Primary large B-cell lymphoma of immune-privileged sites

Haematolymphoid Tumours (5th ed.)

editHAEM5 Conversion Notes

This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Diffuse Large B-cell Lymphoma, Not Otherwise Specified.

Another relevent page is: HAEM4:Primary Diffuse Large B-cell Lymphoma of the CNS

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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

Put your text here and fill in the table (Instruction: Can include references in the table)

Signs and Symptoms	EXAMPLE Asymptomatic (incidental finding on complete blood counts) EXAMPLE B-symptoms (weight loss, fever, night sweats) EXAMPLE Fatigue EXAMPLE Lymphadenopathy (uncommon)
Laboratory Findings	EXAMPLE Cytopenias EXAMPLE Lymphocytosis (low level)

editv4:Clinical Features

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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 fill in the table (Instruction: Can include references 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 fill in the table

Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE t(9;22)(q34;q11.2)	EXAMPLE 3'ABL1 / 5'BCR	EXAMPLE der(22)	EXAMPLE 20% (COSMIC) EXAMPLE 30% (add reference)	Yes	No	Yes	EXAMPLE The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).

editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).

Please incorporate this section into the relevant tables found in:

• Chromosomal Rearrangements (Gene Fusions)
• Individual Region Genomic Gain/Loss/LOH
• Characteristic Chromosomal Patterns
• Gene Mutations (SNV/INDEL)

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:

Individual Region Genomic Gain / Loss / LOH

Put your text here and fill in the table (Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable.)

Chr #	Gain / Loss / Amp / LOH	Minimal Region Genomic Coordinates [Genome Build]	Minimal Region Cytoband	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE 7	EXAMPLE Loss	EXAMPLE chr7:1- 159,335,973 [hg38]	EXAMPLE chr7	Yes	Yes	No	EXAMPLE Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
EXAMPLE 8	EXAMPLE Gain	EXAMPLE chr8:1-145,138,636 [hg38]	EXAMPLE chr8	No	No	No	EXAMPLE Common recurrent secondary finding for t(8;21) (add reference).

editv4:Genomic Gain/Loss/LOH

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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

Characteristic Chromosomal Patterns

Put your text here (EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis)

Chromosomal Pattern	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE Co-deletion of 1p and 18q	Yes	No	No	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

editv4:Characteristic Chromosomal Aberrations / Patterns

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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.

Gene Mutations (SNV / INDEL)

Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity.)

Gene; Genetic Alteration	Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)	Prevalence (COSMIC / TCGA / Other)	Concomitant Mutations	Mutually Exclusive Mutations	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: TP53; Variable LOF mutations EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations	EXAMPLE: TSG	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add Reference)	EXAMPLE: IDH1 R123H	EXAMPLE: EGFR amplification				EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).

Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

editv4:Gene Mutations (SNV/INDEL)

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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

Epigenomic Alterations

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

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE:  KMT2C and ARID1A; Inactivating mutations	EXAMPLE:  Histone modification, chromatin remodeling	EXAMPLE:  Abnormal gene expression program

editv4:Genes and Main Pathways Involved

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

Genetic 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.

Familial Forms

Not Available

Additional Information

Not Available

Links

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References

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Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome. *Citation of this Page: “Primary large B-cell lymphoma of immune-privileged sites”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 12/23/2023, https://ccga.io/index.php/HAEM5:Primary_large_B-cell_lymphoma_of_immune-privileged_sites.