Diffuse large B cell lymphoma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2] Anila Hussain, MD [3]

Diffuse large B-cell lymphoma (DLBCL or DLBL) is a cancer of B cells, a type of white blood cell responsible for producing antibodies. Diffuse large B cell lymphoma may be classified based on location into nodal and extranodal disease and based on molecular, genetic, and immunohistochemical features into more than 20 subgroups. Diffuse large B cell lymphoma may be classified into 2 subtypes based on gene expression profiles. The progression to diffuse large B cell lymphoma involves the microRNAs (miRNAs). On microscopic histopathological analysis, diffuse large B cell lymphoma can be divided into three variants: centroblastic, immunoblastic, and anaplastic. There are no established causes for diffuse large B cell lymphoma. Diffuse large B cell lymphoma is the most common type of non-Hodgkin lymphoma among adults, with an annual incidence of 7–8 cases per 100,000 people per year. This cancer occurs primarily in older individuals, with a median age of diagnosis at approximately 70 years of age, though it can also occur in children and young adults in rare cases. The most potent risk factor in the development of diffuse large B cell lymphoma is immunodeficiency. Diffuse large B cell lymphoma must be differentiated from other diseases such as follicular lymphoma, Mucosa-Associated Lymphatic Tissue lymphoma(MALT), small cell lymphocytic lymphoma, and Mantle cell lymphoma (MCL). The prognosis of diffuse large B cell lymphoma depends on the stage of the disease. Diffuse large B cell lymphoma is associated with a 5 year survival rate ranging from 70% to more than 90% among children. According to the Lugano classification, there are four stages of diffuse large B cell lymphoma based on the number of nodes involved and extranodal status. The most common symptoms of diffuse large B cell lymphoma include a rapidly enlarging, non-painful mass that may be located in neck, groin or abdomen. The less common symptoms of diffuse large B cell lymphoma include fever, weight loss and drenching night sweats. Common physical examination findings of diffuse large B cell lymphoma include a non tender mass which can arise in virtually any part of the body. Laboratory tests of diffuse large B cell lymphoma include complete blood count, blood chemistry studies, flow cytometry, immunohistochemistry, cytology, genetic testing, and immunophenotyping. CT scan, MRI, and PET may be helpful in the diagnosis of diffuse large B cell lymphoma. Lymph node or extranodal tissue biopsy is diagnostic of large B cell lymphoma. Other diagnostic studies for diffuse large B cell lymphoma include laparoscopy, laparotomy, and bone marrow aspiration and biopsy. The optimal therapy for diffuse large B cell lymphoma depends on the stage at diagnosis. The predominant therapy for diffuse large B cell lymphoma is chemotherapy. Adjunctive radiotherapy may be required. Active areas of research include genetic studies to assess the genetic role in diffuse large B cell lymphoma and novel therapeutic regimens that evaluate the efficacy and safety of novel regimens in in newly diagnosed diffuse large B cell lymphoma.

Diffuse large B cell lymphoma may be classified based on location into nodal and extranodal disease and based on molecular, genetic, and immunohistochemical features into more than 20 subgroups.

Diffuse large B cell lymphoma is mainly caused by genetic mutations. Genetic expression of germinal centers B cell like are associated with favourable prognosis. Some studies have established an association between microRNA expression and B cell lymphoma pathogenesis. The studies showed poor prognosis of microRNA expressed lymphomas. MicroRNAs participate in development of B cell receptor signalling, B cell migration, and class switching of immunoglobulins. On microscopic pathology, diffuse large B cell lymphoma has three variant pictures which include centroblastic, immunoblastic, and anaplastic forms of DLBCL.

There are no established causes for diffuse large B cell lymphoma.

Diffuse large B cell lymphoma must be differentiated from other diseases such as follicular lymphoma, Mucosa-Associated Lymphatic Tissue lymphoma(MALT), small cell lymphocytic lymphoma, and mantle cell lymphoma (MCL).

