Diffuse large cell lymphoma (see the image below) is the most common lymphoma, representing 31% of the non-Hodgkin lymphomas (NHLs), and it is rapidly fatal if untreated. Treatment recommendations and prognosis vary with different subtypes of the disease.
Signs and symptoms
Diffuse large cell lymphomas have a rapid growth rate and present as masses infiltrating tissues or obstructing organs. 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
Pedal edema: Caused by extensive pelvic lymphadenopathy
Chest discomfort or shortness of breath: Caused by mediastinal lymphadenopathy
The following are common findings on physical examination:
Lymphadenopathy (ie, cervical, axillary, and inguinal)
Pedal edema: Resulting from extensive pelvic lymphadenopathy
See Clinical Presentation for more detail.
Lab studies used in the diagnosis and assessment of diffuse large cell lymphoma include the following:
Complete blood count: To evaluate involvement of the bone marrow, which may result in anemia, thrombocytopenia, and/or leukopenia
Serum electrolyte levels: Electrolyte abnormalities may occur from renal involvement with lymphoma
Lactate dehydrogenase and uric acid levels: Elevated levels correspond with the tumor burden
Hepatitis B testing: Performed in patients undergoing combination chemoimmunotherapy with rituximab (risk of activation)
Flow cytometry: Helps in determining a clonal cell population and in differentiating between B- and T-cell origins
Imaging studies used in the diagnosis and assessment of diffuse large cell lymphoma include the following:
Gastrointestinal imaging: Upper and lower gastrointestinal series indicated in patients with gastrointestinal symptoms, but these studies 
Central nervous system imaging: Patients with CNS symptoms require brain evaluation with CT scanning with contrast or MRI with gadolinium
Bone imaging: Bone scan for patients with unexplained bone pain or elevated alkaline phosphatase levels
CT scanning of the neck, chest, abdomen, and pelvis: To help identify degree of lymphadenopathy, presence of extranodal disease, or visceral involvement
Gallium-67 scanning - Valuable in staging diffuse large cell lymphomas
Multigated acquisition scanning: To evaluate the patient's ejection fraction before chemotherapy
Positron emission tomography: To stage disease using fluorodeoxyglucose
Biopsy and lumbar puncture
Bone marrow aspiration and biopsy are performed as part of the staging process to help rule out involvement with lymphoma. Lymph node biopsy is required to establish a definitive diagnosis of NHL. The diagnosis of diffuse large cell lymphoma is usually confirmed after positive findings are obtained from a lymph node biopsy specimen.
In patients with advanced-stage disease, a lumbar puncture for cytologic and chemical analysis of the CSF may be necessary.
See Workup for more detail.
Chemotherapeutic regimens used in the treatment of diffuse large cell lymphoma include the following:
CHOP: Cyclophosphamide, doxorubicin (Adriamycin), vincristine, and prednisone; standard treatment for early-stage diffuse large cell lymphoma; current data suggest that either 6 cycles of CHOP or 3-4 cycles of CHOP followed by involved-field radiation therapy (IFRT) is reasonable treatment for early-stage, nonbulky diffuse large cell lymphoma (stage IA or IIA, nonbulky)
R-CHOP: Rituximab plus CHOP; standard therapy for patients with advanced diffuse large cell lymphoma
Dose-adjusted EPOCH (etoposide, prednisone, vincristine [Oncovin], cyclophosphamide, doxorubicin) , plus rituximab 
Salvage chemotherapeutic regimens used in relapse therapy include the following:
DHAP - Dexamethasone, high-dose cytarabine, and cisplatin
ESHAP - Etoposide, methylprednisolone, high-dose cytarabine, and cisplatin
MIME - Mesna, ifosfamide, methotrexate, and etoposide
IMVP-16 - Ifosfamide, methotrexate, and etoposide
After the first relapse, however, the duration of the second complete response to treatment is frequently shorter than 1 year. Patients whose condition relapses and who have chemoresponsive disease, as evaluated after salvage therapy, should be considered for high-dose chemotherapy followed by stem cell rescue.
