 100,000 people per year.[2][3] This cancer occurs primarily in older individuals, with a median age of diagnosis at approximately 70 years of age,[3] though it can also occur in children and young adults in rare cases.[4] DLBCL is an aggressive tumour which can arise in virtually any part of the body,[5] and the first sign of this illness is typically the observation of a rapidly growing mass, sometimes associated with fever, weight loss, and night sweats.[6]

The causes of diffuse large B-cell lymphoma are not well understood. Usually DLBCL arises from normal B cells, but it can also represent a malignant transformation of other types of lymphoma or leukemia. An underlying immunodeficiency is a significant risk factor.[7] Infection with Epstein–Barr virus has also been found to contribute to the development of some subgroups of DLBCL.[8]

Diagnosis of DLBCL is made by removing a portion of the tumour through a biopsy, and then examining this tissue using a microscope. Usually a hematopathologist makes this diagnosis.[9] Several subtypes of DLBCL have been identified, each having a different clinical presentation and prognosis. However, the usual treatment for each of these is chemotherapy, often in combination with an antibody targeted at the tumour cells.[10] Through these treatments, more than half of patients with DLBCL can be cured,[11] and the overall five-year survival rate for older adults is around 58%.[12]


  • Classification 1
    • Morphology 1.1
    • Gene and microRNA expression 1.2
    • Immunohistochemistry 1.3
  • Signs and symptoms 2
  • Treatment 3
    • Chemotherapy 3.1
    • Radiation therapy 3.2
  • Prognosis 4
  • Research 5
  • Recent studies 6
    • Stage 1 6.1
    • Stage 2 6.2
    • Stage 3 6.3
    • Results 6.4
  • See also 7
  • References 8
  • Sources 9


Diffuse large B-cell lymphoma encompasses a biologically and clinically diverse set of diseases,[13] many of which cannot be separated from one another by well-defined and widely accepted criteria. The

  • Swerdlow, S.H.; Campo, E.; Jaffe, E.S.; et al., eds. (2008). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC.  
  • Goldman, Lee; Schafer, Andrew I. (2012). Goldman's Cecil Medicine (24th ed.).  
  • Turgeon, Mary Louise (2005). Clinical hematology: theory and procedures. Hagerstown, MD: Lippincott Williams & Wilkins.  


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  35. ^ Farber, Charles M.; Axelrod, Randy C. (2011). "The Clinical and Economic Value of Rituximab for the Treatment of Hematologic Malignancies". Contemporary Oncology 3 (1). 
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See also

HLA-B: The strongest association in the HLA region was with HLA-B, the SNP rs2523607 and allele HLA-B08: 01, with a very high value linkage. HLA-B encodes a heavy chain of HLA class I, that heterodimerizes with a light chain. The HLA class I has a central role in the presentation of self or foreign antigens, processed intracellularly, to cytotoxic T lymphocytes. HLA molecules of class I have been associated with many diseases and cancers of the immune system. The results suggest a possible association of other loci within the HLA region with this disease, but further study is needed to evaluate this possibility.

COA1: The SNP rs79480871 located in 2p13.3 as susceptibility locus was identified near NCOA1. It is a coactivator for steroid hormones, and the synthesized protein is involved in clathrin-mediated endocytosis. But the connection between the SNP and NCOA1 gene was not clear, because this polymorphism doesn't belong to the same haplotype, so a further study of this region is required.

PVT1: This study has linked two variants for 8q24.21 locus (rs13255292 and rs4736601). This region gives rise to an antisense RNA, involved in the activation of MYC. The proximity of PVT1 and MYC oncogene, which is known to be deregulated in some DLBCLs suggests that germline variation in this region may also contribute to the risk of developing the disease.

EXOC2: This gene is near to the locus rs116446171 located in the region 6p25.3, in the same haplotype. This gene encodes a protein that forms part of a large multiprotein complex responsible for vesicle trafficking and the maintenance. This protein plays an important role in the maintenance of epithelial cell polarity, cell motility, cytokinesis, proliferation and metastasis, which plays a crucial role in carcinogenic processes.

As a result of this study, five SNPs were obtained in four loci significantly associated with the disease, which may be related to the following genes: EXOC2, PVT1, NCOA1 and HLA-B.


In the last stage, replication studies and technical validation were performed. The genotyping of 8 SNPs de novo was performed in the most significant HLA loci outside the region and one within it.

