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.

• Fever

  The patient died 5 days after the first cycle of chemotherapy with severe dyspnea and high fever. [ncbi.nlm.nih.gov]

• Weight Loss

  Other symptoms include fever, night sweats, and weight loss. There are several subtypes of diffuse large B-cell lymphoma. [cancer.gov]

  General symptoms of DLBCL are fevers, night sweats and weight loss. Another symptom is painless and fast growing lymph nodes, these swelling can also occur in the abdomen, liver, lungs, skin and other areas of the body. [drugs.com]

  Symptoms can include swollen, painless lymph nodes anywhere in the body, fever, weight loss, night sweats, weakness, and tiredness. DLBCL is usually an aggressive tumor, and the cause is poorly understood. [medicinenet.com]

• Fatigue

  A 54-year-old female patient with a history of breast cancer for 4 years and receiving tamoxifen the hematology clinic with fatigue and nosebleed. Laboratory parameters were revealed pancytopenia. [ncbi.nlm.nih.gov]

  Nearly three-quarters of the patients (65 of 88, 73.9%) reported an adverse event of grade 3 or higher, with the most common being decreased platelet or neutrophil counts, and fatigue, among other effects. [cancernetwork.com]

• Lymphadenopathy

  A 70-year-old woman with lymphadenopathy was admitted to hospital in 2008. Lymph node biopsy showed reactive lymphoid hyperplasia (RH) with monoclonal proliferation of Epstein-Barr virus (EBV). Her lymphadenopathy regressed without treatment. [ncbi.nlm.nih.gov]

• Falling

  DLBCL not otherwise specified (NOS): When DLBCL doesn’t fall into one of the subtypes listed above, it is classified as DLBCL not otherwise specified (NOS). A large number of diagnoses fall into this category. [lymphoma.org]

  Previous Episode Next Episode Fall 2013 : Diffuse large b-cell lymphoma Diffuse large b-cell lymphoma Diffuse large b-cell lymphoma (DLBCL) is the most common form of non-Hodgkin’s lymphoma (NHL). [mdanderson.org]

  DLBCL would fall in the large lymphocyte region as shown below. The CD45 vs FS gating plot reveals both a small(red) and large (green) population of lymphocytes. [wiki.clinicalflow.com]

• Mediastinal Lymphadenopathy

  For instance, mediastinal lymphadenopathy may be associated with dyspnea, chest pain, and superior vena cava syndrome. Edema may form in poorly drained regions. [symptoma.com]

  lymphadenopathy and displaying some molecular genetic similarities to Hodgkin lymphoma. 3 – 6 A small number of cases do not fit into any of these categories and have been designated as “unclassifiable.” 7 The CHOP (cyclophosphamide, doxorubicin, vincristine [dx.doi.org]

  lymphadenopathy The following are common findings on physical examination: Lymphadenopathy (ie, cervical, axillary, and inguinal) Splenomegaly Low-grade fever Pedal edema: Resulting from extensive pelvic lymphadenopathy See Presentation for more detail [emedicine.medscape.com]

• Splenomegaly

  One month later, he presented with progressive leukocytosis (mostly neutrophilia) and splenomegaly. [ncbi.nlm.nih.gov]

  A mild splenomegaly (13 cm), with multiple enlarged lymph nodes in periumbilical region, largest measuring 20   19 mm, was also identified; there were no other nodes and no free fluid in the abdomen. [wjso.biomedcentral.com]

  […] edema: Caused by extensive pelvic lymphadenopathy Fatigue Chest discomfort or shortness of breath: Caused by mediastinal lymphadenopathy The following are common findings on physical examination: Lymphadenopathy (ie, cervical, axillary, and inguinal) Splenomegaly [emedicine.medscape.com]

• Cervical Lymphadenopathy

  PET (positron emission tomography)/CT (computed tomography) was performed and revealed inguinal, pelvic, retroperitoneal, axillary, and cervical lymphadenopathy. [ncbi.nlm.nih.gov]

  뇌수종, retinochoroiditis(망막맥락막염), cerebral calcification, 정신운동지연, 경련 후천성 톡소포자충증 발열몸살형 (acute febrile illness with cervical lymphadenopathy) 피부뇌염형 (typhus-like, exanthematous type with encephalitis) 수막뇌염형 (CNS type with meningoencephalitis) 망막맥락막형 (retinochoroiditis [endotoday.com]

• Axillary Lymphadenopathy

  We herein report a 56 years old male patient diagnosed with diffuse large B cell lymphoma, after clinically presenting with a visible tumor in the left breast and showing no axillary lymphadenopathy. [ncbi.nlm.nih.gov]