Diffuse large cell lymphoma is the most common lymphoma, representing 31% of the non-Hodgkin lymphomas (NHLs), and it is rapidly fatal if untreated. Clinically, patients with this type of lymphoma usually present with advanced, often extranodal disease. Histologically, these lymphomas contain an equal number of small and large cells (see the images below). (See Prognosis, Presentation, and Workup.)
Under the International Working Formulation, with regard to the classification of intermediate-grade diffuse large cell lymphomas, approximately 79% of these lymphomas were of B-cell origin; 16%, of T-cell origin; and 5%, unclassifiable. Exceptional cases expressed both B-cell and T-cell markers. (See Etiology.)
Incorporation of the Revised European-American Lymphoma (REAL) classification system for lymphomas has been strongly encouraged. In addition to morphologic descriptions, this schema includes immunologic, cytogenetic, and molecular information to define distinct lymphoma entities. Currently, diffuse large B-cell lymphoma is designated under the REAL classification as classic diffuse large cell lymphoma of B-cell origin defined by the working formulation. Lymphomas of T-cell or NK-cell origin exhibit biologic and clinical features distinct from diffuse large B-cell lymphomas. (See Workup.)
Diffuse large cell lymphoma of the REAL classification combines the large cell and the immunoblastic categories of the working formulation. These lymphomas are currently considered a single group, because they behave similarly and, therefore, have similar prognoses.
Historical classification of NHLs
Considerable progress has been made in NHL classification.In 1982, the National Cancer Institute introduced the International Working Formulation, a translation system for other, older classifications, including the Rappaport and the immunologically oriented Lukes-Collins and Kiel systems. The working formulation provided a conceptual framework that groups lymphomas as low grade (indolent), intermediate grade, or high grade, with respect to their natural histories. 
In 1994, the International Lymphoma Study Group proposed the REAL classification schema.  It classifies NHLs as being derived from B or T/NK cells, and it includes disease entities that were not part of the working formulation.
The presence of systemic symptoms, including fever higher than 38°C, night sweats, and/or weight loss of more than 10% of body weight in the 6 months preceding diagnosis, is denoted by the suffix B. Staging of asymptomatic patients is denoted by the suffix A.
B-cell restricted markers (CD19, CD20, CD22) are expressed consistently in diffuse large cell lymphoma. Activation antigens are variably expressed by diffuse large B-cell lymphomas, with human leukocyte antigen (HLA)-DR being the most frequent and CD23 being expressed uncommonly (0-25%). The presence of CD10 or CD5 suggests that at least one third of diffuse large cell lymphomas may have transformed from follicular lymphomas or a small lymphocytic lymphoma.
The majority of diffuse large B-cell lymphomas demonstrate rearrangements of the immunoglobulin genes by deoxyribonucleic acid (DNA) hybridization techniques, proving their B-cell lineage.
Mutations or allelic losses of the TP53 tumor suppressor gene or 17p13.1 are common in diffuse large cell lymphomas, particularly in the immunoblastic type. Changes in TP53 appear to be particularly involved in the evolution of follicular lymphoma to diffuse large cell lymphoma.  A number of cytogenetic abnormalities have been reported in these neoplasms, including t(14;18), t(8;14), trisomy 12, and deletion of 6q. [6, 7]
A study by Pasqualucci et al found that the diffuse large B-cell lymphoma coding genome contains on average more than 30 clonally represented gene alterations per case. Mutations identified included those regulating chromatin methylation (MLL2, seen in 24% of cases) and immune recognition by T cells. 
Alizadeh et al concluded that the measurement of LMO2 and TNFRSF9 can be used to predict overall survival in patients with diffuse large cell lymphomas. 
