Lymphomas are malignancies that arise from lymphocytes and are classified as either Hodgkin lymphomas (characterized by Reed-Sternberg cells) or non-Hodgkin lymphomas (NHLs), which comprise all other types of lymphoma. NHLs are further classified according to cell type, i.e., B cells, T cells, and natural killer (NK) cells; location (nodal or extranodal); and tumor grade. Low-grade tumors originate from mature cells that have a slow growth rate and an indolent clinical course. The most common low-grade B-cell lymphoma is follicular lymphoma, while the most common low-grade T-cell lymphomas are cutaneous T-cell lymphomas, such as mycosis fungoides. High-grade tumors have a rapid growth rate and an aggressive clinical course. Certain subtypes of NHL, such as Burkitt lymphoma, are more common in children and young adults than in older adults. NHL is diagnosed by obtaining a biopsy of the affected tissue and carrying out a detailed assessment, including immunophenotyping, genetics, and molecular testing. These studies allow for the identification of specific NHL subtypes, which guides treatment. Generally, treatment involves a combination of chemotherapy and radiation therapy. Patients with high-grade NHLs and those with low-grade tumors and limited disease are treated with curative intent. Patients with advanced, low-grade tumors who experience symptoms usually receive palliative treatment.
- Incidence: NHL is the most common hematopoietic neoplasm. 
Epidemiological data refers to the US, unless otherwise specified.
- Chromosomal translocations: most commonly t(14;18)
- Infections 
- Autoimmune diseases: Hashimoto thyroiditis, rheumatoid arthritis
- Immunodeficiency: congenital immunodeficiencies, AIDS, history of chemotherapy and/or immunosuppressive therapy
- Environmental factors: aromatic hydrocarbons (e.g., benzene), radiation
B-cell lymphomas (85% of all NHLs)
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T-cell lymphomas (15% of all NHL)
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Think of an aggressive man to remember that the occurrence of mantle cell lymphoma is greater in men and that the disease has an aggressive course.
Nodal disease: typically painless lymphadenopathy associated with fatigue and weakness (multiple noncontiguous lymph nodes may be involved) 
- High grade
- Low grade
- Extranodal disease (primary or secondary): The symptoms are highly dependent on the affected tissue; B symptoms are common. 
- Oncologic emergencies/paraneoplastic syndromes 
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Necrotizing lymphadenitis (Kikuchi-Fujimoto disease) 
- Etiology: unknown
- Clinical features: painful cervical lymphadenopathy and fever
- Diagnostics: Lymph node biopsy shows single or multiple necrotic foci, histiocytic cellular infiltration, without granulocytic involvement.
- Treatment: typically resolves spontaneously within 1–4 months of onset without treatment
The differential diagnoses listed here are not exhaustive.
- Suspect NHL in patients with suggestive clinical or laboratory features.
- Confirm the diagnosis and determine the subtype via lymph node and/or tissue biopsies.
- Stage and classify the disease (see “Staging of NHL”), e.g.:
The clinical presentation of patients with NHL varies (e.g., nodal symptoms, extranodal symptoms, oncologic emergencies, or paraneoplastic syndromes); therefore, clinicians must maintain a high index of suspicion to facilitate early diagnosis.
Laboratory studies 
- Routine laboratory studies
- Markers of disease activity 
- Viral serologies
Confirmatory diagnostics tests 
Histopathological studies are required to diagnose lymphoma. Large samples are preferred as intact tissue architecture is required to classify the subtype. If initial biopsy results are negative in patients with symptoms that are highly suggestive of lymphoma, consider obtaining a larger biopsy sample and repeating the studies.
Selection of biopsy sample
- Select the most appropriate node for biopsy (e.g., a node with significant, progressive, and persistent enlargement).
- Imaging methods such as CT and PET-CT may be used to select a site (see “Staging of NHL”).
- Techniques 
- Extranodal disease
Histopathology and specialized studies
These studies help determine the subtype of NHL.
- Histopathology: provides a detailed morphology of individual proliferating cells and a description of the pattern of lymph node (or tissue) infiltration (e.g., nodular, diffuse)
- Immunophenotype (e.g., flow cytometry, immunohistochemistry)
- Genetic studies
- Bone marrow aspiration and biopsy: indicated in most newly diagnosed patients with NHL
- Assessment of CNS involvement
Lugano classification is the preferred classification method for primary nodal NHL.
- Imaging is used to assess the number and location of affected lymph nodes, tumor bulk, and liver and spleen involvement.
- Bone marrow biopsy to assess bone marrow involvement
- The disease is then classified as either:
- Limited disease (stage I + II): one node or conglomerate (stage I), or ≥ 2 nodes or conglomerates on one side of the diaphragm (stage II)
- Advanced disease (stage III + IV): nodes on both sides of the diaphragm or supradiaphragmatic nodes with splenic involvement (stage III), or diffuse or disseminated disease (stage IV)
- Previously, a version of the B symptoms. was used, excluding the presence of
Most patients with newly diagnosed NHL require chemotherapy, radiotherapy, or both. In some patients with indolent NHLs, such as follicular lymphoma, occasionally a watch and wait strategy can be used. Consultation with a hematologist-oncologist is essential for planning and initiating treatment.
- Pretreatment evaluation
Selection of treatment: based on the subtype of NHL, staging, and prognosis
- Most patients will receive treatment with systemic chemotherapy and/or radiotherapy.
- Select patients may benefit from additional interventions, including splenectomy and hematopoietic stem cell transplantation (HSCT).
- Supportive treatment
Pretreatment evaluation is essential in all patients receiving chemotherapy for NHL to adequately adjust chemotherapeutic doses according to patients' hepatic, renal, and cardiac function.
Treatment options 
- May be curative or palliative
- Can be conventional or combined with immunotherapy (radioimmunotherapy)
Systemic chemotherapy: Regimens usually include combinations of chemotherapeutic agents, steroids, and immunotherapy.
- Antifolates: high-dose methotrexate ; (in combination with leucovorin) for primary CNS lymphoma
- Alkylating agents: e.g., cyclophosphamide (C)
- Topoisomerase II inhibitors: e.g., etoposide (E), doxorubicin/hydroxydaunorubicin (H)
- Alkaloids: e.g., vincristine/oncovin (V/O)
- Steroids: e.g., prednisolone (P), dexamethasone
- Immunotherapy: e.g., rituximab (R)
- Intrathecal chemotherapy: Intrathecal methotrexate can be considered for leptomeningeal involvement.
Specific regimens 
Below is a summary of some of the common treatment regimens found in the literature for select NHL subtypes; these regimens are intended to provide an overview only and treatment decisions should be tailored to the patient and the features of the disease (e.g., specific mutations, location, extent).
|Treatment regimens for non-Hodgkin lymphomas |
|Subtype||Frequently used treatment|
|Mature B-cell neoplasms|
|Mature T-cell neoplasms|| |
|Cutaneous T-cell lymphoma|| |
Some new therapies are emerging as part of the management of certain types of NHLs, including targeted therapies (e.g., ibrutinib) and monoclonal antibodies (e.g., mogamulizumab). If available, a specialist may choose to use them depending on the individual evaluation of each patient.
Additional therapies 
- Typically, the prognosis of NHL is worse than that of Hodgkin lymphoma. 
- Indicators of poor prognosis: old age, number of involved nodal and extranodal sites, ↑ LDH, ↑ beta2 microglobulin