B-cell lymphoma (BCL) is a lymphoid neoplasm originating from precursor cells or mature B-lymphocytes. Accordingly, tumor cells differ with regards to their genotypic and phenotypic features. Patients may suffer from indolent or aggressive variants of BCL, and therapies should be tailored to patient characteristics and the individual course of the disease.
The clinical presentation of BCL varies largely, with the majority of patients remaining asymptomatic for prolonged periods of time. Constitutional symptoms like fever, night sweats, and weight loss are frequently reported, but the growth of solid tumors at nodal and extranodal sites may be observed as well. Lymph node involvement is usually painless and may be diagnosed incidentally; space-occupying masses developing at extranodal sites may induce a broad spectrum of symptoms depending on their interference with the function of the affected organ and neighboring tissues. This spectrum ranges from chest pain and dyspnea to loss of appetite, early satiety, and vomiting, to bone pain - metastases may form anywhere .
Clinical findings may support a tentative diagnosis of lymphoma, but don't allow for its recognition as a B-lymphoid neoplasm. Furthermore, morphological, immunophenotypic, and possibly genetic features have to be evaluated to identify the specific type of BCL. Thus, tissue samples have to be obtained by means of biopsy.
With regard to the immunophenotype of tumor cells, their belonging to the B-cell lineage may be confirmed if they express markers like CD5, CD10, CD19, CD20, CD21, CD23, CD30, CD79, and PAX5. Few of these markers are truly specific for B lymphocytes, so entire gene expression profiles should be evaluated. Gene expression profiles may be unique to certain types of BCL, thereby becoming the basis of diagnosis. The presence of chromosomal or gene aberrations, such as t(11;14) or t(14;18), partial deletions of chromosomes 6, 10, 11, 13, and 17, and duplications of chromosome 1, should be assessed because they may support the diagnosis, be of prognostic value, and be used for monitoring the patient's response to therapy.
The diagnosis of BCL should be followed by a thorough staging procedure. Diagnostic imaging, namely positron emission tomography with fluorodeoxyglucose, plays a key role in BCL staging before and after the initiation of therapy. Bone marrow biopsies are usually indicated to check for bone marrow involvement, but experts may choose to forego this procedure if the likelihood of bone marrow infiltration is low. So far, no consensus could be reached to this end: Studies on the sensitivity of positron emission tomography and bone marrow biopsy for the detection of bone marrow involvement yielded contradictory results. The best approach to staging may be to consider them as complementary methods .
Aggressive BCL is generally treated with cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab (R-CHOP). Irradiation has long since been considered a valuable alternative in case of localized disease only, but recent findings suggest that patients suffering from advanced-stage bulky disease may also benefit from external beam radiation therapy. These individuals should possibly be offered a combined regimen based on R-CHOP and radiotherapy to bulky sites . If an indolent BCL is diagnosed in an asymptomatic patient, watchful waiting is sometimes preferred over aggressive treatment. A therapy should be initiated, though, as soon as the disease becomes symptomatic.
Much effort has been invested in the development of specific treatments, and molecular-targeted therapies are slowly gaining importance in the management of BCL. B-cell receptor signaling is the main target of such therapies and is suppressed by Bruton tyrosine kinase inhibitors like ibrutinib . In Europe and North America, ibrutinib received approval for the treatment of chronic lymphocytic leukemia, mantle cell lymphoma, and lymphoplasmacytic lymphoma. Additional compounds are currently under trial  . To date, the results of the genetic characterization of tumor cells rarely affect treatment decisions. Personalized therapies are already offered to patients suffering from chronic lymphocytic leukemia if mutations of the TP53 gene or del17p involving TP53 are detected. These render the tumor cells refractory to conventional chemotherapy and require the use of ibrutinib or idelalisib with an anti-CD20 monoclonal antibody like rituximab .
Autologous or allogeneic hematopoietic stem cell transplantation may be considered in case of high-risk, relapsed, or refractory BCL. These procedures are associated with significant morbidity and mortality, however, and have not consistently been proven to prolong disease-free or overall survival . Patients who undergo autologous stem cell transplantation are at increased risks of relapse, whereas allogeneic stem cell transplantation offers a chance for cure at the cost of possible non-relapse mortality .
With regard to the course of the disease, indolent BCL may be distinguished from aggressive B-lymphoid neoplasms. Those diagnosed with indolent BCL have a more favorable prognosis, although conventional chemotherapy is not curative of the disease. Patients are likely to live for more than a decade but should be informed about the likelihood of relapses and the probability of a successive shortening of the mean duration of their response to therapies . By contrast, relative five-year survival rates of approximately 50% have been reported for patients suffering from aggressive BCL  . It should be noted that indolent neoplasms may transform into aggressive BCL, even though the causes of transformation remain elusive .
Distinct types of BCL are likely to develop under different circumstances that facilitate the uncontrolled proliferation of precursor or mature lymphoid cells. For the majority of BCL, these circumstances have yet to be defined. Single entities, however, could already be associated with specific causes: The endemic variant of Burkitt lymphoma, for instance, has been related to infections with the Epstein-Barr virus and chronic malaria . Both the Epstein-Barr virus and Plasmodium spp. are known to cause B cell hyperplasia, which may pave the way towards a stepwise dysregulation of the immune system and lymphomagenesis. Furthermore, immunodeficiency due to an infection with the human immunodeficiency virus predisposes to the development of Burkitt lymphoma and other high‐grade, monoclonal B‐cell neoplasms . Iatrogenically induced immunosuppression is another risk factor for BCL. In this context, high doses of azathioprine have been shown to increase the risk for early and late non-Hodgkin lymphoma . Considering these data, immune system dysregulation has been hypothesized to be an essential component of BCL development in otherwise healthy individuals, too .
