Lymphoma

Practice Essentials 

Lymphomas are a diverse group of hematologic malignancies that typically develops in lymph nodes and can originate from B cells, T cells, and natural killer (NK) cells.^1,2 They are broadly divided into two categories, Hodgkin lymphoma and non-Hodgkin lymphoma (NHL).³ In 2016, the World Health Organization (WHO) updated its lymphoma classification, which now includes 60 subtypes of NHL and five subtypes of Hodgkin lymphoma.^4,5

The exact etiology of lymphoma is not known. However, certain environmental, infectious, medical, and genetic factors are known to be associated with the disease.^2-9 There is a higher incidence of NHL than Hodgkin lymphoma, and NHL is the seventh-most common cancer in the United States.

Hodgkin lymphoma was the first form of cancer for which curative treatment was established and the current cure rate is high for all stages. However, because so many patients are cured, long-term effects of treatment are a substantial concern.^4,5,7,8

The survival rate for NHL varies by subtype of disease, stage, and other prognostic factors. Some indolent forms do not require treatment when patients are asymptomatic, but may later require treatment, which is usually not curative. Aggressive forms of NHL necessitate immediate treatment, which has the potential to be curative.^5,8

Diagnosis of lymphoma starts with a thorough history and physical examination that includes attention to signs and symptoms of extranodal disease in addition to typical symptoms of lymphoma such as night sweats, weight loss, or fever.^4,5,7,8

Chemotherapy, radiation therapy, immunotherapy, targeted therapy, and high-dose chemotherapy with autologous hematopoietic stem cell transplantation are all modalities that may be used to treat lymphoma, depending on the subtype, stage, and prognostic criteria.^4,5,7,8

Pathophysiology

The WHO classification of lymphoma identifies four main groups that encompass all types of lymphoma.⁶ These groups are distinguished by their cell lineage and derivation from precursor or mature cells and include precursor B- and T-cell neoplasms, mature B-cell neoplasms, mature T- and NK-cell neoplasms, and Hodgkin lymphomas. Ninety percent of all lymphomas are of B-cell origin.⁷ Specific disease entities are further distinguished by their morphology, immunophenotype, and genetic, molecular, and clinical characteristics.¹

There are two types of Hodgkin lymphoma. Classical Hodgkin lymphoma (which includes 4 subtypes) and nodular lymphocyte-predominant Hodgkin lymphoma account for 95% and 5% of cases, respectively.^1,4 Both derive from mature B lymphocytes and are notable for their low ratio of tumor to reactive cells.⁷

The characteristic tumor cell of classical Hodgkin lymphoma is the Reed-Sternberg cell, a large cell with multiple or multilobulated nuclei that is pathognomonic for the disease.^3,9 By contrast, the tumor cell of nodular lymphocyte-predominant Hodgkin lymphoma is the LP cell, a large cell with a single nucleus containing multilobated or folded features with nucleoli. These two cell types are morphologically and phenotypically distinct.¹

NHL can arise from B, T, or NK cells with mature B-cell lymphomas, accounting for 85% to 90% of cases.¹⁰ Most B-cell lymphomas arise following the gene recombination and somatic hypermutation phases of B-cell development and oncogenesis can result from events such as chromosomal translocations leading to activation of an oncogene or inactivation of a tumor suppressor gene. Similarly, T-cell development involves rearrangement and recombination that can lead to oncogenic errors.⁷  In addition to being classified by cell type, NHL subtypes are also further categorized as aggressive or indolent.¹⁰

Etiology

While the exact cause of lymphomas is unknown, there are certain environmental, infectious, medical, and genetic components that are associated with its development.^2,4,7

Environmental

Agricultural chemicals such as herbicides and pesticides have been linked to increased incidence of NHL. Wood dust, epoxy glue, and organic solvents have also been associated with NHL. Occupational exposure through farming, forestry, painting, and carpentry are additionally associated with increased incidence of NHL.^2,5,7

Infectious

Epstein-Barr virus (EBV) is identified in about 50% of cases of Hodgkin lymphoma. EBV is detected in almost all patients with human immunodeficiency virus (HIV) and classical Hodgkin lymphoma, while it is present in about one-third of patients without HIV who have classical Hodgkin lymphoma. Additionally, EBV is associated with multiple forms of NHL, including Burkitt lymphoma, central nervous system lymphomas, and extranodal nasal NK/T-cell lymphoma.^2,4,5,7,8

Human T-lymphotropic virus type 1 (HTLV-1), hepatitis C virus, human herpesvirus-8, Helicobacter pylori, and possibly Chlamydophila psittaci are additionally implicated causes or associated with development of lymphoma.²

Medical

Autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and sarcoidosis confer increased risk for Hodgkin lymphoma, as does a family history of these diseases.⁴

