Diffuse Large B-Cell Lymphoma

Etiology

B-cell lymphomas result from malignant proliferation of B cells at various stages of development. Depending on the morphology, genetics, and immunophenotype of the neoplastic cells, a cell of origin is proposed. The development of B cells can be categorized into 3 stages: pre-germinal, germinal, and post-germinal center. Most B-cell lymphomas are derived from the germinal center. Like any other malignancy, B-cell lymphomas can result from the genetic mutations affecting the proto-oncogenes and tumor suppressor genes; however, the environment within the lymph nodes can also promote lymphomagenesis.[3]

Genetic alterations in the BCL6 gene are present in 20% to 40% of patients. Chronic immunodeficiency of T cells and B cell stimulation can be the possible cause for NHL in human immunodeficiency virus (HIV) infected patients. Certain infectious agents can directly manipulate DNA, as seen in Burkitt lymphoma, where Epstein-Barr virus DNA is transported into the B cell nucleus, thereby altering B cell growth and development.[4] HIV is a risk factor for neoplasm development, as it decreases the host's ability to regulate malignant cells.

Likewise, an immunosuppressive medication used in transplant patients is a risk factor for the development of B-cell lymphomas. Also, the transformation from different kinds of lymphomas, including splenic marginal zone lymphoma, marginal zone (MALT) lymphoma, and chronic lymphocytic leukemia (Richter transformation), can result in DLBCL. Other risk factors for the development of B-cell lymphomas include family or personal history of lymphoma, radiation exposure, and chemotherapy. Chemical agents such as dyes and pesticides can also increase the risk for lymphoma. Non-Hodgkin lymphoma (NHL) is more common in obese patients and those with an underlying history of autoimmune diseases.[5][6]

Epidemiology

The incidence of non-Hodgkin lymphoma in the United States is approximately 7 cases per 100,000 per year.[7] DLBCL accounts for about 25% of all NHL cases worldwide. DLBCL is the most common NHL, followed by follicular lymphoma.[8] The disease occurs more frequently in whites, followed by African Americans and Asians, with male preponderance and a median age of 64 years. The overall incidence increases exponentially with age.

Pathophysiology

To better understand the molecular diversity among morphologically similar variants of DLBCL, high-throughput technologies such as gene expression profiling (GEP) could classify DLBCL into germinal center B-cell (GCB) and activated B-cell (ABC) subtypes. Most patients with DLBCL show gene rearrangements in the heavy and light chains of immunoglobulins. About 80% of DLBCL express B cell leukemia or lymphoma 2 (BCL2) protein, and 70% expresses B cell lymphoma 6 (BCL6) protein.[9] Some of them also show abnormalities in the MYC gene. The flow cytometry reveals CD19, CD20, CD22, CD45 and CD79a. CD30 can be seen in 25% and carries a favorable prognosis. Very rarely, they can express CD5, which has a poor prognosis.[10]

More than 50% of the DLBCL express surface or cytoplasmic immunoglobulin IgM. Double hit lymphoma presents like DLBCL but has MYC along with BCL2 and/or BCL6. A triple hit lymphoma has rearrangements in BCL2, BCL6, and MYC. The (14;18) translocation is related to disseminated and nodal disease and does not imply a poor prognosis. The t(14; 18) is seen in more than 90% of follicular lymphoma cases and about 30% of DLBCL cases. DLBCL commonly involves extranodal sites, which include the brain, bones, kidneys, adrenal glands, and other soft tissues.[11] 

The pathophysiology of non-Hodgkin B-cell lymphomas is dependent on the type of lymphoma. B-cell lymphomas are categorized by the stage of B-cell development that has resulted in malignancy (eg, mantle cell vs marginal zone lymphoma). Lymphadenopathy results from B-cell proliferation in or around the germinal center. Systemic symptoms (B-symptoms) result from increased cytokine production. Elevated levels of LDH and uric acid suggest high cell turnover and release of degradation products into the bloodstream. 

