While the majority of DLBCL arises de novo, it may also result from the transformation of an indolent lymphoma. Thus, patients previously diagnosed with lymphoproliferative diseases like follicular lymphoma may be suspected to have DLBCL if presenting with symptoms consistent with this aggressive malignancy.

Patients suffering from DLBCL usually present with non-specific constitutive symptoms like fever, night sweats, and weight loss. Local invasiveness and rapid growth characterize solid tumors that most frequently develop in lymph nodes. Nevertheless, extranodal involvement is observed in about a third of DLBCL patients, particularly upon recurrence. Accordingly, lymphadenopathy is common, and patients may claim symptoms due to local mass effects mediated by enlarged lymph nodes. For instance, mediastinal lymphadenopathy may be associated with dyspnea, chest pain, and superior vena cava syndrome. Edema may form in poorly drained regions. Distant metastases may affect virtually any organ and may cause a wide variety of symptoms triggered by functional impairment,local mass effects and consequently pain. Patients should be subjected to a thorough physical examination in order to detect primary tumors as well as metastases and to guide the subsequent workup by means of diagnostic imaging.

With regards to DLBCL-induced paraneoplastic syndrome, cutaneous lesions and neurological deficits like erythroderma and cerebellar degeneration have been described.

The diagnosis of DLBCL is based on histopathological, immunohistochemical and molecular features of tumors and tumor cells. In order to carry out the respective analyses, an excisional biopsy of an enlarged lymph node should be performed. Tissue samples obtained by means of core biopsy may also be examined, particularly if an excisional biopsy is not feasible. Fine-needle aspiration analyses is not advisable for lymphoma diagnosis [11]. In the case of extranodal tumor growth, tissue samples can be obtained from the respective sites.

Computed tomography scans, as well as positron emission tomography/computed tomography (PET/CT) are of great value to visualize tumors in the thoracic or abdominal cavity, while cardiac involvement is generally assessed by means of echocardiography. This information is essential for tumor staging, for estimating the patient's prognosis and choosing an appropriate therapy. It is to be noted that extranodal tumors most commonly develop in the liver,spleen, bone marrow, gastrointestinal tract, lungs, serous membranes, kidneys and adrenal glands, breasts, testicles, skin and the central nervous system. Although bone marrow biopsies have been routinely performed to detect bone marrow involvement in DLBCL patients, they do not seem to add diagnostic or prognostic value after the performance of PET/CT [13].

Furthermore, laboratory analyses of blood samples should be carried out to assess the patient's general condition and organ function as well as lactate dehydrogenase levels. Due to a high incidence rate of DLBCL in people infected with human immunodeficiency virus and hepatitis C virus, patients should be tested in this regards. The distinction between Epstein-Barr virus positive and negative patients is of prognostic relevance [14].

Combination of anti-CD20 monoclonal antibody rituximab with classical chemotherapeutic regimens (namely CHOP: cyclophosphamide, hydroxy daunomycin, vincristine, and prednisone) is the mainstay of DLBCL treatment. Etoposide may be added if so indicated by the results of molecular analyses [11]. Moreover, the combined application of etoposide or methotrexate with doxorubicin, cyclophosphamide, vincristine, prednisolone and bleomycin (VACOP-B or MACOP-B, respectively) has proven effective in DLBCL patients. For patients with bone marrow, testicular or epidural involvement, prophylactic systemic or intrathecal application of methotrexate has been recommended to prevent central nervous system compromise [15]. Evidence proving the efficacy of this procedure is scarce, though. Additionally, patients may be considered for consolidative radiotherapy, especially if low-dose or abbreviated chemotherapy has been employed.

Due to the systemic character of the disease, resection of tumors is rarely curative. However, surgical interventions may relieve symptoms and are an essential part of therapy in certain subtypes of DLBCL, e.g., in primary testicular DLBCL. Patients who don't response favorably to the aforementioned therapies can be recommended for hematopoietic stem cell transplantation (HSCT). Owing to the inherent risks of this procedure and encouraging success rates of chemo-immunotherapy, HSCT is not a first-line treatment even in high-risk patients [15].

It is to be expected that future therapeutic regimens will take greater account of the histological and molecular features of tumor cells encountered in an individual patient. Personalized therapy may target B cell receptor or NF-κB signaling pathways, constitutively active enzymes and cytokine-mediated effects, among others [4].

The prognosis for patients diagnosed with DLBCL depends on a variety of factors:

• Overall survival rates of patients suffering from germinal center DLBCL or primary mediastinal B cell lymphoma are higher than those observed in individuals affected by activated B cell-like DLBCL. For germinal center DLBCL, five-year-survival rates of more than 80% have been reported, while only half of those people diagnosed with activated B cell-like DLBCL remain alive after this time [11].
• Use of the monoclonal antibody rituximab for DLBCL treatment has considerably improved the prognosis of patients with DLBCL.
• Advanced age, enhanced serum concentrations of lactate dehydrogenase, worse Eastern Cooperative Oncology Group performance status, Ann Arbor stage III to IV, and extranodal involvement are unfavorable prognostic factors. Each patient may be assigned an individual risk according to the enhanced International Prognostic Index developed by the National Comprehensive Cancer Network of the United States (NCCN-IPI) [12]. In this context, five-year-survival rates of 90 and 54% have been observed in low- and high-risk patient groups, respectively.

DLBCL is the result of malignant transformation and uncontrolled proliferation of B lymphocytes, but the causes of this degeneration remain unknown. A variety of conditions have been associated with the development of this lymphoproliferative disorder, namely B cell-activating autoimmune disease, acquired immunodeficiency, infection with hepatitis C virus, as well as a family history of non-Hodgkin or Hodgkin lymphoma [2] [3]. These observations imply DLBCL to be a multifactorial disease. Presumably, exposure of a genetically predisposed individual to certain environmental factors provokes the onset of this neoplasm.

