B-Cell Lymphoma: Practice Essentials, Background, Classification

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Tools & Reference>Hematology B-Cell Lymphoma Updated: May 29, 2024

• Author: Mohammad Muhsin Chisti, MD, FACP; Chief Editor: Emmanuel C Besa, MD more...

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Sections B-Cell Lymphoma

• Sections B-Cell Lymphoma
• Overview
  • Practice Essentials
  • Background
  • Classification
  • Pathophysiology and Etiology
  • Epidemiology
  • Prognosis
  • Show All
• Presentation
• DDx
• Workup
  • Approach Considerations
  • Laboratory Studies
  • Other Tests
  • Imaging Studies
  • Histologic Findings
  • Immunophenotypic Analysis
  • Staging
  • Show All
• Treatment
  • Approach Considerations
  • Complications
  • Consultations
  • Transfer
  • Diet
  • Show All
• Guidelines
  • Staging
  • Risk Stratification
  • Follicular Lymphoma
  • Marginal Zone Lymphomas of MALT Type
  • Mantle Cell Lymphoma
  • Diffuse Large B-Cell Lymphoma
  • Burkitt Lymphoma
  • Primary Cutaneous B-Cell Lymphomas
  • Show All
• Medication
  • Medication Summary
  • Hematopoietic Growth Factors
  • Monoclonal Antibodies
  • Corticosteroids
  • Antineoplastic Agents
  • Antineoplastics, Tyrosine Kinase Inhibitor
  • Antineoplastics, PI3K Delta Inhibitors
  • Antineoplastics, Angiogenesis inhibitor
  • PD-1/PD-L1 Inhibitors
  • Antineoplastics, Anti-CD19 Monoclonal Antibodies
  • CAR T-cell Therapy
  • Show All
• Media Gallery
• Tables
• References

Overview

Practice Essentials

B-cell lymphomas are clonal tumors of mature and immature B cells that constitute the majority (80-85%) of non-Hodgkin lymphomas (NHLs). NHLs are a heterogeneous group of lymphoproliferative malignancies with differing patterns of behavior and responses to treatment. [1] NHL usually originates in the lymphoid tissues and can spread to other organs.

NHL must be distinguished from Hodgkin lymphoma with certainty before therapy is initiated. Compared with Hodgkin lymphoma, NHL is much less predictable and has a far greater predilection to disseminate to extranodal sites. The prognosis depends on the histologic type, stage, and treatment.

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Background

NHL can be divided into two general prognostic groups: indolent lymphomas and aggressive lymphomas. Indolent lymphomas carry a relatively good prognosis, with median survival as long as 10 years, but those that have progressed to advanced stages are not usually curable. Early-stage (stage I and II) indolent NHL can be treated effectively with radiation therapy alone. Most of the indolent types are nodular (or follicular) in morphology. The aggressive type of NHL has a shorter natural history, but a significant number of cases are curable with combination chemotherapy regimens.

With modern treatment of patients with NHL, the overall survival rate at 5 years is 74.3.%. [2] Although relapse is common in advanced-stage NHL, patients can often be retreated with considerable success as long as the disease histology remains low grade. Most relapses occur in the first 2 years after therapy. The risk of late relapse is higher in patients with a divergent histology of both indolent and aggressive disease.

Patients who present with aggressive forms of NHL, or whose disease converts to an aggressive form, may achieve complete remission with combination chemotherapy regimens, with or without aggressive high-dose consolidation therapy with marrow or stem cell support. People with HIV infection are at increased risk for aggressive lymphomas, and treatment of these patients requires special consideration.

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Classification

B-cell neoplasms are clonal tumors of mature and immature B cells at various stages of differentiation. B-cell neoplasms tend to mimic stages of normal B-cell differentiation, and the resemblance to normal cell stages is a major basis for their classification and nomenclature. [3]

The World Health Organization (WHO) classification divides B-cell malignancies into two broad categories [3] : (1) precursor B-cell neoplasms, which include B lymphoblastic leukemia/lymphoma with or without recurrent genetic abnormalities, and (2) mature B-cell neoplasms.

The following classification deals with only the mature B-cell neoplasms. Both lymphomas and lymphoid leukemias are included in this classification because both solid and circulating phases are present in many lymphoid neoplasms and distinction between them is artificial. For instance, B-cell chronic lymphocytic leukemia (CLL) and B-cell small lymphocytic lymphoma (SLL) are different manifestations of the same neoplasm, as are lymphoblastic lymphomas and T-cell acute lymphocytic leukemias.