Diffuse large B cell lymphoma is the most common type of non-Hodgkin lymphoma among adults, with an annual incidence of 7–8 cases per 100,000 people per year. This cancer occurs primarily in older individuals, with a median age of diagnosis at approximately 70 years of age, though it can also occur in children and young adults in rare cases.

According to the American Cancer Society, There are several Factors including Old Age, Male Gender, White Ethnicity, Geography, exposure to Certain Drugs and Chemicals, Radiation exposure, and weak Immune System that can increase the chances of getting Non Hodgkin Lymphoma(NHL) among which Diffuse Large B cell Lymphoma is the Most common sub-type. Some Other Risk Factors include hepatitis C virus (HCV) seropositivity, high body mass as a young adult, HIV, and Family History of Lymphoma

Screening for diffuse large B cell lymphoma is not recommended.

The prognosis of diffuse large B cell lymphoma depends on the stage of the disease. Diffuse large B cell lymphoma is associated with a 5 year survival rate ranging from 70% to more than 90% among children.

According to the Lugano classification, there are four stages of diffuse large B cell lymphoma based on the number of nodes involved and extranodal status.

The most common symptoms of diffuse large B cell lymphoma include a rapidly enlarging, non-painful mass that may be located in neck, groin or abdomen. The less common symptoms of diffuse large B cell lymphoma include fever, weight loss and drenching night sweats.

Common physical examination findings of diffuse large B cell lymphoma include a non tender mass which can arise in virtually any part of the body.

Laboratory tests of diffuse large B cell lymphoma include complete blood count, blood chemistry studies, flow cytometry, immunohistochemistry, cytology, genetic testing, and immunophenotyping.

There are no electrocardiogam findings associated with diffuse large B cell lymphoma.

There are no chest X ray findings associated with diffuse large B cell lymphoma.

CT scan may be helpful in the diagnosis of diffuse large B cell lymphoma. Fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT) scan is now recommended as the gold standard for staging DLBCL patients

For suspected lymphoma of the Nervous System, magnetic resonance imaging (MRI) is the modality of choice. Neck MRI is helpful in the diagnosis of diffuse large B cell lymphoma.

Lymph node or extranodal tissue biopsy is diagnostic of large B cell lymphoma.

PET scan may be helpful in the diagnosis of diffuse large B cell lymphoma.

Other diagnostic studies for diffuse large B cell lymphoma include laparoscopy, laparotomy, and bone marrow aspiration and biopsy.

The optimal therapy for diffuse large B cell lymphoma depends on the stage at diagnosis. The predominant therapy for diffuse large B cell lymphoma is chemotherapy. Adjunctive radiotherapy may be required.

Surgical intervention is not recommended for the management of diffuse large B cell lymphoma.

There are no primary preventive measures for diffuse large B cell lymphoma.

There are no secondary preventive measures for diffuse large B cell lymphoma.

Active areas of research include genetic studies to assess the genetic role in diffuse large B cell lymphoma and novel therapeutic regimens that evaluate the efficacy and safety of novel regimens in in newly diagnosed diffuse large B cell lymphoma.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

In 1865, Samuel Wilks used the term “Hodgkin’s disease” in Annals of medicine on the name of “Thomas Hodgkin” who published a paper on some morbid appearances of absorbent glands and spleen in 1832^[1][2][3]. Consequently, the other heterogeneous lymph node neoplastic disorder was later named as Non-Hodgkin’s Lymphoma (NHL). Non-Hodgkin lymphoma is now one of the leading malignancies worldwide and Diffuse Large b cell Lymphoma (DLBCL) is one of the most common types of Non-Hodgkin Lymphoma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2] Anila Hussain, MD [3]

Diffuse large B cell lymphoma may be classified based on location into nodal and extranodal disease and based on pathological and clinical features.