  A follow-up CT scan performed 2 years later showed mildly prominent bilateral axillary lymphadenopathy. One year prior to the current evaluation, the patient noted swelling in the right and left axilla. [diagnosticpathology.biomedcentral.com]

• Cough

  A 28-year-old man presented with 2 months of persistent cough. He had a large lung abscess involving almost the entire right upper lobe. The mass continued to progress in spite of appropriate antibiotic administration. [ncbi.nlm.nih.gov]

  Mediastinal large B-cell lymphoma can lead to symptoms of shortness of breath, cough and pain in the chest and cause swelling of the neck, arms and face due to the swollen lymph nodes pressing on the veins in the chest (this swelling is known as “superior [lymphoma.org.au]

  The lymphoma may press on the trachea and cause trouble breathing or coughing and it can also block the large vein that returns blood to the heart from the arms and head (the superior vena cava), which can make the arms, neck and face swell. [lymphoma.ca]

  […] and can cause problems due to the pressure of the mass on the lungs or gut, or on the superior vena cava (the second largest vein in the body which returns blood from the upper half of the body to the heart).Symptoms include breathlessness, persistent cough [leukaemia.org.au]

• Dyspnea

  The patient died 5 days after the first cycle of chemotherapy with severe dyspnea and high fever. [ncbi.nlm.nih.gov]

  For instance, mediastinal lymphadenopathy may be associated with dyspnea, chest pain, and superior vena cava syndrome. Edema may form in poorly drained regions. [symptoma.com]

  DCM usually presents with any one of the following: (1) Heart failure with symptoms of congestion (edema, orthopnea, paroxysmal nocturnal dyspnea) and/or reduced cardiac output (fatigue, dyspnea on exertion); (2) arrhythmias and/or conduction system disease [flybase.org]

  Presentation usually occurs late in the disease course with any one of the following: Heart failure, characterized by symptoms that include edema, orthopnea, paroxysmal nocturnal dyspnea, fatigue and dyspnea on exertion Arrhythmias and/or conduction system [centogene.com]

• Orthopnea

  DCM usually presents with any one of the following: (1) Heart failure with symptoms of congestion (edema, orthopnea, paroxysmal nocturnal dyspnea) and/or reduced cardiac output (fatigue, dyspnea on exertion); (2) arrhythmias and/or conduction system disease [flybase.org]

  Presentation usually occurs late in the disease course with any one of the following: Heart failure, characterized by symptoms that include edema, orthopnea, paroxysmal nocturnal dyspnea, fatigue and dyspnea on exertion Arrhythmias and/or conduction system [centogene.com]

• Nasal Congestion

  A 62-year-old Chinese female visited the Ear-Nose-Throat Department of our hospital with nasal congestion and rhinorrhea for 2 months. Computed tomography scan revealed a mass with soft tissue density in the left vestibule and nasal cavity. [ncbi.nlm.nih.gov]

• Testicular Mass

  Here, we report a case of CD20-negative DLBCL presented as a testicular mass. To the best of our knowledge, this is one of the first reported cases of testicular unclassifiable CD20-negative DLBCL. [ncbi.nlm.nih.gov]

• Headache

  A 72-year-old woman, first presented 7 years ago with complaints of headache and dizziness. Enhanced magnetic resonance imaging revealed the mass within the splenium of the corpus callosum. [ncbi.nlm.nih.gov]

  […] superior vena cava (the second largest vein in the body which returns blood from the upper half of the body to the heart).Symptoms include breathlessness, persistent cough, difficulty swallowing (dysphagia), swelling of the neck and face, dizziness and headaches [leukaemia.org.au]

  Other symptoms include difficulty swallowing (dysphagia), dizziness and headaches. Treatment usually involves the use of R-CHOP followed by radiotherapy and PMBL usually responds well to treatment. [lymphoma.ca]

  […] the 2017 criteria Diagnosis of Multiple System Atrophy (MSA) Diagnose Multiple Systems Atrophy based on the 2008 criteria Arteriovenous Malformation Coma/Level of Consciousness Demyelinating Disease Dermatome Map Functional Outcome Head & Neck Trauma Headache [qxmd.com]

• Ataxia

  PMID 9824206 Acquired chromosome 11q deletion involving the ataxia teleangiectasia locus in B-cell non-Hodgkin's lymphoma: correlation with clinicobiologic features. [atlasgeneticsoncology.org]

  […] predict overall survival in patients with diffuse large cell lymphomas. [9] Associated conditions Non-Hodgkin lymphomas (NHLs) have been associated with the following conditions, drugs, and chemical agents: Hereditary immunodeficiency disorders such as ataxia-telangiectasia [emedicine.medscape.com]