With regards to the gene defects underlying malignant transformation, considerable differences exist among DLBCL subtypes [1] [4] [5]:

• In germinal center DLBCL, translocation t(14;18) results in a dysregulation of the anti-apoptotic protein encoded by protooncogene BCL2 (B cell lymphoma 2). Furthermore, mutation of BCL6 (B cell lymphoma 6: encodes for a transcription factor involved in cell cycle regulation), deletion of PTEN (phosphatase and tensin homolog: encodes for an enzyme involved in the regulation of cell division and growth), deletion of ING1 and mutation of TP53 (both encoding for tumor suppressors), as well as gain-of-function mutations of oncogene MDM2 (encodes for E3 ubiquitin-protein ligase) and a variety of other gene defects have been reported.
• Dysregulation of BCL2 and BCL6 also contribute to activated B cell-like DLBCL pathogenesis. Mutation or deletion of signaling molecules CD79A and CD79B result in constitutive activation of B cell receptor signaling, while loss of function of proteins encoded by CARD11 (caspase-associated recruitment domain 11) and MYD88 (myeloid differentiation primary response 88) favors an abnormal activation of NF-κB signaling pathways. These and other gene defects provoke genomic instability and a maturation arrest.
• Amplification of chromosomal bands of the short arms of chromosomes 2 and 9 is most characteristic of primary mediastinal B cell lymphoma. Genes located here encode for the anti-apoptotic transcription factor c-Rel, for Janus kinase 2, a non-receptor tyrosine kinase affecting the responsiveness to growth factors, and several other proteins. BCL2 and BCL6 are usually unaltered in this type of DLBCL.

On an average, B cell clones found in DLBCL samples per case present more than 30 gene alterations [6].

DLBCL account for up to 40% of non-Hodgkin lymphoma and their annual incidence has been estimated to 3.8 per 100,000 inhabitants in Europe [7]. During the last decades, incidence rates have been rising [8]. Most patients diagnosed with DLBCL suffer from germinal center DLBCL. Primary mediastinal B cell lymphoma is the least frequent entity and affects less than 10% of this patient group [9].

A slight predilection for males has been observed with the incidence rates increasing with age [7]. However, corresponding epidemiological data vary considerably depending on the subtype of DLBCL. The respective differences are best illustrated by the fact that primary mediastinal B cell lymphoma preferentially affects women in the 30 -35 age group [1].

This malignancy is characterized by an uncontrolled proliferation of B lymphocytes. In general, B cells develop from hematopoietic stem cells and progress through different developmental stages until they arrive in the secondary follicles of lymph nodes and spleen. Secondary follicles comprise a germinal center and are rich in B lymphocytes that proliferate, differentiate and undergo somatic hypermutation before being selected by T helper cells located in the periphery. Additionally, a small proportion of the B cell population may be encountered in the thymus. Their function remains largely unclear, but they have been suggested to be involved in T cell selection [10]. Malignant transformation of B cells during any of the aforementioned developmental stages may give rise to germinal center DLBCL, activated B cell-like DLBCL (also referred to as post-germinal center DLBCL), and primary mediastinal B cell lymphoma.

No specific measures can be recommended to prevent DLBCL.However, it is recommended that necessary steps should be taken to reduce the individual risk of contracting human immunodeficiency virus and hepatitis C virus.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma and refers to a heterogeneous group of malignancies originating from distinct subpopulations of B lymphocytes. Nevertheless, all forms of DLBCL are characterized by diffuse growth patterns and the presence of large, degenerated lymphocytes as observable during histopathological analyses of tissue specimens.

The following subtypes of DLBCL have been identified by means of gene expression profiling [1]:

• Germinal center DLBCL
• Activated B cell-like DLBCL
• Primary mediastinal B cell lymphoma

Further classification of DLBCL may be based on morphological features of tumor cells and immune cells encountered in biopsy samples, site of primary tumor growth, the patient's seropositivity or negativity for Epstein-Barr virus as well as the presence of chronic inflammation.

Diffuse large B-cell lymphoma (DLBCL) is a very common subtype of non-Hodgkin lymphoma. It is characterized by an uncontrolled proliferation of B lymphocytes that may form solid tumors in lymph nodes, liver and spleen and other organs. These tumors typically grow rapidly and may cause pain or functional impairment of affected organs or tissues located in close proximity. Nevertheless, patients suffering from DLBCL may notice non-specific symptoms like fever, night sweats, and weight loss long before tumors become palpable.

Imaging techniques like computed tomography scans and positron emission tomography are employed to detect tumors in the patient's body,and to assess the extension of the disease. Still, histopathological analyses of biopsy specimens are required to confirm a tentative diagnosis of DLBCL. Other types of lymphoma may trigger similar symptoms, but differ with regards to the patient's prognosis and treatment regimens. Additional measures may be taken to rule out the involvement of vital organs such as the bone marrow and the central nervous system.

Patients diagnosed with DLBCL are usually treated with chemotherapeutics. Rituximab, an antibody directed against a specific molecule expressed by B lymphocytes, has been used for a few years in addition to standard chemotherapeutic regimens and survival rates have since increased considerably. Radiotherapy may be indicated in some cases. The usefulness of surgical tumor resection is very limited. A small group of patients may be considered for hematopoietic stem cell transplantation. In sum, five-year-survival rates range between 50 and 90%, depending on the patient's condition at the time of diagnosis and the precise subtype of DLBCL.

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