Stage 3

At this stage the data of three independent previous GWAS, including two unpublished so far (GELA / EPIC and May) and one already published (USCF), with a total of 1,196 cases and 1,445 controls. The analysis was restricted to common SNPs on the basis of the 1000 Genomes Project version 3 because the data used were from different platforms. The criteria of quality control for these studies were adjusted to analyze all cases under the same conditions. In the meta-analysis of all SNPs of steps 1 and 2, 19 significant SNPs were identified, and 134 with a suggestive level of significance; 123 of the total were located in the HLA region on chromosome 6.

Stage 2

At this early stage, to study the genetic susceptibility, a GWAS with DLBCL cases and controls of European ancestry from 22 studies of non-Hodgkin lymphoma (NHL) was performed. To determine the subtype of NHL, hierarchical classification proposed by the single-nucleotide polymorphisms (SNP) that exceeded the quality criteria, genomic significance values, alignment and other statistical values.

Stage 1

– Phase replication: Stage 3.

– Discovery Phase: Stages 1 and 2.

James Cerhan and colleagues,[45] try to determine genetic susceptibility that exists for this cancer by meta-analysis of three genome-wide association studies (GWAS). For this, a total of 3,857 cases and 7,666 controls were analyzed. This study is divided into three stages, which can differentiate into two phases:[45]

James Cerhan and colleagues' study

Recent studies

One area of active research is on separating patients into groups based on their prognosis and how likely they are to benefit from different drugs. Methods like gene expression profiling and next-generation sequencing may result in more effective and more personalized treatment.[43][44]

A second regimen under evaluation is R-EPOCH (rituximab with etoposide-prednisone-vincristine-doxorubicin-cyclophosphamide), which demonstrated a 5-year progression-free survival (PFS) of 79% in a phase II trial. A phase III trial, CALGB 50303, is now comparing R-EPOCH with R-CHOP in patients with newly diagnosed DLBCL.[42]


For children with diffuse large B-cell lymphomas, most studies have found 5-year survival rates ranging from about 70% to more than 90%.[41]

The germinal center subtype has the best prognosis,[34] with 66.6% of treated patients surviving more than five years.[37] The IPI score is used in prognosis in clinical practice.[38] Lenalidomide has been recently shown to improve outcomes in the non-germinal center subtype.[39] Ratios of immune effectors such as CD4 and CD8 to immune checkpoints such as PD-L1 and M2 macrophages are independent of and additive to the cell of origin and IPI in DLBCL, and are applicable to paraffin-embedded biopsy specimens. These findings might have potential implications for selection of patients for checkpoint blockade and/or lenalidomide within clinical trials.[40]


Radiation therapy is often part of the treatment. It is commonly used after completing 3 cycles of treatment in limited stage disease. In extensive disease, radiation therapy can be used after 6-8 cycles of chemotherapy, to areas of bulky involvement. Radiation therapy alone is not an effective treatment for this disease.

Radiation therapy

Standard treatment is CHOP-R,[32] also referred to as R-CHOP, an improved form of CHOP with the addition of rituximab (Rituxan),[33] which has increased the rates of complete responses for DLBCL patients, particularly elderly patients.[34] R-CHOP is a combination of one monoclonal antibody, 3 chemotherapy drugs, and one steroid: rituximab (Rituxan), cyclophosphamide (Cytoxan), doxorubicin (Hydroxydaunorubicin), vincristine (Oncovin), and prednisone.[35] Chemotherapy is administered intravenously and is most effective when it is administered multiple times over a period of months (e.g. every 3 weeks, over 6 to 8 cycles). People often receive chemotherapy through a PICC line (peripherally inserted central catheter) in their arm near the elbow or a surgically implanted venous access port. The number of cycles of chemotherapy given depends on the stage of the disease. Patients with limited stage disease receive 3 cycles of therapy, while patients with extensive disease 6 or 8 cycles of chemotherapy. In the United States, 6 cycles is the preferred approach rather than 8 cycles. A new development is obtaining a PET scan after completing two cycles of chemotherapy, to help make further decisions after chemotherapy. Older people are not able to tolerate therapy well. Multiple lower intensity regimens have been attempted in this age group.[36]



The most typical symptom at the time of diagnosis is a mass that is rapidly enlarging and located in a part of the body with multiple lymph nodes.[31]

