Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). The name typically refers to just the cancerous versions rather than all such tumors. Signs and symptoms may include enlarged lymph nodes, fever, drenching sweats, unintended weight loss, itching, and constantly feeling tired. The enlarged lymph nodes are usually painless. The sweats are most common at night.
The two main categories of lymphomas are the non-Hodgkin lymphoma (NHL) (90% of cases) and Hodgkin lymphoma (HL) (10%). Lymphomas, leukemias and myelomas are a part of the broader group of tumors of the hematopoietic and lymphoid tissues.
Risk factors for Hodgkin lymphoma include infection with Epstein–Barr virus and a history of the disease in the family. Risk factors for common types of non-Hodgkin lymphomas include autoimmune diseases, HIV/AIDS, infection with human T-lymphotropic virus, immunosuppressant medications, and some pesticides. Eating large amounts of red meat and tobacco smoking may also increase the risk. Diagnosis, if enlarged lymph nodes are present, is usually by lymph node biopsy. Blood, urine, and bone marrow testing may also be useful in the diagnosis. Medical imaging may then be done to determine if and where the cancer has spread. Lymphoma most often spreads to the lungs, liver, and brain.
Treatment may involve one or more of the following: chemotherapy, radiation therapy, proton therapy, targeted therapy, and surgery. In some non-Hodgkin lymphomas, an increased amount of protein produced by the lymphoma cells causes the blood to become so thick that plasmapheresis is performed to remove the protein. Watchful waiting may be appropriate for certain types. The outcome depends on the subtype, with some being curable and treatment prolonging survival in most. The five-year survival rate in the United States for all Hodgkin lymphoma subtypes is 89%, while that for non-Hodgkin lymphomas is 74%. Worldwide, lymphomas developed in 566,000 people in 2012 and caused 305,000 deaths. They make up 3–4% of all cancers, making them as a group the seventh-most-common form. In children, they are the third-most-common cancer. They occur more often in the developed world than in the developing world.
Signs and symptoms
Lymphoma commonly presents with painless, persistent lymphadenopathy (swelling of the lymph nodes) and can vary from rapidly enlarging lymph nodes in aggressive lymphomas to fluctuating lymphadenopathy in slow-growing subtypes.
B symptoms are a set of symptoms consisting of fever, night sweats, and unintended weight loss associated with Hodgkin and non-Hodgkin lymphomas. Patients with more advanced stages of lymphoma are more likely to be affected by these symptoms.
The presence of lymphoma outside the lymph nodes can cause a variety of symptoms depending on the affected organ. Extranodal involvement is common in non-Hodgkin lymphoma, with 40% of patients experiencing some form of it. Aggressive non-Hodgkin lymphomas make systemic symptoms more likely.
Mediastinal lymphadenopathy, and less commonly, pulmonary lymphoma, may cause cough, dyspnea, chest pain, or superior vena cava syndrome, due to compression of the windpipe, the superior vena cava, or nerves in the chest.
Lymphoma in bone marrow can cause anemia, thrombocytopenia, and fatigue. Bone marrow involvement is most common in low-grade, non-Hodgkin lymphomas, and especially in follicular, mantle cell, and small B-cell lymphomas (40-90% of cases depending on subtype).
Chronic pain, fullness, early satiety, and gastrointestinal bleeding are symptoms associated with gastrointestinal lymphoma. The gastrointestinal tract is the most common location for extranodal involvement with non-Hodgkin lymphomas, accounting for 30-40% of extranodal lymphomas in general, while in Hodgkin lymphomas, it is rare, accounting for less than 1% of cases.
Although uncommon, involvement with the central nervous system can cause symptoms including confusion, double vision, headaches, nausea, and hearing loss. It is rare in Hodgkin lymphomas, with only 0.2% to 0.5% of patients experiencing it, but occurs more often in non-Hodgkin lymphoma, ranging from 2.8% in indolent forms to 24.4% in high-grade lymphoblastic and Burkitt lymphoma.
Paraneoplastic syndromes are rare in lymphoma. Paraneoplastic cerebellar degeneration is most strongly associated with Hodgkin lymphomas, while polymyositis and dermatomyositis are associated with both Hodgkin and non-Hodgkin lymphomas.
Diagnosis
Lymphoma is definitively diagnosed by a lymph-node biopsy or biopsy of extranodal tissue, which is examined under the microscope. This examination reveals histopathological features that may indicate lymphoma.
Imaging may be performed as part of the initial workup for lymphoma. CT scans can identify enlarged lymph nodes, while fluorodeoxyglucose (FDG) PET imaging identifies areas of increased lymph node activity.
Laboratory tests may also be used as part of initial workup to assess affected organ function, blood counts, and conditions that may affect treatment. Complete blood counts can show signs of bone marrow, spleen, and GI tract involvement through blood count abnormalities, including anemia, both low and high platelet count, and low white cell count.
Testing for HIV and hepatitis B and C may also be performed due HIV being associated with an increased risk for lymphoma and hepatitis potentially reactivating with certain antibody treatments.
After lymphoma is diagnosed, a variety of tests may be carried out to look for specific features characteristic of different types of lymphoma including immunophenotyping (targeting of proteins expressed on cells), flow cytometry, and fluorescence in situ hybridization testing.
