Diffuse Large B-cell Lymphoma, Not Otherwise Specified

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This page from the 4th edition of Haematolymphoid Tumours is being updated. See 5th edition Table of Contents.

Primary Author(s)*

Ashwini Yenamandra, PhD FACMG, Vanderbilt University Medical Center

Cancer Category/Type

Diffuse Large B-Cell Lymphoma (DLBCL): Not Otherwise Specified (NOS)

Cancer Sub-Classification / Subtype

Not Otherwise Specified (NOS)

Definition / Description of Disease

Non-Hodgkin lymphoma (NHL) is one of the most frequently diagnosed cancer types representing approximately 4% of cancers Worldwide. The most common type of NHL is Diffuse Large B-Cell Lymphoma, Not Otherwise Specified (DLBCL, NOS) accounting for 30% of all NHL cases.

Synonyms / Terminology

DLBCL, NOS

Epidemiology / Prevalence

DLBCL, NOS constitutes close to 30% of NHL. It is more common in the elderly with an average age of 60 years, but it is also seen in all age groups. Put your text here

Clinical Features

The primary site of lymphoma, either the lymph node or extra nodal site, is important in assessing clinical features, treatment options and outcome of the disease. Clinical presentation of DLBCL can be variable, usually depends on the site of disease involvement, rapid growth rate, enlarged lymph nodes, extra nodal mass infiltrating into tissues or obstructing organs. The enlarged lymphomatous mass may also exert severe pain. Patients usually experience fever, drenching night sweats, weight loss, anorexia, pedal edema (due to extensive pelvic lymphadenopathy), fatigue, chest discomfort or shortness of breath due to mediastinal lymphadenopathy. Put your text here

Sites of Involvement

Lymph node or extra nodal site, enlarged lymph nodes, extra nodal mass infiltrating into tissues or obstructing organs. The enlarged lymphomatous mass may also exert severe pain.

Morphologic Features

Clinical presentation of DLBCL can be variable, usually depends on the site of disease involvement, rapid growth rate, enlarged lymph nodes, extra nodal mass infiltrating into tissues or obstructing organs. The enlarged lymphoma mass may also exert severe pain. Patients usually experience fever, drenching night sweats, weight loss, anorexia, pedal edema (due to extensive pelvic lymphadenopathy), fatigue, chest discomfort or shortness of breath due to mediastinal lymphadenopathy.

Immunophenotype

Put your text here and/or fill in the table

Finding	Marker
Positive (universal)	EXAMPLE CD1
Positive (subset)	EXAMPLE CD2
Negative (universal)	EXAMPLE CD3
Negative (subset)	EXAMPLE CD4

Chromosomal Rearrangements (Gene Fusions)

Put your text here and/or fill in the table

Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence
EXAMPLE t(9;22)(q34;q11.2)	EXAMPLE 3'ABL1 / 5'BCR	EXAMPLE der(22)	EXAMPLE 5%
EXAMPLE t(8;21)(q22;q22)	EXAMPLE 5'RUNX1 / 3'RUNXT1	EXAMPLE der(8)	EXAMPLE 5%

Characteristic Chromosomal Aberrations / Patterns

Due to the clinicopathologic, biological and genetic diversity, DLBCL is sub divided into morphological variants and molecular subtypes. Initial workup and evaluation of DLBCL has become increasingly complex partly due to the genetic abnormalities that are targets for specific therapy and play an important role in monitoring residual disease. Genomic studies help in clinical management, risk stratification, enrolling patients onto treatment protocols, clinical trials, and detection of therapeutic targets. GS, If IHC is positive for GCB like DLBCL, FISH and Cytogenetics for MYC, BCL2 or BCL6 gene rearrangement are recommended to rule out double and triple hit lymphoma.

Genomic Gain/Loss/LOH

AMPLIFICATION: BCL2, REL, CD274, PDCD1LG2, JAK2, KRAs, TBL1XR1, RB1

DELETION: CDKN2A, TNFAIP3, CDKN2B, TNFRSF14, CD70, CD58, PTEN

Chromosome Number	Gain/Loss/Amp/LOH	Region
EXAMPLE 8	EXAMPLE Gain	EXAMPLE chr8:0-1000000
EXAMPLE 7	EXAMPLE Loss	EXAMPLE chr7:0-1000000

Gene Mutations (SNV/INDEL)

SNV : MLL2, TP53, MYD88, B2M, CREBBP, TNFAIP3, PIM1, BCL2, EZH2, TNFRSF14, CD79B

Gene	Mutation	Oncogene/Tumor Suppressor/Other	Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)	Prevalence (COSMIC/TCGA/Other)
EXAMPLE TP53	EXAMPLE R273H	EXAMPLE Tumor Suppressor	EXAMPLE LOF	EXAMPLE 20%

Other Mutations

Type	Gene/Region/Other
Concomitant Mutations	EXAMPLE IDH1 R123H
Secondary Mutations	EXAMPLE Trisomy 7
Mutually Exclusive	EXAMPLE EGFR Amplification

Epigenomics (Methylation)

Ø Epigenetic Modification : Recurrent mutations in genes that encode for histone/chromatin modifiers that include methyltransferases, acetyltransferases, and histones.

