HAEM5:Extranodal NK/T-cell lymphoma

Haematolymphoid Tumours (5th ed.)

(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples). Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support)

Primary Author(s)*

Teodora Popa, MD, Queen's University

Amanda Xu, MD/MSc, Queen's University

Put your text here (Name and affiliation; example: Jane Smith, PhD, Institute of Genomics)

Cancer Category / Type

Mature T-cell and NK-cell neoplasms

Cancer Sub-Classification / Subtype

EBV-positive T-cell and NK-cell neoplasms

Definition / Description of Disease

Extranodal NK/T-cell lymphoma is a distinct entity in the 5th edition World Health Organization (WHO) classification system. It is referred to as "extranodal NK/T-cell lymphoma, nasal type" in the 2016 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues revised 4th edition.

***Amanda, we do not have the revised 4th edition in our resident office... could you please check the page numbers and update the reference with the correct author and page numbers? thanks!

Extranodal NK/T-cell lymphoma (ENKTL) is a lymphoma of NK or T-cell lineage strongly associated with Epstein-Barr virus (citation needed)

The lineage (NK or T-cell) has no clinical significance (citation needed)

ENKTL is a destructive angiocentric disease characterized by vascular destruction and necrosis (citation needed)

It can be clinically divided into nasal and non-nasal types (citation needed)

Put your text here (Instructions: Brief description of approximately one paragraph - include disease context relative to other WHO classification categories referring to the specific WHO book pages, diagnostic criteria if applicable, and differential diagnosis if applicable)

Synonyms / Terminology

Extranodal NK/T-cell lymphoma, nasal type; EBV-positive extranodal NK/T-cell lymphoma; angiocentric lymphoma (not recommended); lethal midline granuloma (historical)

Epidemiology / Prevalence

ENKTL is most prevalent in East Asia and Latin America. It represents less than 1% of non-Hodgkin lymphomas in the United States, with the highest incidence among Asian Pacific Islanders and Hispanic populations.

Clinical Features

Common clinical presentations of nasal-type ENKTL include nasal mass, obstruction, and bleeding. Patients with abdominal involvement may present with abdominal pain, gastrointestinal (GI) bleed, or perforation. The presence of B symptoms is associated with higher clinical stage.

Signs and Symptoms	Nasal mass, nasal obstruction, nasal bleeding Hoarseness, dysphagia, halitosis, airway obstruction, dysphonia Abdominal pain, GI bleeding, bowel perforation B symptoms (fever, weight loss, night sweats)
Laboratory Findings	No specific findings Cytopenias

Sites of Involvement

Most cases of ENKTL are nasal type, meaning they involve the upper aerodigestive tract. Extranasal ENKTL may involve the skin, testis, and gastrointestinal tract. Bone marrow involvement is uncommon.

Morphologic Features

• Diffuse lymphomatous infiltrate composed of small, medium, or large and anaplastic cells (or a mix of small and large cells). The cells have irregularly folded nuclei and moderate pale cytoplasm.
• Loss of mucosal glands.
• Angiocentric and angiodestructive growth pattern.
• Coagulative necrosis and apoptosis.
• Mitotic figures.

Pitfalls:

• Mucosal ulceration and superimposed inflammation can mimic an inflammatory process, particularly in less aggressive cases.
• Pseudoepitheliomatous hyperplasia of the overlying mucosal epithelium can mimic squamous cell carcinoma.

***Amanda, do you know if we have any good cases we could scan and add photos of?

Immunophenotype

The majority of cases are positive for cytoplasmic CD3ε, CD2, granzyme B, and TIA-1. Most ENKTLs are of NK-lineage and express CD56. Cases of T-lineage express T-cell receptor (TCR) and show clonal TCR gene rearrangements. All cases are EBV positive by in situ hybridization for Epstein-Barr virus-encoded small RNA (EBER). Other markers that may be expressed include HLA-DR, CD25, pSTAT3, CXCL13, IRF4/MUM1, CD16, Fas, FasL, MATK, and CD30.

Finding	Marker
Positive (universal)	CD2, CD56, cytoplasmic CD3ε, cytotoxic markers (TIA-1, granzyme B, perforin) EBER / EBV
Positive (subset)	TCR αβ/γδ, HLA-DR, CD25, pSTAT3, CXCL13, IRF4/MUM1, CD16, Fas, FasL, MATK, CD30
Negative (universal)	CD4, CD8
Negative (subset)	Surface CD3 (subset of T-cell lineage)

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).

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).

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).

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.

Epigenomic Alterations

Put your text here

Genes and Main Pathways Involved

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

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

Genetic Diagnostic Testing Methods

Put your text here

Familial Forms

Put your text here (Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.)

Additional Information

Put your text here

Links

Put your text placeholder here (or anywhere appropriate on the page) and use the "Link" icon at the top of the page (Instructions: Once you have a text placeholder entered to which you want to add a link, highlight that text, select the "Link" icon at the top of the page, and search the name of the internal page to which you want to link this text, or enter an external internet address including the "http://www." portion.)

References

(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference.)

EXAMPLE Book

1. 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

*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: “Extranodal NK/T-cell lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 06/13/2024, https://ccga.io/index.php/HAEM5:Extranodal_NK/T-cell_lymphoma.