The WHO classification of mature B-cell neoplasms is as follows [3] :

• Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)
• Monoclonal B-cell lymphocytosis
• B-cell prolymphocytic leukemia
• Splenic marginal zone lymphoma
• Hairy cell leukemia
• Splenic B-cell lymphoma/leukemia, unclassifiable
• Splenic diffuse red pulp small B-cell lymphoma
• Hairy cell leukemia–variant
• Lymphoplasmacytic lymphoma
• Waldenström macroglobulinemia
• Monoclonal gammopathy of undetermined significance (MGUS), IgM
• Heavy-chain diseases (μ, γ, α)
• MGUS, IgG/A
• Plasma cell myeloma
• Solitary plasmacytoma of bone
• Extraosseous plasmacytoma
• Monoclonal immunoglobulin deposition diseases
• Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)
• Nodal marginal zone lymphoma
• Pediatric nodal marginal zone lymphoma
• Follicular lymphoma
• In situ follicular neoplasia
• Duodenal-type follicular lymphoma
• Pediatric-type follicular lymphoma
• Large B-cell lymphoma with IRF4 rearrangement
• Primary cutaneous follicle center cell lymphoma
• Mantle cell lymphoma
• In situ mantle cell neoplasia
• Diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS)
• Germinal center B-cell type
• Activated B-cell type
• T-cell/histiocyte-rich large B-cell lymphoma
• Primary DLBCL of the central nervous system (CNS)
• Primary cutaneous DLBCL, leg type
• Epstein-Barr virus (EBV)–positive DLBCL, NOS
• EBV-positive mucocutaneous ulcer
• DLBCL associated with chronic inflammation
• Lymphomatoid granulomatosis
• Primary mediastinal (thymic) large B-cell lymphoma
• Intravascular large B-cell lymphoma
• Anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma
• Plasmablastic lymphoma
• Primary effusion lymphoma
• Human herpesvirus 8 (HHV-8)–associated DLBCL, NOS
• Burkitt lymphoma
• Burkitt-like lymphoma with 11q aberration
• High-grade B-cell lymphoma with MYC and BLC2 and/or BCL6 rearrangements
• High-grade B-cell lymphoma, NOS
• B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma

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Pathophysiology and Etiology

Any of the following may play a role in the etiology of non-Hodgkin lymphoma (NHL) in a particular patient:

• Genetic abnormalities
• Environmental factors
• Viral infections
• Immunodeficiency states
• Connective-tissue disorders

Chromosomal translocations and molecular rearrangements

Non-random chromosomal and molecular rearrangements (see the table below) play an important role in the pathogenesis of many lymphomas and correlate with histology and immunophenotype.

Table 1. Chromosomal Abnormalities in B-Cell Non-Hodgkin Lymphoma (Open Table in a new window)

Cytogenetic Abnormality	Histology	Antigen Rearrangement	Oncogene Expression
t(14;18)(q32;q21)	Follicular, diffuse large cell	IgH*	bcl- 2
t(11;14)(q13;q32)	Mantle cell	IgH	cyclin-D1/bcl-1
t(1;14)(p22;q32)	MALT lymphoma	IgH	bcl- 10
t(11;18)(q21;q21)	MALT lymphoma	IgH	Unknown
t(9;14)(p13;q32)	Lymphoplasmacytic lymphoma	IgH	PAX-5
8q24 translocations t(8;14)(q24;q32) t(2;8)(p11-12;q24) t(8;22)(q24;q11)	Burkitt lymphoma	IgH Ig-8 Ig-6	c-myc
Trisomy 12, deletion 11q22-23, 17p13, and 6q21	CLL	…	…
*Immunoglobulin H (IgH) MALT = Mucosa-associated lymphoid tissue.

The most common chromosomal abnormality associated with NHL is the t(14;18)(q32;q21) translocation, which is found in 85% of follicular lymphomas and 25-30% of intermediate-grade NHLs. This translocation results in the juxtaposition of the bcl-2 apoptotic inhibitor oncogene at band 18q21 to the heavy-chain region of the immunoglobulin (Ig) locus within band 14q32, resulting in its overexpression.

The t(11;14)(q13;q32) translocation results in overexpression of bcl -1 (cyclin-D1/PRAD1), a cell cycle control gene on band 11q13, and is diagnostic of mantle cell lymphoma.

For the workup of any high-grade B-cell lymphoma of germinal center origin, fluorescence in situ hybridization (FISH) studies for evaluation of myc, bcl-6, and bcl-2 rearrangements should typically be ordered, in order to establish classification of "double hit" lymphomas. Double hit B-cell lymphomas are a specific subtype of diffuse large B-cell lymphoma (DLBCL) that have a much more aggressive clinical course and are associated with translocations of two of the three oncogenes (myc, bcl-2, and bcl-6).