Non-Hodgkin lymphomas (NHLs) have been associated with the following conditions, drugs, and chemical agents:
Hereditary immunodeficiency disorders such as ataxia-telangiectasia syndrome, Bruton-type agammaglobulinemia, severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, Duncan syndrome, and Chediak-Higashi syndrome
Infections such as with human immunodeficiency virus (HIV), Epstein-Barr virus (EBV), Helicobacter pylori, hepatitis C virus (HCV), human T-cell leukemia virus (HTLV), and human herpes viruses (HHVs) 
Autoimmune disorders such as rheumatoid arthritis, Sjögren syndrome, and systemic lupu s erythematosus
Use of drugs such as immunosuppressants and chemotherapeutic agents 
Occupational factors - These present a weak or an inconsistent risk
Occurrence in the United States
The incidence of non-Hodgkin lymphoma (NHL) has been increasing more rapidly than many other malignancies. Overall, the incidence increased more than 73% between 1973 and 1991. The current US age-adjusted rate is 15.1 cases per 100,000 person-years for both sexes. The estimated rate for diffuse large cell lymphomas is approximately 4.68 cases per 100,000 person-years.
According to 2016 published cancer statistics, approximately 72,580 new cases of NHL will be diagnosed and 20,150 patients will die from NHL, despite currently available treatment.  Lymphomas are a heterogeneous group of malignancies with diverse biology, clinical behavior, and prognosis.
In general, lymphomas can be divided into two groups, Hodgkin (HL) and NHL. While infrequent, HL (8,500 estimated new cases in 2016) is commonly diagnosed in younger patients and is curable with appropriate therapy in 85% of cases. In contrast, NHL is the sixth most common cancer in the United States and accounts for 4% of cancer-related deaths in the United States.  Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL diagnosed in the Western hemisphere, representing 30-40% of all NHL cases diagnosed every year in the United States. 
DLBCL typically affects patients in their sixth decade, except for primary mediastinal DLBCL variant, which affects mostly females in their late 20s or early 30s. Over the past decades, the incidence of DLBCL has been increasing, a trend that has been independent of the human immunodeficiency virus (HIV) infection epidemic. 
In general, the age-adjusted incidence of diffuse large cell lymphomas is higher in developed countries. For males, it varied from 3.7 to 14 cases per 100,000 persons per year from 1983 to 1987. Since the late 20th century, rates for men and women have increased by 50% or more in 20 different countries. 
The rates by subtype, such as the subtypes Burkitt lymphoma (Epstein-Barr virus [EBV]–associated lymphoma) and human T-cell leukemia virus (HTLV) type 1–associated lymphoma/leukemia, also vary widely in different geographic areas, with specific subtypes being much more frequent in their endemic areas.
Race-, sex-, and age-related demographics
White individuals have higher rates than people of African or Asian descent  ; the Surveillance, Epidemiology, and End Results (SEER) registry demonstrates rates in white men that are 49% higher than in black men, 54% higher than in Japanese American men, and 27% higher than in Chinese American men.  These differences also apply to women.
A study by Flowers et al found differences between white and black patients with regard to presentation by and survival rate for individuals with diffuse large B-cell lymphoma. According to the study (a retrospective cohort analysis of 533 white patients with diffuse large B-cell lymphoma and 144 black patients with the disease), the median age of diagnosis was 50 years for black patients and 57 years for white patients. A higher percentage of black patients presented with elevated lactate dehydrogenase (LDH) levels, while more whites had a family history of lymphoma than did black patients (8% vs 3%, respectively). 
In the study, the survival rate among black patients was lower than among white patients, but both groups demonstrated an improved survival rate with R-CHOP (cyclophosphamide, Adriamycin, vincristine, prednisone plus rituximab) therapy.
There is a slight male disease preponderance, with a male-to-female disease incidence ratio of 1.3:1. However, diffuse large B-cell lymphoma affects females more often than males.
Although diffuse large cell lymphomas can occur at any age, they generally develop in middle-aged and older adults. Most patients with diffuse large B-cell lymphoma are diagnosed during the seventh or eighth decade of life, with a median age of 63 years.
Data suggest that 5-year survival rates in diffuse large cell lymphoma are higher for white persons than they are for people of African descent, which may or may not reflect socioeconomic factors. Women also have a better survival outcome, as do patients younger than 65 years. 