Diffuse large B cell lymphoma may be classified based on location:

• Nodal disease
• Extranodal disease

According to the updated WHO classification, diffuse large B cell lymphoma may be classified based on pathological and clinical features into the following:

• Diffuse large B-cell lymphoma, NOS (represents more than 80% of cases of large B-cell lymphomas)

• Molecular subtypes: GCB subtype, about 60%; ABC subtype, about 25–30%; unclassifiable, about 10–15%; new molecular entities recently characterized

Diffuse proliferation of medium or large lymphoid B cells typically expressing CD19, CD20, CD22, CD79a, PAX5, and surface or cytoplasmic immunoglobulin; molecular techniques (e.g., GEP) or IHC-based algorithms recommended to classify subtypes

• The median age is 65–70 yr

• Nodal presentation is the most common and 30–40% of cases are primary extranodal

• prognosis is variable

• Few large B cells embedded in a background of T cells and histiocytes; distinguish from nodular lymphocyte-predominant Hodgkin lymphoma
• Commonly found in middle-aged men, advanced stage with extranodal involvement (liver, spleen, bone marrow); poor prognosis

• Typically ABC subtype; frequent loss of HLA class I/II; frequent mutation of MYD88
• Exclusively in CNS or intraocular region, rare systemic involvement; poor prognosis; specialized treatment with CNS-penetrating agents, with or without radiation therapy, required; targeted therapies under investigation

• Typically ABC subtype; frequent mutation of MYD88; distinguish from other cutaneous B-cell lymphoma
• Typically in elderly patients and women; presents with skin nodules in lower legs; 10–15% of cases arise in other sites; poor prognosis

• Variable histologic features, including Hodgkin-like lesions, monomorphic to polymorphic patterns; EBV detectable in tumor and frequently in serum
• Typically in patients older than 50 yr; more frequent in Asia and Latin America than elsewhere; extranodal involvement common; prognosis varies

• Polymorphic infiltrate with frequent Hodgkin-like cells; EBV is detectable in tumor
• Presents as localized, ulcerated lesions in oral mucosa, intestine, or skin; dissemination is rare; commonly occurs as iatrogenic or age-related disease in immunocompromised patients; favorable prognosis; consider reduction of immunosuppressive therapy

• Morphologically similar to DLBCL, NOS but strongly associated with EBV; also called pyothorax-associated lymphoma, when associated with chronic pyothorax
• Occurs in context of chronic inflammation, involving pleural cavity or other sites such as bone and joints; male predominance; poor prognosis

• EBV-driven angiocentric and angiodestructive lymphoproliferation with reactive T cells; grade based on proportion of EBV positive B cells and cytologic features
• Commonly involves extranodal sites (lung >90%); often in context of immunodeficiency; prognosis varies; no standard therapy

• Strong expression of IRF4/MUM1, usually with IRF4 rearrangement; diffuse-to-follicular morphologic features; distinguish from pediatric-type follicular lymphoma
• Commonly in children and young adults; typically involves Waldeyer’s ring or cervical lymph nodes; favorable prognosis

• Putative thymic B-cell origin; medium-to-large B cells, frequently with sclerosis; distinctive phenotype (CD30, CD23, PDL1, PDL2) and unique GEP signature; frequent 9p21 amplification, genomic alterations of CIITA
• Typically in young adults, female predominance; mediastinal prominence with local invasion; can involve other nodal or extranodal sites (kidney and liver); prognosis varies; DA-EPOCH-R an option

• Lymphoma cells exclusively within lumina of small or intermediate vessels; bone marrow and skin biopsy may be useful to establish diagnosis
• Wide intravascular dissemination (lung, bone marrow, skin, CNS, kidney), often associated with fever of unknown origin or neurologic or cutaneous symptoms; poor prognosis

• ALK–positive large B cells, immunoblastic features and plasma cell phenotype, typically CD20-negative
• Typically in young men with generalized lymphadenopathy; prognosis varies

• Immunoblastic or plasmablastic B cells, plasma-cell phenotype (CD138–positive, CD20–negative), often EBV–positive; distinguish from multiple myeloma
• Often associated with HIV infection or immunosuppression; frequently extranodal; poor prognosis; consider more intensive regimens