Environmental factors

The risk of NHL is increased in certain workers, including the following:

• Farmers
• Pesticide applicators
• Flour millers
• Meat workers
• Painters
• Mechanics
• Workers in the petroleum, rubber, plastics, and synthetics industries

Chemicals that have been linked to the development of NHL include the following:

• Pesticides and herbicides (eg, organophosphates, chlorophenols)
• Solvents and organic chemicals (eg, benzene, carbon tetrachloride)
• Wood preservatives

Patients who receive cancer chemotherapy, radiation therapy, or both are at increased risk of developing NHL.

Viruses

Several viruses have been implicated in the pathogenesis of NHL. Epstein-Barr virus (EBV) is linked to Burkitt lymphoma (especially in endemic areas of Africa), sinonasal lymphoma in Asia and South America, and lymphomas in immunocompromised patients. Human T-lymphotropic virus 1 (HTLV-1) is linked to adult T-cell lymphoma/leukemia. Human herpesvirus 8 (HHV-8) is implicated in body cavity–based lymphomas in patients with HIV infection.

Results of an Italian study support a role for chronic hepatitis C virus infection in NHL, and suggest involvement of hepatitis B virus infection. Associations were clearest for B-cell NHL and diffuse large B-cell lymphoma. [4]

Immunodeficiency states

Immunodeficiency states that seem to predispose to NHL include congenital immunodeficiency states (eg, ataxia telangiectasia, Wiskott-Aldrich syndrome, common variable hypogammaglobulinemia, and severe combined immunodeficiency), as well as acquired immunodeficiency states (eg, HIV infection and iatrogenic immunosuppression for solid organ or bone marrow transplant recipients). [5]

Connective-tissue disorders

Connective-tissue disorders associated with an increased risk of NHL include the following:

• Sjögren syndrome
• Rheumatoid arthritis
• Chronic lymphocytic thyroiditis
• Systemic lupus erythematosus (SLE)

Other disease states

Increased incidence of gastrointestinal (GI) lymphomas is observed in patients with celiac sprue and inflammatory bowel disease. Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is observed most frequently, but not exclusively, in association with Helicobacter pylori infection.

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Epidemiology

United States statistics

After a striking increase in incidence rates between 1970 and 1995 (which may in part have reflected improved diagnosis), the rates of new non-Hodgkin lymphoma (NHL) cases stabilzed. From 2012-2021, rates of new cases fell on average 0.7% each year, and from 2013-2022, death rates fell on average 2.1% each year. [2]

The lifetime risk of being diagnosed with NHL is 2.1%. [2] The American Cancer Society estimates that 80,620 new cases of NHL will be diagnosed in 2024, with 20,140 deaths. In US males, NHL is the seventh most common cancer, accounting for 4% of new cancers and cancer-related deaths; in females it is the sixth most common cancer, accounting for 4% of new cancers and 3% of cancer deaths. [6]

International statistics

Worldwide, the incidence of NHL has shown a rising trend over the past decade, particularly in developed countries, older men, and younger individuals. Huang et al reported an annual age-standardized incidence rate of 5.8 per 100,000 population and a mortality rate of 2.6 per 100,000 population. [7]

Perry and colleagues identified the following significant differences in the epidemiology of NHL in developing countries, compared with the developed countries [8] :

• Higher percentage of males
• Lower median age at diagnosis for both low- and high-grade B-cell lymphoma
• Lower frequency of B-cell lymphoma and a higher frequency of T- and NK-cell lymphoma
• Approximately 20% more cases of high-grade B-cell lymphoma and 10% fewer cases of low-grade B-cell lymphoma

In developing regions, diffuse large B-cell lymphoma was the most common subtype (42.5%) Other subtypes seen more frequently were Burkitt lymphoma (2.2%), precursor B- and T-lymphoblastic leukemia/lymphoma (1.1% and 2.9%) and extranodal natural killer (NK)/T-cell lymphoma (2.2%). [8]

In Europe, NHL is the 11th most common cancer, representing 3% of the total cancer diagnoses in 2012. [9]

Certain endemic geographic factors appear to influence the development of NHL in specific areas. For example, in equatorial Africa, a variant of Burkitt lymphoma associated with Epstein-Barr virus (EBV) is the most common childhood malignancy.

In the Middle East, heavy-chain disease (alpha) is a disorder of B-lymphoid cells that is characterized by diffuse thickening of the small intestine caused by a lymphoplasmacytic infiltrate with secretion of incomplete immunoglobulin A (IgA) heavy chains. This clinicopathologic entity is rarely encountered in individuals who are not of Mediterranean ethnicity.

Follicular lymphomas are more common in North America and Europe but are rare in the Caribbean, Africa, China, Japan, and the Middle East.

Age-, sex-, and race-associated differences in incidence

NHL is most frequently diagnosed in persons 65-74 years old. High-grade lymphoblastic and small noncleaved-cell lymphomas are the only subtypes of B-cell NHL that are observed more commonly in children and young adults.