Certain medications are also associated with the development of NHL, including methotrexate, digoxin, phenytoin, and tumor necrosis factor (TNF) alpha inhibitors. Current or prior radiation, as well as prior chemotherapy, also increase one’s risk for development of NHL.⁷

Immunosuppression and immunodeficiency are associated with increased risk of both Hodgkin lymphoma and NHL. HIV, organ transplantation, and rare inherited immunodeficiencies like ataxia telangiectasia and Wiskott-Aldrich syndrome all increase risk for lymphomas, especially highly aggressive types in some cases. Among patients with HIV, NHL is the most common tumor and the diffuse large B-cell lymphoma (DLBCL) subtype accounts for 80% to 90% of cases.^5,7

Genetic

A family history of NHL or personal history of NHL or Hodgkin lymphoma are all risk factors for the development of NHL.⁵ Patients with certain genetic HLA haplotypes (i.e., HLA-A*01) are at higher risk of developing Hodgkin lymphoma, as are individuals with a first-degree relative with Hodgkin lymphoma.⁴ A monozygotic twin has a significantly higher risk of developing Hodgkin lymphoma when their twin is affected than a dizygotic twin.⁹

Epidemiology

NHL is the seventh-most common type of cancer in the United States and more than 70,000 new cases are diagnosed yearly.^2,11 The incidence of NHL is approximately 10 times higher than that of Hodgkin lymphoma.⁶ NHL accounts for 4.3% of all neoplasms in the United States and is the fifth-most common cause of cancer deaths.²

Among children younger than 14 years old, lymphoma is the third-most common type of cancer. It is the most common type of cancer in children ages 15 to 19 years old and accounts for more than 25% of new cancer diagnoses in this age group.³

Both Hodgkin lymphoma and NHL are more common in men.^7,8 Hodgkin lymphoma has a bimodal age distribution with peak incidence among patients in their 20s and 80s.⁸ By contrast, the incidence of NHL increases exponentially with increasing age. However, certain forms of NHL are exceptions to this pattern of age distribution, such as lymphoblastic lymphoma, which occurs most often in children. Similarly, Burkitt lymphoma occurs most often in the 20- to 64-year-old population, and primary mediastinal B-cell lymphoma peaks in incidence at age 35 years.²

The incidence of NHL subtypes also varies by geographic region. In the United States, DLBCL is the most common subtype of NHL, accounting for 30% of cases; follicular lymphoma, the second-most common subtype, accounts for 20% to 25% cases.⁵ However, in Japan, the overall incidence of NHL is lower than in the United States, but the incidence of extranodal lymphoma is higher. In sub-Saharan Africa, Burkitt lymphoma is the most common NHL subtype.²

The incidence of NHL nearly doubled between 1975 and 1995. However, since 1995, the incidence has remained stable. The cause of this rise in cases is not entirely clear but is thought to be related to several factors, including cancer registrations, improved testing capabilities, and increased investigation of symptoms in older patients.²

Prognosis

The prognosis for patients with Hodgkin lymphoma is overall quite favorable, with a five-year relative survival rate of 88.3%, dependent on disease stage at the time of diagnosis and additional prognostic factors.⁴ The five-year relative survival rate from 2011-2017 by stage is as follows:¹² 

• Stage I: 92.2%
• Stage II: 94.3%
• Stage III: 85.5%
• Stage IV: 78.5%

Late treatment-related adverse effects are a significant concern in Hodgkin lymphoma. Due to the high rate of survivorship in early-stage disease, some studies have shown that a greater proportion of patients die from late effects of therapy than from the disease itself.⁸

Unfavorable prognostic criteria for early-stage disease include bulky mediastinal mass, elevated erythrocyte sedimentation rate (ESR), multiple nodal sites, extranodal involvement, age >50 years, or massive splenic disease. For advanced-stage disease, unfavorable features according to the International Prognostic Index (IPI) include male sex, age >45 years, stage IV disease, serum albumin <4 g/dL, hemoglobin <10.5 g/dL, white blood cell count (WBC) of >15,000/mm³, and lymphocyte count <8% of WBC count or absolute lymphocyte count <600/mm³.^4,9

From 2011-2017, the overall five-year relative survival rate for NHL was 73.2%. Like Hodgkin lymphoma, prognosis worsens with advancing disease stage at diagnosis. The five-year relative survival rate for NHL by stage is as follows:¹¹

• Stage I: 84.3%
• Stage II: 77.1%
• Stage III: 71.1%
• Stage IV: 63.7%

Overall, 50-60% of patients with aggressive NHL achieve complete remission. Prognostic criteria for these patients include subtype, patient age, and extent of disease. Patients with indolent disease may achieve a relatively long survival despite the lack of cure from chemoimmunotherapy.⁵

 

References

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