The clinical outcome of lymphoma patients has improved over the last decades as a result of several factors that include the following:
A better understanding of the pathogenesis and biology of lymphoid malignancies
Advances in technology resulting in a more precise diagnosis (ie, immunophenotyping, cytogenetic or gene expression profiling studies) and staging (ie, functional imaging)
The identification and validation of clinically based score indices or biomarkers capable of predicting clinical outcomes and/or response to therapy
The adoption of high-dose chemotherapy and autologous stem cell support (HDC-ASCS) for patients with relapsed/refractory disease
The development and adoption of novel and effective agents in the management of lymphoid malignancies (ie, monoclonal antibodies).
Risk stratification and prognostic markers in DLBCL
Risk stratification plays an important role in the management of patients with diffuse large B-cell lymphoma (DLBCL) and should be performed before starting therapy.
The International Prognostic Index (IPI) score system was the result of a collaborative effort of 16 institutions in Europe and North America that used a dataset containing clinical information of almost 2000 patients.  Briefly, the IPI score system is calculated by the sum of the presence or absence of 5 variables easily available in most clinical practices (age ≥ 65 y, performance status ≥ 2, elevated lactate dehydrogenase (LDH), Ann Arbor stage III or IV, and ≥2 extranodal sites of disease). Based on the total score, DLBCL patients are assigned into 4 risk category groups (low, low-intermediate, high-intermediate, and high) with overall survival ranging from 23-75%.
The IPI score has been validated in multiple clinical trials before and after the incorporation of rituximab into the frontline therapy of patients with DLBCL. The IPI score has also been validated in relapsing aggressive non-Hodgkin lymphoma (NHL). 
In addition, modifications from the original predictive score have been formulated, such as the age-adjusted IPI score for patients younger than 65 years and the rituximab-IPI score with similar prognostic power.
While the clinical value of the IPI score is extremely important, especially when analyzing results across multiple clinical trials, it does not provide insightful information in regard to disease biology, including mechanisms of resistance to active treatments. This fact stresses the need to further identify and validate more biologically representative biomarkers of disease response using novel technology such as gene expression profiling (GEP), proteomics, or comparative chromosomal analysis.
In a large multi-center cohort, Alinari et al reported that patients with de novo CD5+ DLBCL have a poor prognosis despite initial rituximab-containing chemotherapy. Moreover, their results suggested that stem cell transplantation fails to salvage the majority of these patients  .
Prognostic factors in early stage disease
A number of studies have analyzed factors predicting better or worse survival rates for patients with limited-stage diffuse large cell lymphoma (stage IA and IIA, nonbulky) treated with combined modality programs.
In a study by the Southwestern Oncology Group (SWOG), a subgroup analysis showed that the 5-year survival rate was better in patients who had a favorable IPI score.  Similar results were found in a study of 308 patients with limited disease treated with 3 cycles of a doxorubicin-containing regimen followed by radiotherapy.
In an Eastern Cooperative Oncology Group (ECOG) study, the 6-year disease-free survival rate for patients who achieved complete remission was greater in patients who received chemotherapy plus radiation therapy than it was in patients who received only chemotherapy (73% vs 56%, respectively).  The study compared 8 courses of a regimen of cyclophosphamide, Adriamycin, vincristine, prednisone (CHOP), with or without radiation, in patients with previously untreated bulky or extranodal stage I or II diffuse large cell lymphoma.
Despite the differences in disease-free survival, overall survival rates in the 2 groups were similar (64% for the radiation group vs 60% for the other patients).  Patients with 3 or more disease sites or a poor performance status were more likely to have treatment failure with the CHOP regimen, with or without radiotherapy.
The results from all of these studies suggest that combined modality therapy can be used to successfully treat patients with limited stage I disease and a stage-modified IPI score of zero. This approach appears to be less successful in patients with bulky stage I or II disease, 3 or more involved disease sites, and/or a stage-modified IPI score of 1 or more.