NHL is more common in men: the reported incidence is 23.0 cases per 100,000 population in men, compared with 15.8 cases per 100,000 population in women. However, the incidence of NHL in some anatomic sites, such as the thyroid, may be higher in women. [2]

The incidence of NHL is highest in Whites: it is reported to be 24.7 cases per 100,000 population in White men, compared with 20.2 and 17.4 cases per 100,000 population in Hispanic and African-American men, respectively. The incidence rates are lowest among Asians, Pacific Islanders, and Native Americans. [2]

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Prognosis

Overall, the prognosis for non-Hodgkin lymphoma (NHL) varies with the histology, the stage of disease at diagnosis, the response of disease to therapy, and other factors as listed in the International Prognostic Index (IPI) score.

The IPI was originally designed as a prognostic factor model for aggressive NHL, but can be useful for predicting the outcome of patients with low-grade lymphoma. This index is also used to identify patients at high risk of relapse based on specific sites of involvement, including bone marrow, central nervous system, liver, testis, lung, and spleen. [10] Separate indices have been developed for follicular and mantle cell lymphoma. [11, 12, 13]

The IPI includes the following risk factors (for each factor that is present, the patient receives 1 point) [10] :

• Age ≥60 y
• Elevated lactate dehydrogenase (LDH) level
• Stage III or IV disease
• Eastern Cooperative Oncology Group (ECOG) performance status ≥2
• Two or more extranodal sites

Based on the IPI score, patients can be categorized as follows:

• Low risk (0-1)
• Low-intermediate risk (2)
• High-intermediate risk (3)
• High risk (4-5)

With this model, relapse-free and overall survival rates at 5 years are as follows:

• 0-1 risk factors - 75%
• 2-3 risk factors - 50%
• 4-5 risk factors - 25%

Previous Clinical Presentation

References

1. Silkenstedt E, Salles G, Campo E, Dreyling M. B-cell non-Hodgkin lymphomas. Lancet. 2024 May 4. 403 (10438):1791-1807. [QxMD MEDLINE Link].

2. Cancer Stat Facts: Non-Hodgkin Lymphoma. National Cancer Institute: Surveillance, Epidemiology, and End Results Program. Available athttps://seer.cancer.gov/statfacts/html/nhl.html. Accessed: May 29, 2024.

3. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues. 4th Edition, revised. Lyon, France: IARC; 2016.

4. Taborelli M, Polesel J, Montella M, Libra M, Tedeschi R, Battiston M, et al. Hepatitis B and C viruses and risk of non-Hodgkin lymphoma: a case-control study in Italy. Infect Agent Cancer. 2016. 11:27. [QxMD MEDLINE Link].

5. Tanyildiz HG, Dincaslan H, Yavuz G, Unal E, Ikinciogulları A, Dogu F, et al. Lymphoma Secondary to Congenital and Acquired Immunodeficiency Syndromes at a Turkish Pediatric Oncology Center. J Clin Immunol. 2016 Aug 4. [QxMD MEDLINE Link].

6. Cancer Facts & Figures 2024. American Cancer Society. Available athttps://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2024/2024-cancer-facts-and-figures-acs.pdf. Accessed: May 29, 2024.

7. Huang J, Chan SC, Lok V, Zhang L, Lucero-Prisno DE 3rd, Xu W, et al. Global burden, risk factors, and trends of non-Hodgkin lymphoma: A worldwide analysis of cancer registries. Cancer Med. 2024 Mar. 13 (5):e7056. [QxMD MEDLINE Link].

8. Perry AM, Diebold J, Nathwani BN, MacLennan KA, Müller-Hermelink HK, Bast M, et al. Non-Hodgkin lymphoma in the developing world: review of 4539 cases from the International Non-Hodgkin Lymphoma Classification Project. Haematologica. 2016 Jun 27. [QxMD MEDLINE Link].

9. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013 Apr. 49 (6):1374-403. [QxMD MEDLINE Link].

10. International Non-Hodgkin's Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med. 1993 Sep 30. 329(14):987-94. [QxMD MEDLINE Link].

11. Federico M, Bellei M, Marcheselli L, Luminari S, Lopez-Guillermo A, Vitolo U, et al. Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol. 2009 Sep 20. 27 (27):4555-62. [QxMD MEDLINE Link].[Full Text].

12. Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood. 2004 Sep 1. 104(5):1258-65. [QxMD MEDLINE Link].[Full Text].

13. Hoster E, Dreyling M, Klapper W, et al. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood. 2008 Jan 15. 111(2):558-65. [QxMD MEDLINE Link].[Full Text].

14. Choi WW, Weisenburger DD, Greiner TC, et al. A new immunostain algorithm classifies diffuse large B-cell lymphoma into molecular subtypes with high accuracy. Clin Cancer Res. 2009 Sep 1. 15(17):5494-502. [QxMD MEDLINE Link].