• HHV8–positive IgM lambda plasmablasts; often associated with HHV8-positive multicentric Castleman disease
• Often associated with HIV infection; lymphadenopathy and splenomegaly are common; poor prognosis; no standard therapy

• Immunoblastic or plasmablastic B cells, HHV8-positive and usually EBV–positive; plasma-cell phenotype lacking usual B-cell markers; CD20-negative
• Often associated with HIV infection or immunosuppression; presents as pleural, pericardial, or peritoneal serous effusions, often without detectable tumor mass; poor prognosis; DA-EPOCH an option

• High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements or both (doublehit or triple-hit lymphoma) (4–8% of large B-cell cases)
• Variable morphology, including DLBCL, B-cell lymphoma unclassifiable (with features intermediate between DLBCL and Burkitt lymphoma), and blastoid features; MYC and BCL2 and/or BCL6 rearrangements, detected by FISH
• Frequently aggressive clinical presentation; higher risk of CNS involvement; poor prognosis; consider more intensive immunochemotherapy regimens, such as DA-EPOCH-R

• Heterogeneous category; often has morphologic features intermediate between DLBCL and Burkitt lymphoma; lacks MYC and BCL2 and/or BCL6 rearrangements
• Frequently aggressive clinical presentation; increased risk of CNS involvement; poor prognosis; consider more intensive immunochemotherapy regimens

• B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classic Hodgkin lymphoma (grey-zone lymphoma) (rare)
• Overlapping morphologic or immunophenotypic features, or both, between DLBCL and classic Hodgkin lymphoma
• Male predominance, younger age (20–40 yr); mediastinal presentation most common (80% of cases) but can occur in other sites; prognosis varies; no standard therapy, consider therapy suitable for DLBCL or Hodgkin lymphoma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2] Anila Hussain, MD [3]

Diffuse large B cell lymphoma is mainly caused by genetic mutations. Genetic expression of germinal centers B cell like are associated with favourable prognosis. Some studies have established an association between microRNA expression and B cell lymphoma pathogenesis. The studies showed poor prognosis of microRNA expressed lymphomas. MicroRNAs participate in development of B cell receptor signalling, B cell migration, and class switching of immunoglobulins. On microscopic pathology, diffuse large B cell lymphoma has three variant pictures which include centroblastic, immunoblastic, and anaplastic forms of DLBCL.

• Gene expression profiling studies have also attempted to distinguish heterogeneous groups of diffuse large B cell lymphoma from each other.
• These studies examine thousands of genes simultaneously using a DNA microarray, looking for patterns which may help in grouping cases of diffuse large B cell lymphoma.
• Many studies now suggest that cases of diffuse large B cell lymphoma, not otherwise specified can be separated into two groups on the basis of their gene expression profiles:

• Germinal centre B-cell-like (GCB)
• Activated B-cell-like (ABC).^[1][2][3]

• Tumor cells in the Germinal centre B-cell-like subgroup resemble normal B cells in the germinal centrer closely, and are generally associated with a favourable prognosis.^[4][5]
• Activated B-cell-like tumor cells are associated with a poorer prognosis,^[5] 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.^[6]

• Recent gene expression studies is the importance of the cells and microscopic structures interspersed between the malignant B cells within the diffuse large B cell lymphoma tumor, an area commonly known as the tumor 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.^[5][7]
• Alternatively, expression of genes coding for pro-angiogenic factors is correlated with poorer survival.^[5]

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
• Production and class-switching of immunoglobulins^[8]

MiRNAs influence B cell maturation, generation of pre-, marginal zone, follicular, B1, plasma and memory B cells.^[8]

