Non-Hodgkin lymphoma (NHL)

Exploring dysfunctional pathways, mechanisms, and biomarkers in non-Hodgkin lymphoma to discover new insights into the progression of the disease.


NHL accounts for 3.8% of all new cancer cases and 2.7% of all cancer deaths worldwide.1

NHL is more common in developed regions; Australasia, Western and Northern Europe, and high-income Northern America have the highest incidence rates.1


Median age at diagnosis is 67 years.2

Incidence & Mortality

There were an estimated 666,000 new cases of NHL and 231,000 deaths worldwide in 2015.1

  • An estimated 72,240 persons in the US will be diagnosed with NHL during 2017 (4.3% of all new cancer cases).2,3
  • An estimated 20,140 persons in the US will die from NHL during 2017 (3.4% of all cancer deaths).2,3

89.3% of NHL cases are diagnosed in persons older than 44 years.2

  • NHL is most frequently diagnosed among people aged 65 to 74 years.
  • The median age at diagnosis is 67 years.

Survival varies widely by cell type and stage of the disease.4

  • Approximately 71% of patients in the US will survive 5 years past diagnosis.2
  • In Europe, the average is 59%, ranging from 44% in Poland to 74% in Iceland.4

NHL are a heterogeneous group of neoplasms that originate in any of the lymphoid cells: B cells, T cells, or NK cells.4 There are over 60 subtypes identified by the World Health Organization, each categorized by cell of origin, histological appearance, immunophenotype, and genetic characteristics.5

B-cell lymphomas account for about 90% of NHL. Major NHL subtypes include6:

  • Diffuse large B-cell lymphoma (DLBCL): ~33%
  • Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): ~19%
  • Follicular lymphoma (FL): ~17%
  • Marginal zone lymphoma (MZL): ~8%
  • Mantle cell lymphoma (MCL): ~4% (US); 7% to 9% (Europe)7

NHL subtypes are further characterized according to how the disease progresses.8

  • Indolent lymphomas
    • Slow-moving and slow-growing
    • Few signs and symptoms when first diagnosed
    • About 40% of all NHL cases
    • FL is the most common subtype of indolent NHL
  • Aggressive lymphomas
    • Fast-moving
    • Account for about 60% of all NHL cases
    • DLBCL is the most common subtype of aggressive NHL
  • MCL shares some characteristics of both indolent and aggressive NHLs

Subtypes of NHL have varied epidemiological and genetic risk factors.9 In most cases however, people diagnosed with NHL do not have any obvious risk factors, and many people who have risk factors for the disease never develop it.10


  • Increased young adult body-mass index (BMI), history of B cell-activating autoimmune diseases, and HCV seropositivity are associated with increased risk of developing DLBCL.9
  • BCL-2 protein overexpression is detected in approximately 30% of DLBCL cases; in approximately 90% of those cases, BCL-2 protein levels are very high.11,12
  • Expressing both MYC and BCL-2 proteins correlates with an aggressive clinical course and a poor outcome.11
  • DLBCL may be further classified by its cell of origin.13
    • Germinal center B-cell (GCB)-type
    • Activated B-cell (ABC)-type (poor prognosis)


  • Family history of NHL and being overweight as a young adult are associated with increased risk of developing FL.9
  • BCL-2 protein overexpression is detected in over 60% of FL cases.11
  • The vast majority of patients with BCL-2 protein overexpression develop chemoresistance and experience higher relapse rates compared with BCL-2-negative patients.11


  • The etiology of MCL is likely multifactorial.9
  • MCL is characterized by the t(11,14) translocation that results in constitutive expression of cyclin D1.7,9
  • The BCL-2 pathway is commonly deregulated in MCL cases and the BCL-2 gene is often amplified.14,15

Presentation of NHL varies greatly depending on the type and aggressiveness of the lymphoma, as well as the area of involvement.16

An incisional or excisional lymph node biopsy is used to establish a pathologic diagnosis of NHL. Immunophenotypic analysis by flow cytometry and/or immunohistochemistry is essential for the differentiation of various subtypes of NHL.17

Lugano Modification of Ann Arbor Staging System (for primary nodal lymphomas)
Disease category Stage Involvement Extranodal status
Limited I One node or a group of adjacent nodes Single extranodal lesions without nodal involvement
II Two or more nodal groups on the same side of the diaphragm Stage I or II by nodal extent with limited contiguous extranodal involvement
II bulky* II as above with "bulky" disease Not applicable
Advanced III Nodes on both sides of the diaphragm; nodes above the diaphragm with spleen involvement Not applicable
IV Additional non-contiguous extralymphatic involvement Not applicable

Lugano modification of Ann Arbor staging system (for primary nodal lymphomas)

Disease category: Limited
Stage I
One node or a group of adjacent nodes
Extranodal status
Single extranodal lesions without nodal involvement
Stage II
Two or more nodal groups on the same side of the diaphragm
Extranodal status
Stage I or II by nodal extent with limited contiguous extranodal involvement
Stage II bulky*
II as above with "bulky" disease
Extranodal status
Not applicable
Disease category: Advanced
Stage III
Nodes on both sides of the diaphragm; nodes above the diaphragm with spleen involvement
Extranodal status
Not applicable
Stage IV
Additional non-contiguous extralymphatic involvement
Extranodal status
Not applicable

NHLs are staged using this general scheme; subtype-specific grading scales are used to more accurately identify the best course of treatment for disease.17

Immunochemotherapy (rituximab or obinutuzumab + chemotherapy) has emerged as the standard of care for most B-cell NHL.18


  • Immunochemotherapy is the standard of care for DLBCL.
  • Approximately one-third of patients eventually relapse or are initially refractory to these treatments.