15. American Joint Committee on Cancer, American Cancer Society, American College of Surgeons. Non-Hodgkin's lymphoma. Fleming ID, Cooper JS, Henson DE, Hutter RVP, Kennedy BJ, Murphy GP, O'Sullivan B, Sobin LH, Yarbro JW, eds.AJCC Cancer Staging Manual. 5th ed. Philadelphia, Pa: Lippincott-Raven; 1997. 289-294.

16. Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014 Sep 20. 32 (27):3059-68. [QxMD MEDLINE Link].[Full Text].

17. [Guideline] NCCN Clinical Practice Guidelines in Oncology. B-Cell Lymphomas. National Comprehensive Cancer Network. Available athttps://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Version 2.2024 — April 30, 2024; Accessed: May 29, 2024.

18. Maude SL, Barrett D, Teachey DT, Grupp SA. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J. 2014 Mar-Apr. 20 (2):119-22. [QxMD MEDLINE Link].

19. FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma. U.S. Food & Drug Administration. Available athttps://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm581216.htm. October 18, 2017; Accessed: January 23, 2023.

20. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019 Jan. 20 (1):31-42. [QxMD MEDLINE Link].[Full Text].

21. FDA approves tisagenlecleucel for adults with relapsed or refractory large B-cell lymphoma. U.S. Food and Drug Administration. 2018 May 03. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm606540.htm?utm_campaign=Oncology%205%2F1%2F2018_Kymriah&utm_medium=email&utm_source=Eloqua&elqTrackId=5578022d641d45d5a723adaf982a493c&elq=933c3d8ba491426680135d5ae119dcc6&elqaid=3339&elqat=1&e.

22. Schuster SJ, et al; JULIET Investigators. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2019 Jan 3. 380 (1):45-56. [QxMD MEDLINE Link].[Full Text].

23. Breyanzi (lisocabtagene maraleucel) [package insert]. Bothell, WA: Bristol Myers Squibb. 2/2021. Available at [Full Text].

24. Enli Liu, David Marin, Pinaki Banerjee, Homer A Macapinlac, Philip Thompson, Rafet Basar, et al. Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors. N Engl J Med. 2020 February 6. 2020; 382:545-553:[QxMD MEDLINE Link].

25. FDA approves polatuzumab vedotin-piiq for diffuse large B-cell lymphoma. FDA. 2019 June 10. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-polatuzumab-vedotin-piiq-diffuse-large-b-cell-lymphoma.

26. Sehn LH, Herrera AF, Flowers CR, Kamdar MK, McMillan A, Hertzberg M, et al. Polatuzumab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2020 Jan 10. 38 (2):155-165. [QxMD MEDLINE Link].

27. Stephen J. Schuster, MD. Early-Phase Trial Shows Mosunetuzumab Induces Durable Complete Remissions in Patients With B-Cell Non-Hodgkin Lymphoma. ashclinicalnews.org. 2020 Jan 15. Available at https://www.ashclinicalnews.org/lymphomas-lymphoid-neoplasia/mosunetuzumab-induces-durable-complete-remissions-patients-b-cell-non-hodgkin-lymphoma/.

28. Jaffe ES. The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology Am Soc Hematol Educ Program. 2009. 523-31. [QxMD MEDLINE Link].[Full Text].

29. Brice P, Bastion Y, Lepage E, Brousse N, Haïoun C, Moreau P, et al. Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d'Etude des Lymphomes Folliculaires. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol. 1997 Mar. 15 (3):1110-7. [QxMD MEDLINE Link].

30. [Guideline] Zucca E, Arcaini L, Buske C, Johnson PW, Ponzoni M, Raderer M, et al. Marginal zone lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020 Jan. 31 (1):17-29. [QxMD MEDLINE Link].[Full Text].

31. [Guideline] Dreyling M, Campo E, Hermine O, et al. Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017. 28 (suppl 4):iv62–iv71. [QxMD MEDLINE Link].[Full Text].

32. Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002 Jun 20. 346 (25):1937-47. [QxMD MEDLINE Link].

33. [Guideline] Tilly H, Gomes da Silva M, Vitolo U, Jack A, Meignan M, Lopez-Guillermo A, et al. Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015 Sep. 26 Suppl 5:v116-25. [QxMD MEDLINE Link].[Full Text].

34. [Guideline] Senff NJ, Noordijk EM, Kim YH, Bagot M, Berti E, Cerroni L, et al. European Organization for Research and Treatment of Cancer and International Society for Cutaneous Lymphoma consensus recommendations for the management of cutaneous B-cell lymphomas. Blood. 2008 Sep 1. 112 (5):1600-9. [QxMD MEDLINE Link].[Full Text].

35. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005 May 15. 105 (10):3768-85. [QxMD MEDLINE Link].[Full Text].

36. Kim YH, Willemze R, Pimpinelli N, Whittaker S, Olsen EA, Ranki A, et al. TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC). Blood. 2007 Jul 15. 110 (2):479-84. [QxMD MEDLINE Link].[Full Text].

37. Noy A, de Vos S, Thieblemont C, Martin P, Flowers CR, Morschhauser F, et al. Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma. Blood. 2017 Apr 20. 129 (16):2224-2232. [QxMD MEDLINE Link].[Full Text].

38. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med. 2017 Dec 28. 377 (26):2531-2544. [QxMD MEDLINE Link].[Full Text].

39. Schuster S, et al. Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma. 59th American Society of Hematology Annual Meeting and Exposition. Abstract #577. Atlanta, GA. December 9-12, 2017.

40. Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak Ö, et al. Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas. N Engl J Med. 2017 Dec 28. 377 (26):2545-2554. [QxMD MEDLINE Link].

41. Sehn LH, Chua N, Mayer J, Dueck G, Trněný M, Bouabdallah K, et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 2016 Jun 23. [QxMD MEDLINE Link].

42. Barta SK, Li H, Hochster HS, Hong F, Weller E, Gascoyne RD, et al. Randomized phase 3 study in low-grade lymphoma comparing maintenance anti-CD20 antibody with observation after induction therapy: A trial of the ECOG-ACRIN Cancer Research Group (E1496). Cancer. 2016 Jun 28. [QxMD MEDLINE Link].

43. Kansara R, Connors JM, Savage KJ, Gerrie AS, Scott DW, Slack GW, et al. Maintenance rituximab following induction R-CHOP chemotherapy in patients with composite or discordant, indolent and aggressive, B-cell non-Hodgkin lymphomas. Haematologica. 2016 Jun 16. [QxMD MEDLINE Link].[Full Text].

44. [Guideline] Dreyling M, Ghielmini M, Marcus R, Salles G, Vitolo U, Ladetto M, et al. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014 Sep. 25 Suppl 3:iii76-82. [QxMD MEDLINE Link].[Full Text].

45. Colombat P, Salles G, Brousse N, et al. Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation. Blood. 2001 Jan 1. 97(1):101-6. [QxMD MEDLINE Link].

46. Hainsworth JD, Litchy S, Shaffer DW, Lackey VL, Grimaldi M, Greco FA. Maximizing therapeutic benefit of rituximab: maintenance therapy versus re-treatment at progression in patients with indolent non-Hodgkin's lymphoma--a randomized phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2005 Feb 20. 23 (6):1088-95. [QxMD MEDLINE Link].

47. Stiff PJ, Unger JM, Cook JR, Constine LS, Couban S, Stewart DA, et al. Autologous transplantation as consolidation for aggressive non-Hodgkin's lymphoma. N Engl J Med. 2013 Oct 31. 369(18):1681-90. [QxMD MEDLINE Link].

48. Hambley B, Caimi PF, William BM. Bortezomib for the treatment of mantle cell lymphoma: an update. Ther Adv Hematol. 2016 Aug. 7 (4):196-208. [QxMD MEDLINE Link].[Full Text].

49. Robak T, Huang H, Jin J, Zhu J, Liu T, Samoilova O, et al. Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma. N Engl J Med. 2015 Mar 5. 372 (10):944-53. [QxMD MEDLINE Link].

50. Zhou Z, Sehn LH, Rademaker AW, Gordon LI, Lacasce AS, Crosby-Thompson A, et al. An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood. 2014 Feb 6. 123 (6):837-42. [QxMD MEDLINE Link].

51. Castillo JJ, Winer ES, Olszewski AJ. Population-based prognostic factors for survival in patients with Burkitt lymphoma: an analysis from the Surveillance, Epidemiology, and End Results database. Cancer. 2013 Oct 15. 119 (20):3672-9. [QxMD MEDLINE Link].

52. WHO's cancer pain ladder for adults. World Health Organization. Available athttps://www.who.int/cancer/palliative/painladder/en/. Accessed: April 22, 2023.

53. National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin's Lymphoma Pathologic Classification Project. Cancer. 1982 May 15. 49 (10):2112-35. [QxMD MEDLINE Link].

54. Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood. 1994 Sep 1. 84 (5):1361-92. [QxMD MEDLINE Link].[Full Text].

55. Rohatiner A, d'Amore F, Coiffier B, Crowther D, Gospodarowicz M, Isaacson P, et al. Report on a workshop convened to discuss the pathological and staging classifications of gastrointestinal tract lymphoma. Ann Oncol. 1994 May. 5 (5):397-400. [QxMD MEDLINE Link].