• With the apparent success of gene expression profiling in separating biologically distinct cases of diffuse large B cell lymphoma, not otherwise specified, some researchers examined whether a similar distinction could be made using immunohistochemical staining, 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, immunohistochemical staining is a desirable alternative.^[9][10]
• Many of these studies focused on stains against the products of prognostically significant genes which had been implicated in diffuse large B cell lymphoma gene expression studies. Examples of such genes include BCL2, BCL6, MUM1, LMO2, MYC, and p21. Several algorithms for separating diffuse large B cell lymphoma cases by immunohistochemical staining arose out of this research, categorizing tissue samples into groups most commonly known as Germinal centre B-cell-like subgroup and Non-Germinal centre B-cell-like subgroup.^{[10][11][12][13]}
• The correlation between these Germinal centre B-cell-like/Non-Germinal centre B-cell-like immunohistochemical groupings and the Germinal centre B-cell/Activated B-cell-like groupings used in gene expression profiling studies is uncertain.^[4][12], as is their prognostic value^[4].This uncertainty may arise in part due to poor inter-rater reliability in performing common immunohistochemical stains.^[9]

The cells in DLBCL are large Lymphoid cells that are diffusely arranged in a pattern that effaces normal nodal or extranodal architecture^[14]

Following Morphological Subgroups are seen in DLBCL

• Most common variant, 80 percent of all cases
• Appearance of medium-to-large-sized lymphocytes
  • with moderate amount of cytoplasm
  • Prominently visible oval/round nuclei that contain fine chromatin
  • Two to four nucleoli within each nucleus
• Tumor may be monomorphic, composed almost entirely of Centroblasts(>90%)
• The majority of cases are polymorphic (mixture of Centroblasts(<90%), Immunoblasts and Centrocytes)

• 8-10 percent of all cases of DLBCL
• Greater than 90% of its cells are immunoblasts
• Large lymphoid cells with Significant basophilic cytoplasm
• Trapezoid shaped centrally located nucleolus with fine chromatin strands that are attached to nuclear membrane(also known as spider legs)

• Less common variant comprising almost 3 percent of all cases of DLBCL
• Tumor cells which appear very differently from their normal B cell counterparts
  • Very large cells with a round, oval, or polygonal shape that may resemble Reed-Sternberg cells of Hodgkin’s lymphoma or Anaplastic Large cell Lymphoma
  • Pleomorphic nuclei
  • Sinusoidal Pattern

• Does not meet any of the above criteria
• Cells can have cloverleaf-shaped or multilobated nuclei^[15]
• Most commonly extranodal( eg primary Mediastinal B cell Lymphoma)
• Cells can have Signet cell or spindle cell appearance

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2]

There are no established causes for diffuse large B cell lymphoma.

The causes of diffuse large B-cell lymphoma are not well understood. Usually diffuse large B-cell lymphoma arises from normal B cells, but it can also represent a malignant transformation of other types of lymphoma or leukemia. Infection with Epstein-Barr virus has also been found to contribute to the development of some subgroups of diffuse large B cell lymphoma.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2]

Diffuse large B cell lymphoma must be differentiated from other diseases such as follicular lymphoma, Mucosa-Associated Lymphatic Tissue lymphoma(MALT), small cell lymphocytic lymphoma, and mantle cell lymphoma (MCL).

Diffuse large B cell lymphoma must be differentiated from other diseases such as

• Infectious mononucleosis
• Burkitt Lymphoma^[1]
• Follicular lymphoma
• Hodgkin Lymphoma
• Mucosa-Associated Lymphatic Tissue lymphoma (MALT)
• Small cell lymphocytic lymphoma
• Mantle cell lymphoma (MCL)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2] Anila Hussain, MD [3]

Diffuse large B cell lymphoma is considered the most common type of non-Hodgkin lymphoma in adult population. The annual incidence is about 150,000 people worldwide. It mainly affects older individuals, with a median age of diagnosis at approximately 70 years old; however, it may affect children and young adults in rare cases.