Staging
After a diagnosis and before treatment, cancer is staged. This refers to determining if the cancer has spread, and if so, whether locally or to distant sites. Staging is reported using a scale, from I (confined) to IV (spread). The stage of a lymphoma helps predict a patient's prognosis and is used to help select the appropriate therapy.
The Lugano classification system, a modified version of the older Ann Arbor staging system (from 1971), is the standard used for staging of both HL and NHL.
The specific criteria for each stage are as follows: +Lugano classificationStageDescriptionLimited stageISingle node or group of adjacent nodesII≥ 2 groups of nodes on one side of diaphragmAdvanced stageIIINodes on both sides of the diaphragm; or nodes above diaphragm with spleen involvementIVDiffuse or disseminated extranodal disease, with or without involvement of lymph nodes; or non-contiguous extranodal involvement in addition to stage II/III disease. The presence of B symptoms (one or more of the following: unintentional loss of 10% body weight in the last 6 months, night sweats, or persistent fever of 38°C or more) or their absence is expressed with a B or A suffix, respectively. This modifier is only used with Hodgkin lymphoma patients, as correlation with prognosis was not found within cases of NHL.
FDG-PET/CT imaging is used for staging fluorodeoxyglucose-avid lymphomas, like Hodgkin lymphoma, while CT scans are used for non-FDG-avid lymphomas, which include some non-Hodgkin subtypes. In Hodgkin lymphoma and some non-Hodgkin lymphomas, like diffuse large B-cell lymphoma, PET/CT can replace bone marrow biopsy.
Differential diagnosis A variety of infections and conditions can mimic lymphoma, owing to the diverse presentation of lymphoma subtypes, particularly within non-Hodgkin lymphomas. The differential diagnosis varies according to the type of lymphoma and the organs affected within the body.
Hodgkin lymphoma Hodgkin lymphoma can resemble several other lymphoma subtypes and non-cancerous diseases, including:
Diffuse large B-cell lymphoma Primary mediastinal B-cell lymphoma (sometimes called gray zone lymphoma when features overlap with classical HL) Peripheral T-cell lymphoma Anaplastic large cell lymphoma Infectious mononucleosis Hemophagocytic lymphohistiocytosis
Non-Hodgkin lymphoma The differential diagnosis for non-Hodgkin lymphoma varies according to subtype and affected organs. Diseases that present similarly are often other lymphoid disorders, metastatic cancers, infections (especially in aggressive subtypes), and lymphoproliferative disorders, including:
Hodgkin lymphoma Appendicitis and intussusception Toxoplasmosis Epstein-Barr viral infection Systemic lupus erythematosus Castleman disease, granulocytic sarcoma, or other lymphoproliferative disorders Metastases from primary tumors Bacterial infections, especially mycobacterial infections
Certain lymphomas (extranodal NK/T-cell lymphoma, nasal type and type II enteropathy-associated T-cell lymphoma) can be mimicked by two benign diseases that involve the excessive proliferation of nonmalignant NK cells in the GI tract, natural killer cell enteropathy, a disease wherein NK cell infiltrative lesions occur in the intestine, colon, stomach, or esophagus, and lymphomatoid gastropathy, a disease wherein these cells' infiltrative lesions are limited to the stomach. These diseases do not progress to cancer, may regress spontaneously, and do not respond to or require chemotherapy or other lymphoma treatments.
Classification
According to the World Health Organization (WHO), lymphoma classification should reflect in which lymphocyte population the neoplasm arises. Thus, neoplasms that arise from precursor lymphoid cells are distinguished from those that arise from mature lymphoid cells. Most mature lymphoid neoplasms comprise the non-Hodgkin lymphomas. Because of their common involvement with lymphoid tissue, mature histiocytic and dendritic cell (HDC) neoplasms were historically discussed alongside mature lymphoid neoplasms, even though they are distinct in cellular origin.
Lymphoma can also spread to the central nervous system, often around the brain in the meninges, known as lymphomatous meningitis (LM).
Hodgkin lymphoma
Hodgkin lymphoma accounts for about 10% of lymphomas. It differs from other forms of lymphomas in its prognosis and several pathological characteristics. A division into Hodgkin and non-Hodgkin lymphomas is used in several of the older classification systems. A Hodgkin lymphoma is marked by the presence of a type of cell called the Reed–Sternberg cell.National Cancer Institute, "Hodgkin Lymphoma", , accessed on 2013-08-05National Cancer Institute. "What You Need To Know About Hodgkin Lymphoma". U.S. Dept of Health and Human Services, (online at ), pg 4.
Non-Hodgkin lymphomas Non-Hodgkin lymphomas, which are defined as all lymphomas except Hodgkin lymphoma, are more common than Hodgkin lymphoma. A wide variety of lymphomas are in this class, and the causes, the types of cells involved, and the prognoses vary by type. The number of cases annually of non-Hodgkin lymphoma increases with age. It is further divided into several subtypes.
Epstein–Barr virus-associated lymphoproliferative diseases
Epstein–Barr virus-associated lymphoproliferative diseases are a group of benign, premalignant, and malignant diseases of lymphoid cells (i.e., B cells, T cells, NK cells, and histiocytic-dendritic cells) in which one or more of these cell types is infected with the Epstein–Barr virus (EBV). The virus may be responsible for the development and/or progression of these diseases.
In addition to EBV-positive Hodgkin lymphomas, the World Health Organization (2016) includes the following lymphomas, when associated with EBV infection, in this group of diseases:
WHO classification