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 an experienced 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 overall survival for older adults at five years is around 58%.[12]

Classification

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

In some cases, a tumour may share many features with both DLBCL and Burkitt 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”.

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.

Morphology

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]

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.

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.

Gene and microRNA expression

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 centre B-cell-like (GCB) and activated B-cell-like (ABC).[13][18][19][20] Tumour cells in the germinal centre B-cell-like subgroup resemble normal B cells in the germinal centre 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]

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]

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]

Immunohistochemistry

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]

Signs and symptoms

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]

Treatment

Chemotherapy

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). 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

Older people are not able to tolerate therapy well. Muliple lower intensity regimens have been attempted in this age group.[36]

People receiving chemotherapy commonly have a PICC line (Peripherally inserted central catheter) in their arm near the elbow or a surgically implanted port.

Radiation therapy

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

Prognosis

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]

For children with diffuse large B-cell lymphomas, most studies have found 5-year survival rates ranging from about 70% to more than 90%.[40]

Research

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.[41]

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.[42][43]

Recent studies

James Cerhan and colleagues' study

James Cerhan and colleagues,[44] 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: [44]

– Discovery Phase: Stages 1 and 2.

– Phase replication: Stage 3.

Stage 1

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 World Health Organization (WHO) was used. All cases of DLBCL with enough DNA and a subset of controls, matched for age and sex, along with 4% duplicates were genotyped. They were selected in this stage 611.844 SNPs that exceeded the quality criteria, genomic significance values, alignment and other statistical values.

Stage 2

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 3

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.

Results

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.

– 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.

– 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.

– NCOA1: 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.

– 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.

See also

References

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  19. ↑ Rosenwald, Andreas; Wright, George; Chan, Wing C.; Connors, Joseph M.; Campo, Elias; Fisher, Richard I.; Gascoyne, Randy D.; Muller-Hermelink, H. Konrad; Smeland, Erlend B.; Giltnane, Jena M.; Hurt, Elaine M.; Zhao, Hong; Averett, Lauren; Yang, Liming; Wilson, Wyndham H.; Jaffe, Elaine S.; Simon, Richard; Klausner, Richard D.; Powell, John; Duffey, Patricia L.; Longo, Dan L.; Greiner, Timothy C.; Weisenburger, Dennis D.; Sanger, Warren G.; Dave, Bhavana J.; Lynch, James C.; Vose, Julie; Armitage, James O.; Montserrat, Emilio et al. (2002). "The Use of Molecular Profiling to Predict Survival after Chemotherapy for Diffuse Large-B-Cell Lymphoma". New England Journal of Medicine 346 (25): 1937–47. doi:10.1056/NEJMoa012914. PMID 12075054.
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  34. ↑ 34.0 34.1 Turgeon 2005, pp. 285–6.
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  36. ↑ Zaja, F.; Tomadini, V.; Zaccaria, A.; Lenoci, M.; Battista, M.; Molinari, A. L.; Fabbri, A.; Battista, R.; Cabras, M. G.; Gallamini, A.; Fanin, R. (2006). "CHOP-rituximab with pegylated liposomal doxorubicin for the treatment of elderly patients with diffuse large B-cell lymphoma". Leukemia & Lymphoma 47 (10): 2174–80. doi:10.1080/10428190600799946. PMID 17071492.
  37. ↑ http://abstract.asco.org/AbstView_114_99225.html[][]
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  39. ↑ Nowakowski, G. S.; Laplant, B.; Macon, W. R.; Reeder, C. B.; Foran, J. M.; Nelson, G. D.; Thompson, C. A.; Rivera, C. E.; Inwards, D. J.; Micallef, I. N.; Johnston, P. B.; Porrata, L. F.; Ansell, S. M.; Gascoyne, R. D.; Habermann, T. M.; Witzig, T. E. (2014). "Lenalidomide Combined with R-CHOP Overcomes Negative Prognostic Impact of Non-Germinal Center B-Cell Phenotype in Newly Diagnosed Diffuse Large B-Cell Lymphoma: A Phase II Study". Journal of Clinical Oncology 33 (3): 251–7. doi:10.1200/JCO.2014.55.5714. PMID 25135992.
  40. ↑ http://www.cancer.org/Cancer/Non-HodgkinLymphomainChildren/OverviewGuide/non-hodgkin-lymphoma-in-children-overview-survival-rates[]
  41. ↑ http://www.onclive.com/publications/oncology-live/2012/april-2012/Beyond-R-CHOP-21-Whats-New-in-Diffuse-Large-B-Cell-Lymphoma[]
  42. ↑ Sehn, L. H. (2012). "Paramount prognostic factors that guide therapeutic strategies in diffuse large B-cell lymphoma". Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program 2012: 402–9. doi:10.1182/asheducation-2012.1.402 (inactive 2015-04-11). PMID 23233611.
  43. ↑ Barton, S.; Hawkes, E. A.; Wotherspoon, A.; Cunningham, D. (2012). "Are We Ready to Stratify Treatment for Diffuse Large B-Cell Lymphoma Using Molecular Hallmarks?". The Oncologist 17 (12): 1562–73. doi:10.1634/theoncologist.2012-0218. PMC 3528389. PMID 23086691.
  44. ↑ 44.0 44.1 Cerhan, James R; Berndt, Sonja I; Vijai, Joseph; Ghesquières, Hervé; McKay, James; Wang, Sophia S; Wang, Zhaoming; Yeager, Meredith; Conde, Lucia; De Bakker, Paul I W; Nieters, Alexandra; Cox, David; Burdett, Laurie; Monnereau, Alain; Flowers, Christopher R; De Roos, Anneclaire J; Brooks-Wilson, Angela R; Lan, Qing; Severi, Gianluca; Melbye, Mads; Gu, Jian; Jackson, Rebecca D; Kane, Eleanor; Teras, Lauren R; Purdue, Mark P; Vajdic, Claire M; Spinelli, John J; Giles, Graham G; Albanes, Demetrius et al. (2014). "Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma". Nature Genetics 46 (11): 1233–8. doi:10.1038/ng.3105. PMC 4213349. PMID 25261932.
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