56. Ruskoné-Fourmestraux A, Dragosics B, Morgner A, Wotherspoon A, De Jong D. Paris staging system for primary gastrointestinal lymphomas. Gut. 2003 Jun. 52 (6):912-3. [QxMD MEDLINE Link].[Full Text].

Media Gallery

• Neoplastic follicles comprising cleaved cells (centrocytes) and larger cells with vesicular nuclei and prominent 2-3 nucleoli (centroblasts).
• Mantle cell lymphoma. Small lymphoid cells with oval to slightly irregular nuclei and clumped chromatin and rare admixed pink histiocytes.
• Diffuse large B-cell non-Hodgkin lymphoma. Large cells with abundant cytoplasm and large round-ovoid nuclei with thick nuclear membrane and multiple prominent nucleoli.
• Burkitt lymphoma. Normal architecture is entirely replaced by lymphoma cells and evenly dispersed macrophages, starry sky (250×).
• Burkitt lymphoma cells with round noncleaved nuclei and strongly basophilic cytoplasm (1000×).
• Compartmentalizing fibrosis and infiltrate of medium-sized to large lymphoid cells.
• Lymphoma cells show strong membranous positivity with CD20 indicative of B-cell origin.

of 7

Tables

• Table 1. Chromosomal Abnormalities in B-Cell Non-Hodgkin Lymphoma
• Table 2. Characteristic Immunophenotypes of Major Subtypes of Lymphoma
• Table 3. Lugano Modification of the Ann Arbor Staging System.
• Table 4. Non-Hodgkin lymphoma staging.
• Table 3. International Society for Cutaneous Lymphoma/European Organization for Research and Treatment of Cancer tumor-node-metastasis classification for cutaneous B-cell lymphoma

Table 1. Chromosomal Abnormalities in B-Cell Non-Hodgkin Lymphoma

Cytogenetic Abnormality	Histology	Antigen Rearrangement	Oncogene Expression
t(14;18)(q32;q21)	Follicular, diffuse large cell	IgH*	bcl- 2
t(11;14)(q13;q32)	Mantle cell	IgH	cyclin-D1/bcl-1
t(1;14)(p22;q32)	MALT lymphoma	IgH	bcl- 10
t(11;18)(q21;q21)	MALT lymphoma	IgH	Unknown
t(9;14)(p13;q32)	Lymphoplasmacytic lymphoma	IgH	PAX-5
8q24 translocations t(8;14)(q24;q32) t(2;8)(p11-12;q24) t(8;22)(q24;q11)	Burkitt lymphoma	IgH Ig-8 Ig-6	c-myc
Trisomy 12, deletion 11q22-23, 17p13, and 6q21	CLL	…	…
*Immunoglobulin H (IgH) MALT = Mucosa-associated lymphoid tissue.

Table 2. Characteristic Immunophenotypes of Major Subtypes of Lymphoma

Lymphoma	Immunophenotype
Follicular	CD20+, CD3-, CD10+, CD5-, BCL2+, CD23-/+, CD43-, cyclinD-1-, BCL6+
Small lymphocytic	CD 20+, CD3-, CD10-, CD5+, CD23+,
MALT	CD20+, CD3-, CD 10-, CD5-, CD23-/+, BCL2+
Marginal zone	CD20+, CD3-, CD 10-, CD5-, CD23-/+, CD43-/+, cyclinD-1-, BCL2
Mantle cell	CD20+, CD23-/+, CD10-/+, CD5+, CD43-/+, cyclinD-1+
Mediastinal large B-cell	CD20+, CD30+, MUM-1+
Burkitt	slg+,CD20+, Tdt-, CD10+, BCL2--, BCL6+, Ki-67+ (≥95%)
B-lymphoblastic	slg-, CD19+, CD10-/+, CD20-/+, TdT+
MALT = mucosa-associated lymphoid tissue.

Table 3. Lugano Modification of the Ann Arbor Staging System.

Stage		Area of Involvement	Extranodal (E) Status
I	Single node or adjacent group of nodes		Single extranodal lesions without nodal involvement
II	Multiple lymph node groups on same side of diaphragm		Stage I or II by nodal extent with limited contiguous extranodal involvement
II bulky*	Multiple lymph node groups on same side of diaphragm with “bulky disease”.		N/A
III	Multiple lymph node groups on both sides of diaphragm; nodes above the diaphragm with spleen involvement		N/A
IV	Multiple noncontiguous extranodal sites		N/A
*Stage II bulky disease considered limited or advanced as determined by histology and a number of prognostic factors. Suffixes A and B are not required X for bulky disease replaced with documenting of largest tumor diameter Definition of “Bulky” disease varies depending on lymphoma histology.

Table 4. Non-Hodgkin lymphoma staging.