Diffuse large B cell lymphoma is considered the most common type of non-Hodgkin lymphoma in adult population representing approximately 30% of non-Hodgkin lymphoma cases.^[1] The annual incidence is about 150,000 people worldwide.^[2]

Diffuse large B cell lymphoma mainly affects older individuals, with a median age of diagnosis at approximately 70 years of age;^[3] however, it may affect children and young adults in rare cases.^[4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anila Hussain, MD [2] Sowminya Arikapudi, M.B,B.S. [3]

There are several factors including family history, old age, male gender, white ethnicity, geography, certain viruses, exposure to certain drugs and chemicals, radiation exposure, autoimmune diseases, and weak immune system that can increase the chances of getting Non-Hodgkin Lymphoma (NHL). Diffuse Large B cell Lymphoma ((DLBC) is the most common sub-type^[1][2][3][4].On the other hand, factors that are associated with a decreased risk of DLBCL include blood transfusion, alcohol consumption, vegetables consumption, sun exposure, and allergies.

Genetic susceptibility is an important risk factor. TNF/LTA; 6p25.3; 6p21.33; 2p23.3; 8q24-21 loci have been identified.

Old age is a strong risk factor for lymphoma with the majority of cases occurring at age 60 or more; however, some cases can be seen in young population depending upon the type of Lymphoma

The overall risk of Non-Hodgkin Lymphoma is higher in men than in women, but there are certain types that are more commonly seen in women. Reasons for this finding are unknown.

In the USA, Non-Hodgkin Lymphoma is most commonly seen in white population than African-Americans or Asian-Americans

Worldwide, it is more common in developed countries with USA and Europe having the highest prevalence.

Some viruses can increase the risk such as HIV, EBV, HHV-8, HBV, and HCV.

Some chemicals like Benzene and Herbicides and Insecticides may be associated with an increased risk of NHL but research is in progress to clarify these links. Some chemotherapeutic drugs might be associated as a treatment for Hodgkin Lymphoma increases the risk of NHL but it is unclear whether it is treatment related or related to disease itself.

There is an increased risk of many types of cancers in people exposed to high intensity. It has been reported that survivors of several nuclear reactor accidents and atomic bombs tend to have certain types of cancers including NHL, Leukemia and Thyroid cancer. Also, people with Hodgkin Lymphoma who get treated with radiotherapy have a slightly increased incidence to develop NHL later in life.

There is an increased risk of NHL in people with immunodeficiency. Examples include organ transplant recipients who are on immunosuppressive drugs, HIV Infection. Some genetic conditions in which children are born with weak immune system like Wiskott-Aldrich Syndrome and Ataxia-telengectasia(AT) also have a higher risk of NHL. However, type 2 diabetes mellitus has no significant effect.

Some autoimmune diseases also increase the risk slightly such as Sjogren syndrome, celiac disease, and SLE.

Blood transfusion, alcohol consumption, vegetables consumption, sun exposure, and allergies are associated with decreased risk of developing DLBCL.^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2]

There is insufficient evidence to recommend routine screening for diffuse large B cell lymphoma.

There is insufficient evidence to recommend routine screening for diffuse large B cell lymphoma.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anila Hussain, MD [2] Sowminya Arikapudi, M.B,B.S. [3]

The prognosis of diffuse large B cell lymphoma (DLBCL) depends on the stage of the disease. Diffuse large B cell lymphoma is associated with a 5 year survival rate ranging from 70% to more than 90% among children. There are several biologic factors a that are associated with the outcomes in patients with DLBCL

Several subtypes of diffuse large B cell lymphoma 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 tumor cells. The IPI (International Prognostic Index) score is used in prognosis in clinical practice.^[1][2]

INTERNATIONAL PROGNOSTIC INDEX (IPI)
Interantional Prognostic Index			Estimated 3 year Overall Survival (95% CI)
Risk Factors	Age >60 years
	Serum LDH >Normal
	Stage III-IV
	Performance Status 2-4
	Extranodal Sites >1
Risk categories	Low	0-1	91(89-94)
	Low Intermediate	2	81(73-86)
	High Intermediate	3	65(58-73)
	High	4-5	59(49-69)
AGE ADJUSTED INTERNATIONAL PROGNOSTIC INDEX (aaIPI) In Patients < or equal to 60 years
Risk Factors	Serum LDH >Normal
	Stage III-IV
	Performance Status 2-4
Risk Categories	Low	0	98(96-100)
	Low Intermediate	1	92(87-95)
	High Intermediate	2	75(66-82)
	High	3

