Trusted medical expertise in seconds.

Access 1,000+ clinical and preclinical articles. Find answers fast with the high-powered search feature and clinical tools.

Try free for 5 days
Evidence-based content, created and peer-reviewed by physicians. Read the disclaimer.

Non-Hodgkin lymphomas

Last updated: August 18, 2021

Summarytoggle arrow icon

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.

Epidemiological data refers to the US, unless otherwise specified.

B-cell lymphomas (85% of all NHLs)

B-cell lymphomas
Grade Lymphoma Features

Indolent (low-grade)

  • Follicular lymphoma
  • Most common low-grade lymphoma in adults
  • Slowly progressive and painless course with an alternating (waxing and waning) pattern of lymphadenopathy and splenomegaly
  • Translocation t(14,18), which involves the heavy-chain Ig (chromosome 14) and Bcl-2 gene (chromosome 18) overexpression of Bcl-2 → dysregulation of apoptosis (normally inhibited by Bcl-2)
  • Centrocyte: nodular, small cells with cleaved nuclei
  • Hairy cell leukemia
  • Small lymphocytic lymphoma (SLL) [3]

Aggressive (high-grade)

  • Most common in adult men
  • Translocation t(11;14) involving cyclin D1 (chromosome 11) and heavy-chain Ig (chromosome 14) increased levels of cyclin D1 → promotes the transition of cells to S phase
  • CD5+
  • Spreads rapidly; most patients are diagnosed with advanced disease (stage IV)
  • Burkitt lymphoma [7]
    • Sporadic: typically located in the abdomen or pelvis
    • Endemic: associated with EBV (most prevalent in equatorial Africa and South America) and is typically located in the maxillary and mandibular bones
    • AIDS related

T-cell lymphomas (15% of all NHL)

T-cell lymphomas
Grade Lymphoma Features

Indolent (low-grade)

Aggressive (high-grade)
  • Aggressive NK-cell leukemia [10]
  • Angioimmunoblastic T-cell lymphoma [11]

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.

Hair can get TRAPped in the hairdryer: hairy cell leukemia, TRAP stain, dry tap.

See ”Differential diagnosis of B symptoms”, “Enlarged lymph nodes”, and “Differential diagnosis of granulomatous disease for more information.

Extranodal masses

The 4 T's of anterior mediastinal masses: Thymoma, Teratoma (and other germ cell tumors), Thyroid neoplasm, and Terrible lymphoma.

Necrotizing lymphadenitis (Kikuchi-Fujimoto disease) [14]

  • Etiology: unknown
  • Epidemiology
    • Rare; most commonly reported in Asian population
    • Sex: >
    • Mean age: 30 years
  • 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.

Approach [15][16][17]

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 [16]

Confirmatory diagnostics tests [13][15][17]

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

Histopathology and specialized studies

These studies help determine the subtype of NHL.

It is important to identify CD20-positive lymphomas, as patients may benefit from targeted therapy with CD20 antibodies (e.g., rituximab).

Staging [15]

  • Imaging
    • Indicated in all patients for staging and to assess response to therapy
    • Choice of imaging modality depends on the suspected subtype of NHL (uptake of FDG varies between subtypes)
  • Bone marrow aspiration and biopsy: indicated in most newly diagnosed patients with NHL
  • Assessment of CNS involvement

Classification [15]

  • 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 Cotswolds-modified Ann Arbor system was used, excluding the presence of B symptoms.

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.

Approach [16][22]

Pretreatment evaluation is essential in all patients receiving chemotherapy for NHL to adequately adjust chemotherapeutic doses according to patients' hepatic, renal, and cardiac function.

Medical therapy

Treatment options [22]

Specific regimens [16][22]

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).

CHOP is the most common regimen in NHL, with the addition of rituximab (CD20 antibody) for B-cell neoplasms (R-CHOP).

Treatment regimens for non-Hodgkin lymphomas [16][22]
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 [22][24]