The causes of BCL development in those patients who don't belong to any of the aforementioned risk groups - malaria, viral disease, immunosuppressive therapy - are the focus of intense research. Besides viruses and parasites, bacteria have been implicated in lymphomagenesis. Helicobacter pylori can be isolated from >90% of patients with gastric MALT lymphoma, and Chlamydophila psittaci has been related to ocular adnexal MALT lymphoma. Furthermore, a predisposition to BCL has been described for patients suffering from autoimmune diseases like Sjögren's syndrome and systemic lupus erythematosus .
BCL are the most common hematopoietic cancers in the developed world . They account for at least 85% of non-Hodgkin lymphomas, whose incidence has been estimated to be 23 and 16 per 100,000 male and female inhabitants, respectively  . A patient's individual risk of developing BCL increases with age, but there are certain types of BCL that are more frequently diagnosed in the young: Primary mediastinal B-cell lymphoma, a subtype of diffuse large B-cell lymphoma, preferentially affects women in their fourth decade of life, and the endemic variant of Burkitt lymphoma is typically diagnosed in patients aged <10 years.
Although a variety of pathogens has been implicated in the pathogenesis of BCL, tumor cells don't usually express B-cell receptors that recognize the antigens of these agents. It thus seems likely that chronic antigenic stimulation contributes to lymphomagenesis by creating a pro-inflammatory microenvironment that favors the proliferation of B cells . It remains to be clarified whether antigenic stimulation precedes the malignant degeneration of B lymphocytes, or whether it facilitates the proliferation of clones that previously acquired cancerogenic mutations.
During lymphomagenesis, B cells accumulate a variety of chromosomal and gene abnormalities that may affect their response to DNA damage and the induction of apoptosis, B-cell receptor, T-cell receptor, and NF-κB signaling, NOTCH signaling, MAPK signaling, chromatin modulation, and epigenetic modification . Chromosomal translocations involving one of the immunoglobulin loci and a proto-oncogene are particularly common. It is unclear whether they constitute the initiating event, but they are known to put the proto-oncogene under the control of the active immunoglobulin locus. The physiological process of somatic hypermutation may significantly contribute to the acquisition of these anomalies .
Additional aberrations that are highly recurrent in BCL involve tumor suppressor TP53 and the MYD88 gene. Mutations of the TP53 gene are detected in about one-fourth of cases of diffuse large B-cell lymphoma, which is the most common type of BCL. TP53 mutations are associated with resistance to chemotherapy and poor survival, and altered growth kinetics have been hypothesized to underly this unfavorable outcome . Mutations of the MYD88 gene have been shown to induce rapid B-cell division .
Few recommendations can be given to prevent the development of BCL. The incidence of BCL with an infectious genesis may be reduced by taking measures against the spread of the etiological agents of the underlying diseases. Similarly, BCL related to immunosuppression may be prevented by avoiding the transmission of the human immunodeficiency virus. Immunosuppressive therapy should be administered in doses as high as necessary, but as low as possible.
According to the current classification of the World Health Organization, there are three major groups of lymphoma, namely B-cell, T-cell, and Hodgkin lymphoma  . BCL may derive from precursor cells or mature B-lymphocytes, so B-lymphoblastic leukemia/lymphoma is distinguished from mature B-cell neoplasms. Beyond that, BCL are categorized according to clinical, morphological, immunophenotypic, and molecular genetic features. In detail, the following entities are listed in the World Health Organization classification of B-lymphoid neoplasms:
Precursor B-lymphoid neoplasms
Mature B-cell neoplasms
B-cell lymphoma (BCL) is a neoplasm arising from B lymphocytes. These cells fulfill a myriad of functions in the immune system, e.g., they produce antibodies against pathogens. If B cells proliferate in an uncontrolled manner, BCL may develop. BCL is a type of cancer that may manifest in a number of different ways. Affected individuals may note their lymph nodes to be swollen, or they may claim symptoms associated with the growth of tumors in the skin, gastrointestinal tract, lungs, bones, or elsewhere. Frequently, BCL is associated with fever, night sweats, and weight loss.
BCL may be treated with chemotherapy, immunotherapy, radiation therapy, or stem cell transplantation. Most patients receive chemotherapy and immunotherapy, which help to control the disease. The cure of BCL is rarely achieved. Stem cell transplantation offers a chance for cure but comes at the cost of high morbidity and mortality. Patients diagnosed with indolent BCL, a slow-growing, yet incurable variant of BCL, may not receive any treatment at all but rather be recommended active surveillance. In sum, there are more than two dozen types of BCL, and the treating physician has to consider patient characteristics and the individual course of the disease before recommending a determined treatment regimen. The outcome depends on similar parameters and varies according to the age and general condition of the patient, the type of BCL, and the stage of the disease at the time of diagnosis.