• Nausea

  Rarely ( CASE PRESENTATION: A 53-year old man presented to our Dermatology Clinic due to a 1-year history of generalized itching, fatigue of 2-3 month's duration, nausea and mid back rash that was biopsied. [ncbi.nlm.nih.gov]

  This can be a tough process because you may get side effects such as mouth and throat sores or nausea and vomiting. You can take medication that eases some of these side effects. [webmd.com]

  However, the cause of the condition is unknown, and it is researched that certain genetic factors may be involved The lymphoma can cause abdominal pain, nausea and vomiting, weight loss, and other general signs and symptoms, such as fever, fatigue, and [dovemed.com]

• Gingival Swelling

  CASE PRESENTATION: A 73-year-old Asian man who had gingival swelling of the labial area of the left maxillary lateral incisor presented to our institution. [ncbi.nlm.nih.gov]

• Tachycardia

  Clinical examination revealed signs of tachycardia, pallor and splenomegaly. He had no evidence of peripheral stigmata of chronic liver disease. [ncbi.nlm.nih.gov]

  (DO) catecholaminergic polymorphic ventricular tachycardia 1 dilated cardiomyopathy 1A dilated cardiomyopathy 1AA dilated cardiomyopathy 1B dilated cardiomyopathy 1BB dilated cardiomyopathy 1C dilated cardiomyopathy 1CC dilated cardiomyopathy 1D dilated [rgd.mcw.edu]

  […] patients 60 years of age receiving R-CHOP as compared with CHOP alone: pyrexia (56% vs. 46%), lung disorder (31% vs. 24%), cardiac disorder (29% vs. 21%), and chills (13% vs. 4%) A review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia [rituxan.com]

  Polymorphism Allelic disorders Hypertrophic cardiomyopathy: CMH25 LGMD 2G Dilated cardiomyopathy 1O (CMD 1O): With ventricular tachycardia Sulfonylurea receptor 2 (SUR2, ABCC9) ; Chromosome 12p12.1; Dominant or Sporadic Genetics 2 patients Mutations: [neuromuscular.wustl.edu]

  […] infections were defined by at least one of the following: a clinically documented febrile episode; other signs attributed to a systemic response to infection, such as hypothermia (temperature below 35.6 C), low-grade fever (temperature, 37.5 to 37.9 C), tachycardia [oadoi.org]

• Otalgia

  Administrated with 9 cycles of multiagent combined chemotherapy, he felt right ear progressive hearing loss, otalgia, aural fullness. Otoendoscopic examination revealed a pitchy mass obstructing the right external auditory canal. [ncbi.nlm.nih.gov]

• Anterior Uveitis

  We describe a case of spontaneous hyphema associated with anterior uveitis presents in a 69-year old female as the prominent sign of the intraocular spread of systemic diffuse large B-cell lymphoma (DLBCL). [ncbi.nlm.nih.gov]

• Neck Pain

  Cancer is an uncommon cause of radicular neck pain but should be considered in the differential, particularly when constitutional complaints are also present. [ncbi.nlm.nih.gov]

• Migratory Polyarthritis

  Suspicion of carcinomatous polyarthritis should be made in those with migratory polyarthritis and should be thoroughly investigated to exclude underlying malignancy. [ncbi.nlm.nih.gov]

• Night Sweats

  Other symptoms include fever, night sweats, and weight loss. There are several subtypes of diffuse large B-cell lymphoma. [cancer.gov]

  General symptoms of DLBCL are fevers, night sweats and weight loss. Another symptom is painless and fast growing lymph nodes, these swelling can also occur in the abdomen, liver, lungs, skin and other areas of the body. [drugs.com]

  Symptoms can include swollen, painless lymph nodes anywhere in the body, fever, weight loss, night sweats, weakness, and tiredness. DLBCL is usually an aggressive tumor, and the cause is poorly understood. [medicinenet.com]

  sweats and weight loss. [orpha.net]

• Pruritus

  A 52-year-old man complained of worsening appetite, abdominal distension, and pruritus. [ncbi.nlm.nih.gov]

  Signs and symptoms include the following: Pain in an enlarged lymph node or organ: May be noted if the lymphomatous mass enlarges rapidly B symptoms (Ann Arbor staging): Including fever, drenching night sweats, and weight loss Generalized pruritus Anorexia [emedicine.medscape.com]

• Numb Chin Syndrome

  We present a 59-year-old man with unusual clinical presentation of numb chin syndrome (NCS) as the first symptom of disease. [ncbi.nlm.nih.gov]

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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