  • Due to the vast heterogeneity, there is no uniform standard approach for treating FL and patient factors must be considered when deciding therapy.
  • While most patients have disseminated disease at diagnosis, they are frequently asymptomatic and have historically been observed without initial therapy ("watch-and-wait").21,22
    • There is no evidence that either immediate therapy increases survival or that delaying therapy decreases survival. However, most studies suggesting no impact on survival by delaying therapy were conducted pre-rituximab.
    • Patient may prefer therapy based on anxiety about not treating a known cancer.
  • Despite the improved effectiveness of immunochemotherapy regimens, approximately 20% of patients with FL experience progression of disease within 2 years of first-line therapy.19,20


  • For patients with asymptomatic newly diagnosed MCL and low tumor burden, close observation is acceptable, deferring therapy to the time of disease progression.7,23
  • In general, young and/or fit patients are considered for intensive immunochemotherapy strategies.7
  • Older MCL patients should be spared intensive strategies as the risk-to-benefit profile is not favorable.7,23
  • Although high overall response rates (ORRs) of 60% to 97% are observed after initial therapy, most often they are short lived, and most patients will eventually relapse.24

Relevant Biomarker Pathways

  1. Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Allen C, Barber RM, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: A systematic analysis for the Global Burden of Disease Study. JAMA Oncol. 2017;3(4):524-548.
  2. Howlader N, Noone AM, Krapcho M, et al (eds). SEER Cancer Statistics Review, 1975-2014, National Cancer Institute. Bethesda, MD,, based on November 2016 SEER data submission, posted to the SEER web site, April 2017.
  3. American Cancer Society. Global Cancer Facts & Figures 3rd Edition. Atlanta: American Cancer Society; 2015.
  4. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67(1):7-30.
  5. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127:2375-2390.
  6. Al-Hamadani M, Habermann TM, Cerhan JR, Macon WR, Maurer MJ, Go RS. Non-Hodgkin lymphoma subtype distribution, geodemographic patterns, and survival in the US: A longitudinal analysis of the National Cancer Data Base from 1998 to 2011. Am J Hematol. 2015;90(9):790-795.
  7. Vose JM. Mantle cell lymphoma: 2017 update on diagnosis, risk-stratification, and clinical management. Am J Hematol. 2017;92(8):806-813.
  8. Leukemia & Lymphoma Society. NHL Subtypes. Accessed November 2017.
  9. Glass S, Phan A, Williams JN, Flowers CR, Koff JL. Integrating understanding of epidemiology and genomics in B-cell non-Hodgkin lymphoma as a pathway to novel management strategies. Discov Med. 2016;21(115):181-188.
  10. Mayo Foundation for Medical Education and Research. Diseases and Conditions: Non-Hodgkin's Lymphoma: Risk Factors. Accessed December 2017.
  11. Mahmoud HM, El-Sakhawy YN. Significance of Bcl-2 and Bcl-6 immunostaining in B-non Hodgkin's lymphoma. Hematol Rep. 2011;3(3):e26.
  12. Wang J, Zhou M, Xu J, Chen B, Ouyang J. Combination of BCL-2 and MYC protein expression improves high-risk stratification in diffuse large B-cell lymphoma. Onco Targets Ther. 2015;8:2645-2650.
  13. Scott DW, et al. Prognostic significance of diffuse large B-cell lymphoma cell of origin determined by digital gene expression in formalin-fixed paraffin-embedded tissue biopsies. J Clin Oncol. 2015;33(26):2848-2856.
  14. Perez-Galan P, Dreyling M, Wiestner A. Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era. Blood. 2003;101(6):2125-2131.
  15. Parekh S, Weniger MA, Wiestner A. New molecular targets in mantle cell lymphoma. Semin Cancer Biol. 2011;21(5):335-346.
  16. National Cancer Institute. Adult Non-Hodgkin Lymphoma Treatment (PDQ®)-Health Professional Version. Accessed December 2017.
  17. Cheson B, 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;32:3059-3067.
  18. Amin AD, Peters TL, Li L, et al. Diffuse large B-cell lymphoma: can genomics improve treatment options for a curable cancer? Cold Spring Harb Mol Case Stud. 2017;3(3):a001719.
  19. Press OW, et al. Phase III randomized intergroup trial of CHOP plus rituximab compared with CHOP chemotherapy plus 131iodine-tositumomab for previously untreated follicular non-Hodgkin lymphoma: SWOG S0016. J Clin Oncol. 2013;31(3):314-320.
  20. Casulo C, et al. Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the National LymphoCare Study. J Clin Oncol. 2015;33(23):2516-2522.
  21. Armitage JO, Longo DL. Is watch and wait still acceptable for patients with low-grade follicular lymphoma? Blood. 2016;127(23):2804-2808.
  22. Kahl B. Is there a role for "watch and wait" in follicular lymphoma in the rituximab era? Hematology Am Soc Hematol Educ Program. 2012;2012:433-438.
  23. Fakhri B, Kahl B. Current and emerging treatment options for mantle cell lymphoma. Ther Adv Hematol. 2017;8(8):223-234.
  24. Parrott M, Rule S, Kelleher M, Wilson J. A systematic review of treatments of relapsed/refractory mantle cell lymphoma. Clin Lymphoma Myeloma Leuk. 2017 Oct 13. [Epub ahead of print]

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