Histopathology

The normal architecture of lymph nodes is distorted and is replaced by sheets of atypical lymphoid cells with large nuclei, basophilic cytoplasm, and high proliferation rate.

History and Physical

Most NHLs spread hematogenously, whereas Hodgkin lymphoma disseminates via the lymphatic system. Due to the hematogenous spread, most present with advanced disease (stage III or IV). A whole-body lymphoid survey should be performed, including the head, neck, cervical, supraclavicular, axillary, mesenteric, femoral, and inguinal lymph nodes. An abdominal examination should be performed to evaluate for enlargement of the liver and spleen. DLBCL commonly presents with enlarged lymph nodes or a rapidly growing mass, along with B symptoms, including fever, night sweats, and weight loss. The B symptoms can be seen in 30% of the patients. Bone marrow involvement is more common in indolent disease and can be seen in up to 50% of cases.[12]

About 50% of the patients have extranodal involvement. The stomach or gastrointestinal tract is the most common primary extranodal site, followed by the skin. Renal involvement can be secondary to bulky disease or lymphadenopathy, causing a ureteral obstruction, or due to tumor lysis syndrome. Extralymphatic involvement is seen in aggressive NHL. DLBCL can also present with symptoms suggestive of superior vena cava syndrome and compression of the airways. The symptoms can be related to the infiltrated organ if the disease spreads beyond the lymphatics in so-called extranodal disease. Extranodal disease can manifest in the skin, bones, spinal cord, and testicles, among other sites. A variety of paraneoplastic syndromes may also be associated with B-cell lymphomas.[13]

The presentation of B-cell lymphomas varies depending on whether the subtype is aggressive or indolent. The aggressive B-cell lymphomas, such as DLBCL and Burkitt lymphoma, typically present with a rapidly growing mass. Epidural spinal cord compression can be the manifestation of NHL or can happen at the time of relapse.[14] Indolent lymphomas, such as follicular lymphoma and marginal zone lymphoma, develop over time, and the history reveals intermittent or progressive lymphadenopathy. Follicular lymphoma typically presents with painless lymphadenopathy and near-normal LDH levels.

Evaluation

A detailed clinical and physical examination and laboratory and imaging studies are essential for the diagnosis of lymphoma. Laboratory data include Complete blood count with differential (CBC), comprehensive metabolic profile (CMP), lactate dehydrogenase (LDH), HIV and Hepatitis B and C serologies, and serum protein electrophoresis. CBC can show cellular atypia on smears as well as cytopenias. Patients with symptoms or at risk of central nervous system (CNS) involvement should have a lumbar puncture. HIV should be tested, as B-cell lymphomas can be an AIDS-defining illness. Besides, as the treatment involves significant immunosuppression, it requires consideration of the patient’s HIV and hepatitis status. Renal involvement can be seen in up to 14% of patients. LDH is elevated in more than 50% of the cases. LDH is a predictor of survival.[15]

Excisional biopsy of the lymph node is preferred over fine-needle aspiration (FNA) to assess the entire nodal architecture, along with histologic and immunologic studies. Morphology and immunophenotyping, along with staining for B-cell markers, are required for diagnosis. Imaging of choice includes positron emission tomography (PET) and computed tomography for disease staging. PET is useful in most B-cell lymphomas, as the sites with high standardized uptake value (SUV) may indicate aggressive disease. PET is less useful in CLL because it is fluoro-deoxyglucose (FDG)- nonavid.[16] Along with staging, imaging can help identify the least invasive site for diagnostic biopsy. In the absence of significant lymphadenopathy, tissue sampling of the involved organs should be considered. 