Prognostic factors in advanced-stage disease
The International Non-Hodgkin Lymphoma Prognostic Factors Project developed a predictive model of outcome for aggressive non-Hodgkin lymphoma (NHL); ie, stage II bulky or stage III or IV.  The specific 5 pretreatment characteristics that independently were statistically significant for higher-risk disease were as follows:
Age older than 60 years
Tumor stage III or IV (advanced)
More than 1 extranodal site involved by disease
Patient performance status of 2 or more
LDH elevation above the reference range
Based on these 5 characteristics, patients were stratified into 4 categories, as follows:
Low-risk patients - 0 or 1 adverse factor.
Low-risk to intermediate-risk patients - 2 factors.
High-risk to intermediate-risk patients - 3 factors.
High-risk patients - 4 or 5 factors.
When patient outcomes were analyzed by risk stratification, they had different outcomes with regard to complete response, disease-free survival, and overall survival. For example, patients with a low risk had a complete response rate of 87% and a 5-year survival rate of 73%, as compared with a complete response rate of 44% and a 5-year survival rate of 26% in the high-risk group.
Subsequent studies have confirmed the reproducibility of the IPI for predicting clinical outcome for patients with diffuse large cell lymphoma. Currently, poor-risk patients (despite achieving complete response) may be considered for aggressive therapy with high-dose chemotherapy and peripheral stem cell/bone marrow transplantation in first remission.
Tumor lysis syndrome
Tumor lysis syndrome is a potential complication following treatment of diffuse large cell lymphoma. This condition manifests as a rapid rise in potassium, phosphorus, and uric acid and a drop in calcium. TLS can lead to a sudden death from electrolyte abnormalities. Treatment that includes aggressive intravenous hydration, urine alkalinization, and administration of allopurinol usually prevents tumor lysis syndrome.
Occasionally, patients with significant tumor volume and rapidly growing disease can avoid tumor lysis syndrome by receiving dose-modified or attenuated chemotherapy as the first treatment, followed by conventional chemotherapy in subsequent treatment cycles.
Uric acid nephropathy
Uric acid nephropathy, with or without tumor lysis syndrome, usually can be prevented by administering allopurinol or alkalinizing the urine.
Neutropenic fevers and sepsis
Neutropenic fevers and sepsis are the most common potentially serious complications of chemotherapy. If not recognized and treated aggressively, these infections can cause rapid deterioration of the patient's condition, which could lead to death.
The use of cytokines (granulocyte colony-stimulating factors [G-CSFs] or granulocyte-macrophage colony-stimulating factors [GM-CSFs]) has been helpful in preventing infections by shortening, and in some cases preventing, the neutropenic period. The use of prophylactic antibiotics (especially with the fluoroquinolones [eg, ciprofloxacin, levofloxacin]) has been shown to be effective in preventing neutropenic infections.
Chemotherapy-associated complications may also include the following:
Cardiomyopathy - Related to anthracycline
Infections - During neutropenia, postchemotherapy
Gonadal dysfunction - Sterility related to chemotherapy
Secondary leukemias - Related to alkylating agents
Complications related to bone marrow transplantation
Patients with diffuse large B-cell lymphoma should receive information about the following:
Postchemotherapy thrombocytopenia and the tendency to bleed with minimal trauma
Avoidance of pregnancy in reproductive-aged women
Chemotherapy-induced nausea and vomiting
Chemotherapy-associated menstrual dysregulation (females) and the possibility of sexual dysfunction
Other sequelae of chemotherapeutic agents - Including secondary leukemias, myelodysplastic syndrome, anaphylactic reactions, and potentially fatal infections
Sperm banking and risk of sterility for males
Clearly explain transfusions (red blood cells and platelets) and associated complications. In addition, discuss the possibility of (1) long-term complications of higher doses of chemoradiotherapy and (2) mortality rates as high as 3-5% from the conditioning regimen in patients who require HDC and ASCT.
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- Approach Considerations
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- CNS Prophylaxis in DLBCL
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- Supportive Care in Chemotherapy
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