Ø Gain of function -EZH2-mutations in 22% GCB

Ø Loss of Functiom-MLL2(KMT2D, methyl transferase, truncating)/MLL3 -mutations-35% in GCB and ABC

Ø Loss of unction F-CREBBP(25%)/EP300 (5%)-inactivation of the acetyltransferase genes, mutations, and deletions, 30% in GCB and 15% in ABC

Genes and Main Pathways Involved

B-Cell differentiation, TP53 pathway, NF-kB pathway, Apoptosis, Cell migration, Immune response,BCR-MYD88 signaling, PI3K-AKT-mTCR pathway

Diagnostic Testing Methods

NGS, If IHC is positive for GCB like DLBCL, FISH and Cytogenetics for MYC, BCL2 or BCL6 gene rearrangement are recommended to rule out double and triple hit lymphoma.

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

Prognosis: Diagnosis this disease may allow appropriate prophylactic measures, including H1 and H2 blockers, proton pump inhibitors and steroids, to be initiated to minimize its protean complications.

Therapeutic Implications:

Familial Forms

Not Available

Other Information

Not Available

Links

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References

1. Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD, Jaffe ES. WHO: The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016 19; 127(20):2375-90. PMID: 26980727

2. Bolen, C.R., Klanova, M., Trneny, M., Sehn, L.H., He, J., Tong, J., Paulson, J.N., Kim, E., Vitolo, U., Di Rocco, A. and Fingerle-Rowson, G., 2020. Prognostic impact of somatic mutations in diffuse large B-cell lymphoma and relationship to cell-of-origin: data from the phase III GOYA study. haematologica, 105(9). PMID: 31727768

3. Sujobert P, Salles G, Bachy E. Molecular classification of diffuse large B-cell lymphoma: what is clinically relevant? Hematology/Oncology Clinics. 2016 1; 30(6):1163-77. PMID: 27888873

4. 3. Tilly H, Gomes da Silva M, Vitolo U, Jack A, Meignan M, Lopez-Guillermo A, Walewski J, André M, Johnson PW, Pfreundschuh M, Ladetto M. Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of oncology. 2015 1; 26(suppl_5):116-25. PMID: 26314773

5. Shi Y, Han Y, Yang J, Liu P, He X, Zhang C, Zhou S, Zhou L, Qin Y, Song Y, Liu Y. Clinical features and outcomes of diffuse large B-cell lymphoma based on nodal or extra nodal primary sites of origin: Analysis of 1,085 WHO classified cases in a single institution in China. Chinese Journal of Cancer Research. 2019 31(1):152-161. PMID: 30996573

6. 5. Shipp MA. International non-Hodgkin's lymphoma prognostic factors project. A predictive model for aggressive non-Hodgkin's lymphoma. N Eng J Med. 1993 329; 987-94. PMID: 8141877

7. Ziepert M, Hasenclever D, Kuhnt E, Glass B, Schmitz N, Pfreundschuh M and Loeffler M: Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B cell lymphoma in the rituximab era. J Clin Oncol 2010 28: 2373 80. PMID: 20385988

8. Boltežar L, Prevodnik VK, Perme MP, Gašljević G, Novaković BJ. Comparison of the algorithms classifying the ABC and GCB subtypes in diffuse large B-cell lymphoma. Oncology letters. 2018 1; 15(5):6903-12. PMID: 29731865

9. Schmitz R, Wright GW, Huang DW, Johnson CA, Phelan JD, Wang JQ, Roulland S, Kasbekar M, Young RM, Shaffer AL, Hodson DJ. Genetics and pathogenesis of diffuse large B-cell lymphoma. New England journal of medicine. 2018 Apr 12; 378(15):1396-407. PMID: 29641966

10. https://www.biooncology.com/pathways/cancer-tumor-targets/b-cell/dlbcl/dlbcl-diagnosis.html, Genentech, Bio oncology.

11. NCCN Practice Guidelines in Oncology, B- Cell Lymphomas, Version 1, 2020, NCCN.org.

EXAMPLE Book

Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.

Notes

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