Treatment / Management

The treatment of B-cell lymphomas depends not only on their stage but also on the disease type (indolent or aggressive) and the molecular subtype. Though DLBCL is aggressive, with appropriate chemotherapy, survival can be long, but with a limited cure rate. Patients with GCB DLBCL respond well to 6 cycles of the rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone (R-CHOP) regimen, given every 21 days.[17][18] Rituximab is an anti-CD20 monoclonal antibody and is administered intravenously at 375 mg/m² on day 1 of chemotherapy. ABC DLBCL, along with double-hit and triple-hit lymphomas, had poor outcomes with R-CHOP.(A1)

Studies have shown that patients with ABC DLBCL should be enrolled in clinical trials, and that the use of R-CHOP, along with lenalidomide, bortezomib, or ibrutinib, is indicated. The more aggressive approach is rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP), followed by consolidation with methotrexate and leucovorin.[19] Studies have suggested using 6-8 cycles of rituximab, etoposide, prednisone, vinblastine, cyclophosphamide, and doxorubicin (R-EPOCH) in patients with advanced double-hit DLBCL. Intravenous rituximab therapy has become the backbone of treatment for indolent lymphomas. Other regimens include (R-CHOP); bendamustine or cyclophosphamide, doxorubicin, and prednisone (R-CVP).(A1)

The treatment for indolent lymphomas, such as follicular lymphoma, marginal zone lymphoma, and small lymphocytic lymphoma, often depends upon the bulk of the disease and, in symptomatic cases. Some patients with the aggressive low-grade disease have been treated with allogeneic transplants with curative intent. Radiotherapy should be considered in patients with bulky disease. Mantle cell lymphomas are treated aggressively with immunochemotherapy and autologous stem cell transplants. Burkitt lymphoma and lymphoblastic lymphoma are considered high-grade and need aggressive chemotherapy along with prophylactic intrathecal chemotherapy.

Differential Diagnosis

The differential diagnoses include infectious mononucleosis, Hodgkin lymphoma, T-cell lymphomas, and other large-cell malignancies, such as carcinomas, melanoma, and Kikuchi disease. Melanomas can also involve the lymph nodes, but can be differentiated from DLBCL by positive staining for S100, HMB-45, and Melan A.

Toxicity and Adverse Effect Management

Toxicity and adverse effect management considerations in DLBCL include the following:

• Infection risk
• Febrile neutropenia
• Reactivation of hepatitis
• Progressive multifocal leukoencephalopathy

Staging

Originally, the Ann Arbor staging system was introduced for Hodgkin lymphoma in 1974 and later modified in 1988. The current staging system, the Lugano classification, is based on the Ann Arbor classification.[20] A single lymph node region is a node or group of adjacent nodes.

• Stage I - NHL involving 1 lymph node region or an extranodal site
• Stage IE - Involvement of a single extra lymphatic site. "E" stands for limited extranodal involvement.
• Stage II - Involving 2 or more lymph nodes on the same side of the diaphragm
• Stage III - Involving lymph nodes on both sides of the diaphragm
• Stage IV - Spreads into 1 or more extra-lymphatic organs (bone marrow, liver, lung) with or without the involvement of the lymph node.

Prognosis

Overall, the prognosis of NHL depends on disease staging, histopathology, extranodal involvement, age, and performance status. Treatment response is monitored by clinical examination, laboratory values, and imaging studies. The International Prognostic Index (IPI) can be used to prognosticate DLBCL. Age greater than 60 years, Eastern Cooperative Oncology Group (ECOG) performance status greater than 2, elevated LDH, clinical stage III/IV, and more than 1 extranodal site of involvement are associated with decreased overall survival. DLBCL is an aggressive disease that can be cured in up to 50% of patients who achieve a complete remission following treatment with first-line therapy. The GCB cell type has a better prognosis compared to the ABC type. Double-hit and triple-hit lymphomas carry a poor prognosis when compared to DLBCL.

Complications

Complications associated with DLBCL include the following: 

• Involvement of bone marrow leading to cytopenias and increased risk of infection. 
• Renal failure
• CNS involvement