Stage		Area of Involvement	Extranodal (E) Status
I	Single node or adjacent group of nodes		Single extranodal lesions without nodal involvement
II	Multiple lymph node groups on same side of diaphragm		Stage I or II by nodal extent with limited contiguous extranodal involvement
II bulky*	Multiple lymph node groups on same side of diaphragm with “bulky disease”		N/A
III	Multiple lymph node groups on both sides of diaphragm; nodes above the diaphragm with spleen involvement		N/A
IV	Multiple noncontiguous extranodal sites		N/A

Table 3. International Society for Cutaneous Lymphoma/European Organization for Research and Treatment of Cancer tumor-node-metastasis classification for cutaneous B-cell lymphoma

Tumor	Involvement	Node	Involvement	Metastatic Spread	Involvement
T1	Solitary skin involvement T1a: ≤5 cm diameter T1b: >5 cm diameter	N0	No lymph node involvement	M0	No evidence of extracutaneous non-lymph node disease
T2	Multiple lesions limited to one body region or two contiguous body regions T2a: all-disease in a < 15-cm diameter T2b: all-disease in a >15- and < 30-cm diameter T2c: all-disease in a >30-cm diameter	N1	Involvement of one peripheral lymph node region	M1	Evidence of extracutaneous non-lymph node disease
T3	Generalized skin involvement T3a: multiple lesions involving two noncontiguous body regions T3b: multiple lesions involving three body regions	N2	Involvement of two or more peripheral lymph node regions or involvement of any lymph node region that does not drain an area of current or prior skin involvement
N3	Central lymph nodes involvement

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Contributor Information and Disclosures

Author

Mohammad Muhsin Chisti, MD, FACP Associate Professor of Medicine (Hematology and Oncology), Oakland University William Beaumont School of Medicine; Medical Director of Research, Karmanos Cancer InstituteMohammad Muhsin Chisti, MD, FACP is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Clinical Oncology, American Society of Hematology, Medical Society of the State of New YorkDisclosure: Nothing to disclose.

Coauthor(s)

Haresh Kumar, MBBS Resident Physician, Department of Internal Medicine, St Joseph Mercy Oakland HospitalDisclosure: Nothing to disclose.

Sumeet K Yadav, MD, MBBS Resident Physician, Department of Internal Medicine, St Joseph Mercy Oakland HospitalSumeet K Yadav, MD, MBBS is a member of the following medical societies: American College of Physicians, Asian Medical Students' Association International, Bangladesh Medical and Dental Council, European Society for Medical Oncology, Nepal Medical Association, We Care, Jahurul Islam Medical College and HospitalDisclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug ReferenceDisclosure: Received salary from Medscape for employment.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson UniversityEmmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of SciencesDisclosure: Nothing to disclose.

Additional Contributors

Ajeet Gajra, MD Associate Professor of Medicine, Director of Hematology/Oncology Fellowship Program, State University of New York Upstate Medical University; Consulting Staff, Department of Internal Medicine, Division of Hematology and Oncology, Veterans Affairs Medical CenterAjeet Gajra, MD is a member of the following medical societies: American Association for Cancer Research, American Medical Association, American Society of HematologyDisclosure: Nothing to disclose.

Neerja Vajpayee, MD Associate Professor, Department of Pathology, State University of New York Upstate Medical UniversityNeerja Vajpayee, MD is a member of the following medical societies: American Society of Hematology, College of American Pathologists, United States and Canadian Academy of PathologyDisclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors Sara J Grethlein, MD, and Uzma Athar, MD, to the development and writing of the source article.

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• Sections B-Cell Lymphoma
• Overview
  • Practice Essentials
  • Background
  • Classification
  • Pathophysiology and Etiology
  • Epidemiology
  • Prognosis
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• Presentation
• DDx
• Workup
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  • Histologic Findings
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• Treatment
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  • Complications
  • Consultations
  • Transfer
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• Guidelines
  • Staging
  • Risk Stratification
  • Follicular Lymphoma
  • Marginal Zone Lymphomas of MALT Type
  • Mantle Cell Lymphoma
  • Diffuse Large B-Cell Lymphoma
  • Burkitt Lymphoma
  • Primary Cutaneous B-Cell Lymphomas
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• Medication
  • Medication Summary
  • Hematopoietic Growth Factors
  • Monoclonal Antibodies
  • Corticosteroids
  • Antineoplastic Agents
  • Antineoplastics, Tyrosine Kinase Inhibitor
  • Antineoplastics, PI3K Delta Inhibitors
  • Antineoplastics, Angiogenesis inhibitor
  • PD-1/PD-L1 Inhibitors
  • Antineoplastics, Anti-CD19 Monoclonal Antibodies
  • CAR T-cell Therapy
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• Media Gallery
• Tables
• References

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