Signs and symptoms

With the apparent success of gene expression profiling in separating biologically distinct cases of DLBCL, NOS, some researchers examined whether a similar distinction could be made using immunohistochemical staining (IHC), a widely used method for characterizing tissue samples. This technique uses highly specific antibody-based stains to detect proteins on a microscope slide, and since microarrays are not widely available for routine clinical use, IHC is a desirable alternative.[26][27] Many of these studies focused on stains against the products of prognostically significant genes which had been implicated in DLBCL gene expression studies. Examples of such genes include BCL2, BCL6, MUM1, LMO2, MYC, and p21. Several algorithms for separating DLBCL cases by IHC arose out of this research, categorizing tissue samples into groups most commonly known as GCB and non-GCB.[27][28][29][30] The correlation between these GCB/non-GCB immunohistochemical groupings and the GCB/ABC groupings used in gene expression profiling studies is uncertain,[21][29] as is their prognostic value.[21] This uncertainty may arise in part due to poor inter-rater reliability in performing common immunohistochemical stains.[26]


Recently, it was described that short non-coding RNAs named microRNAs (miRNAs) have important functions in lymphoma biology. In malignant B cells miRNAs participate in pathways fundamental to B cell development like B cell receptor (BCR) signalling, B cell migration/adhesion, cell-cell interactions in immune niches, and the production and class-switching of immunoglobulins.[25] MiRNAs influence B cell maturation, generation of pre-, marginal zone, follicular, B1, plasma and memory B cells.[25]

Another notable finding of recent gene expression studies is the importance of the cells and microscopic structures interspersed between the malignant B cells within the DLBCL tumor, an area commonly known as the tumour microenvironment. The presence of gene expression signatures commonly associated with macrophages, T cells, and remodelling of the extracellular matrix seems to be associated with an improved prognosis and better overall survival.[22][24] Alternatively, expression of genes coding for pro-angiogenic factors is correlated with poorer survival.[22]

Gene expression profiling studies have also attempted to distinguish heterogeneous groups of DLBCL from each other. These studies examine thousands of genes simultaneously using a DNA microarray, looking for patterns which may help in grouping cases of DLBCL. Many studies now suggest that cases of DLBCL, NOS can be separated into two groups on the basis of their gene expression profiles; these groups are known as germinal center B-cell-like (GCB) and activated B-cell-like (ABC).[13][18][19][20] Tumour cells in the germinal center B-cell-like subgroup resemble normal B cells in the germinal center closely, and are generally associated with a favourable prognosis.[21][22] Activated B-cell-like tumour cells are associated with a poorer prognosis,[22] and derive their name from studies which show the continuous activation of certain pathways normally activated when B cells interact with an antigen. The NF-κB pathway, which is normally involved in transforming B cells into plasma cells, is an important example of one such pathway.[23]

Gene and microRNA expression

The third morphologic variant, anaplastic, consists of tumour cells which appear very differently from their normal B cell counterparts. The cells are generally very large with a round, oval, or polygonal shape and pleomorphic nuclei, and may resemble Hodgkin cells or Reed-Sternberg cells.

Immunoblasts have significant basophilic cytoplasm and a central nucleolus. A tumour can be classified as immunoblastic if greater than 90% of its cells are immunoblasts.[16] This distinction can be problematic, however, because hematopathologists reviewing the microscope slides may often disagree on whether a collection of cells is best characterized as centroblasts or immunoblasts.[17] Such disagreement indicates poor inter-rater reliability.

Within cellular morphology three variants are most commonly seen: centroblastic, immunoblastic, and anaplastic. Most cases of DLBCL are centroblastic, having the appearance of medium-to-large-sized lymphocytes with scanty cytoplasm. Oval or round nuclei containing fine chromatin are prominently visible, having two to four nucleoli within each nucleus. Sometimes the tumour may be monomorphic, composed almost entirely of centroblasts. However, most cases are polymorphic, with a mixture of centroblastic and immunoblastic cells.[16]


When a case of DLBCL does not conform to any of the well-defined subtypes, and is also not considered unclassifiable, then it is classified as “diffuse large B-cell lymphoma, not otherwise specified” (DLBCL, NOS). The majority of DLBCL cases fall into this category. Much research has been devoted to separating this still-heterogeneous group; such distinctions are usually made along lines of cellular morphology, gene expression, and immunohistochemical properties.

In some cases, a tumour may share many features with both DLBCL and Burkitt's lymphoma. In these situations, the tumour is classified as simply “B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma”. A similar situation can arise between DLBCL and Hodgkin's lymphoma; the tumour is then classified as “B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Hodgkin’s lymphoma”.

[15].mediastinal lymph nodes or thymus", which arises within the Primary mediastinal (thymic) large B cell lymphoma), and whether the patient has certain other illnesses related to DLBCL. One of these well-defined groupings of particular note is "T cells each of which can be differentiated based on the location of the tumour, the presence of other cells within the tumour (such as [14]

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