  • Typically, the prognosis of NHL is worse than that of Hodgkin lymphoma. [25]
    • Low-grade lymphomas: median survival of 6–10 years
    • High-grade lymphomas: survival typically several months (years in less aggressive variants)
  • Indicators of poor prognosis: old age, number of involved nodal and extranodal sites, LDH, beta2 microglobulin [26]
  1. Non-Hodgkin Lymphoma Risk Factors. https://www.cancer.org/cancer/non-hodgkin-lymphoma/causes-risks-prevention/risk-factors.html. Updated: June 9, 2020. Accessed: October 16, 2020.
  2. Kellerman RD. Conn's Current Therapy 2020. Elsevier ; 2019
  3. Goldman L, Schafer AI. Goldman-Cecil Medicine, 2-Volume Set. Elsevier ; 2019
  4. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification. J Clin Oncol. 2014 . doi: 10.1200/JCO.2013.54.8800 . | Open in Read by QxMD
  5. Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2). McGraw-Hill Education / Medical ; 2018
  6. Kroft SH, Sever CE, Bagg A, et al. Laboratory Workup of Lymphoma in Adults. Arch Pathol Lab Med. 2020 . doi: 10.5858/arpa.2020-0261-sa . | Open in Read by QxMD
  7. Li SJ, Chen HP, Chen YH, Zhang LH, Tu YM, Liu ZH. Renal involvement in non-Hodgkin lymphoma: proven by renal biopsy. PLoS ONE. 2014; 9 (4): p.e95190. doi: 10.1371/journal.pone.0095190 . | Open in Read by QxMD
  8. Oliver Tavabie, Abid R. Suddle. Lymphoma and hematological conditions: I. Lymphoma and liver complications of bone marrow transplant. Clinical Liver Disease. 2016; 8 (1): p.1-5. doi: 10.1002/cld.560 . | Open in Read by QxMD
  9. A.N. Pavlidis, J. Kalef-Ezra, L.C. Bourantas, A. Lambrou, A. Mavridis. Serum Tumor Markers in Non-Hodgkin's Lymphomas and Chronic Lymphocytic Leukemia. Int J Biol Markers. 1993; 8 (1): p.14-20. doi: 10.1177/172460089300800103 . | Open in Read by QxMD
  10. Mahajan T, Merriman RC, Stone MJ. Kikuchi-Fujimoto Disease (Histiocytic Necrotizing Lymphadenitis): Report of a Case with Other Autoimmune Manifestations. Baylor University Medical Center Proceedings. 2007; 20 (2): p.149-151. doi: 10.1080/08998280.2007.11928275 . | Open in Read by QxMD
  11. Caligiuri M, Levi MM, Kaushansky K, et al. Williams Hematology, 9E. McGraw-Hill Education / Medical ; 2015
  12. Belay Y, Yirdaw K, Enawgaw B. Tumor Lysis Syndrome in Patients with Hematological Malignancies. Journal of Oncology. 2017; 2017 : p.1-9. doi: 10.1155/2017/9684909 . | Open in Read by QxMD
  13. Weledji EP, Orock GE. Surgery for Non-Hodgkin's Lymphoma.. Oncology reviews. 2015; 9 (1): p.274. doi: 10.4081/oncol.2015.274 . | Open in Read by QxMD
  14. Jingjing Ma, Qing Li, Jie Shao, Yan Ma, Zhiguang Lin, Hui Kang, Bobin Chen. Central Nervous System Involvement in Patients with Diffuse Large B Cell Lymphoma: Analysis of the Risk Factors and Prognosis from a Single-Center Retrospective Cohort Study. Cancer Manag Res. 2019; Volume 11 : p.10175-10185. doi: 10.2147/cmar.s225372 . | Open in Read by QxMD
  15. Key Statistics for Non-Hodgkin Lymphoma. https://www.cancer.org/cancer/non-hodgkin-lymphoma/about/key-statistics.html. Updated: January 8, 2020. Accessed: October 17, 2020.
  16. Survival Rates and Factors That Affect Prognosis (Outlook) for Non-Hodgkin Lymphoma. https://www.cancer.org/cancer/non-hodgkin-lymphoma/detection-diagnosis-staging/factors-prognosis.html. Updated: January 8, 2020. Accessed: October 16, 2020.
  17. Gayer G, Luboshitz J, Hertz M, et al. Congenital Anomalies of the Inferior Vena Cava Revealed on CT in Patients with Deep Vein Thrombosis. American Journal of Roentgenology. 2003; 180 (3): p.729-732. doi: 10.2214/ajr.180.3.1800729 . | Open in Read by QxMD
  18. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL). http://www.lymphoma.org/site/pp.asp?c=bkLTKaOQLmK8E&b=6300147. Updated: December 1, 2016. Accessed: February 8, 2017.
  19. Pasqualucci L. The genetic basis of diffuse large B-cell lymphoma.. Curr Opin Hematol. 2013; 20 (4): p.336-44. doi: 10.1097/MOH.0b013e3283623d7f . | Open in Read by QxMD
  20. Cerami E. AACR Project GENIE: Powering Precision Medicine through an International Consortium. Cancer Discovery. 2017; 7 (8): p.818-831. doi: 10.1158/2159-8290.cd-17-0151 . | Open in Read by QxMD
  21. Mantle Cell Lymphoma. https://rarediseases.org/rare-diseases/mantle-cell-lymphoma/. Updated: January 1, 2005. Accessed: October 18, 2020.
  22. Freedman AS, Aster JC. Epidemiology, clinical manifestations, pathologic features, and diagnosis of Burkitt lymphoma. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/epidemiology-clinical-manifestations-pathologic-features-and-diagnosis-of-burkitt-lymphoma?source=search_result&search=burkitt%20lymphoma&selectedTitle=1~76.Last updated: September 14, 2016. Accessed: February 8, 2017.
  23. Rook AH, Olsen EA, Kuzel TM, Zic JA, Rosmarin AG. Clinical Presentation, Pathologic Features, and Diagnosis of Sézary Syndrome. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/clinical-presentation-pathologic-features-and-diagnosis-of-sezary-syndrome.Last updated: July 14, 2016. Accessed: February 8, 2017.
  24. Matutes E. Adult T-cell leukaemia/lymphoma. J Clin Pathol. 2006; 60 (12): p.1373-1377. doi: 10.1136/jcp.2007.052456 . | Open in Read by QxMD
  25. Ishida F. Aggressive NK-Cell Leukemia. Frontiers in Pediatrics. 2018; 6 . doi: 10.3389/fped.2018.00292 . | Open in Read by QxMD
  26. Angioimmunoblastic T-Cell Lymphoma. https://rarediseases.org/rare-diseases/angioimmunoblastic-t-cell-lymphoma/. Updated: July 18, 2017. Accessed: October 16, 2020.
  27. Freedman AS, Friedberg DW. Evaluation, staging, and response assessment of non-Hodgkin lymphoma. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/evaluation-staging-and-response-assessment-of-non-hodgkin-lymphoma.Last updated: February 2, 2017. Accessed: February 8, 2017.