• Through the treatments, more than half of patients with diffuse large B cell lymphoma can be cured^[3] and overall survival for older adults at five years is around 58%.^[4]
• For children with diffuse large B-cell lymphomas, most studies have found 5-year survival rates ranging from about 70% to more than 90%.^[5]
• The Germinal-center subtype has the best prognosis, with 66.6% of treated patients surviving more than five years.^[6]
• Lenalidomide has been recently shown to improve outcomes in the Non-germinal center subtype.^[7]

• Various technologies (gene array, digital expression profiling, multiplex RT-PCR–based methods)

• ABC subtype is associated with poor prognosis

• ABC subtype may be associated with an increased risk of CNS relapse

• Various IHC-based algorithms to assign molecular subtype; most commonly the Hans algorithm

• Non-GCB subtype is associated with poor prognosis, although this is not confirmed in some studies

• Dichotomizes patients into GC and non-GCB subgroups and represents an approximation of molecular subtype as assessed by GEP

• FISH is used primarily in clinical practice; the use of break-apart probes is recommended; GEP-based assays may identify additional cases with double-hit signature undetected by FISH with similar biologic features and outcome
• Double- or triple-hit cases are associated with poor prognosis; poor prognosis may be limited to cases in which the MYC translocation partner is an immunoglobulin gene locus
• Now classified by the WHO as high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements; majority of cases are GCB subtype; may benefit from more intensive therapies

• IHC measurement to estimate the percentage of cells expressing MYC or BCL2 protein or both; 40% cutoff threshold for MYC and 50% for BCL2
• Double expression of MYC and BCL2 or expression of BCL2 alone is associated with worse prognosis
• May have prognostic significance mainly in GCB-type DLBCL; MYC-BCL2 double expression may be associated with an increased risk of CNS relapse

• IHC measurement of proliferation marker Ki67; no established cutoff threshold
• Higher proliferation may be associated with poorer prognosis, although it has not consistently been shown to be an independent prognostic marker
• High proliferation rate (>80%) may increase suspicion that patient has high-grade B-cell lymphoma (with or without double- or triple-hit rearrangements)

• PCR, NGS, or gene array for detection of mutation or deletion of TP53
• TP53 mutations in the DNA-binding domain are associated with poor prognosis
• May cluster with a genetic subset of DLBCL

• Gene array, FISH, or PCR for detection of deletion of the CDKN2A locus or loss of the 9p21 region
• Deletion of the CDKN2A locus or loss of the 9p21 is associated with poor prognosis
• May cluster with some genetic subsets of DLBCL

• IHC measurement of partial or complete loss of MHC class II expression
• Loss of expression of MHC class II may be associated with a poor prognosis (more frequent in non-GCB subtype)
• Primarily observed in primary mediastinal B-cell lymphoma and in tumors with EZH2 mutations

• Measured in peripheral blood; low lymphocyte count (<1×109/liter) or low lymphocyte:monocyte ratio (various cutoff thresholds)
• Low lymphocyte count or low lymphocyte:monocyte ratio is associated with poor prognosis
• May have implications for immune-based therapies

• Single nucleotide variation in 5q23.2 or 6q21 (PCR or single nucleotide polymorphism array)
• Single nucleotide variation in 5q23.2 or 6q21 is associated with poor prognosis
• Further investigation is needed

Complications can be disease associated or treatment related. some of the complications included are^[9]:

• Infection (most commonly Pneumonia or Sepsis), that can lead to multiorgan failure
• Hepatic Failure (treatment Related)
• Gastrointestinal Bleeding (disease-related)
• Disease Progression leading to death

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