Indolent T-cell lymphoma of the gastrointestinal tract

Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification

This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Indolent T-cell Lymphoproliferative Disorder of the Gastrointestinal Tract.

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Primary Author(s)*

Derick Okwan-Duodu MD, PhD; Sumire Kitahara, MD

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	T-cell and NK-cell lymphoid proliferations and lymphomas
Family	Mature T-cell and NK-cell neoplasms
Type	Intestinal T-cell and NK-cell lymphoid proliferations and lymphomas
Subtype(s)	Indolent T-cell lymphoma of the gastrointestinal tract

Definition / Description of Disease

• Indolent T-cell lymphoproliferative disorders of the gastrointestinal tract (GI TLPD) are rare neoplasms that mimic intestinal T-cell lymphoma and other inflammatory diseases of the GI tract, including Crohn's disease. However, it has distinct cellular derivation, pathobiological features and genomic landscape that remains to be fully elucidated

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Synonyms / Terminology

• N/A

Epidemiology / Prevalence

• Extremely rare
• Etiology not understood, but some have a history of Crohn disease

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Clinical Features

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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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• Abdominal pain
• Diarrhea
• Dyspepsia
• Weight loss
• Endoscopic findings:
  • Thickened, nodular, hyperemic mucosal surface with superficial erosions
  • If presenting as intestinal polyps, may mimic lymphomatous polyposis
• No association with celiac disease

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Sites of Involvement

• Small intestine and colon (predominant)
• Any gastrointestinal mucosa possible
• May present as polypoid lesions in the stomach, duodenum, terminal ileum and colon

Morphologic Features

• Small, monotonous, round, lymphocytes with scant cytoplasm
• Lymphoid infiltrate expands lamina propria and displaces mucosal glands, but does not cause destruction of underlying architecture, and usually does not invade epithelium
• Admixed inflammatory cells are uncommon

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Immunophenotype

Finding	Marker
Positive (universal)	CD3, CD2, CD5, TIA1 (in CD8+ cases), TCR alpha beta
Positive (frequent)	CD8 > CD4
Positive (rare)	CD4+CD8+ (double positive)
Negative (universal)	TCR-gamma, EBER, NKp46, CD56
Negative (frequent)	Granzyme B, CD103
Negative (rare)	CD4-CD8- (double negative)
Ki-67	< 10%

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Chromosomal Rearrangements (Gene Fusions)

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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).

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Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Features
t(9;17)(p24.1;q21.2)	STAT3-JAK2	Appears to be unique to CD4+ cases (in a series of 10 unselected GI TLPDs, the only cases with JAK-STAT activation were in 4 out of 5 CD4+ cases; none was observed in the CD8+ or CD4+CD8+ double positive cases)

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

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

• Diagnosis
  • Clinical history, imaging, morphologic and immunophenotypic characterization
  • No pathognomonic diagnostic markers (molecular or otherwise)
  • Differential diagnosis include extranodal NK/T-cell lymphoma, monomorphic epitheliotropic intestinal lymphoma, peripheral T-cell lymphoma not otherwise specified, inflammatory bowel disease (Crohn's disease, ulcerative colitis), celiac disease

Alterations	Significance	Note
STAT3-JAK2 fusion	Likely role in diagnosis (inclusion)	Likely present in CD4+ GI TLPD and absent in EATL, MEITL, and other T-cell lymphomas
EBV	Possible role in diagnosis (exclusion)	helps distinguishes from T/NK extranodal intestinal lymphoma
MATK, SYK	Possible role in diagnosis (exclusion)	strongly favors monomorphic epithelieotropic intestinal lymphoma
Anti-transglutaminase antibodies	Possible role in diagnosis (exclusion)	May help distinguish from enteropathy associated T- cell lymphoma (EATL)
TCR clonal rearrangement	Possible role in diagnosis (inclusion)	May be necessary to distinguish from inflammatory disease (Crohn's disease, celiac for cases with epitheliotropism)
NKp46	Possible role in diagnosis (exclusion)	Positive stain does not favor the diagnosis but seen in type 2 refractory celiac disease, EATL and MEITL

• Prognosis
  • Indolent, but chronic relapsing clinical course

• Therapeutic Implications
  • Generally unresponsive to therapy
    • The potential use of JAK-STAT inhibitors such as tofacinib and AZD1480 has not been formally tested

Individual Region Genomic Gain / Loss / LOH

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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).

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Chromosome Number	Gain/Loss/Amp/LOH	Region	Genes
1p	gain	p32.1; p36	JUN, NDRG1; PAX7, SDHB
8q	gain	q24.22	WISP1
15q	gain	q21.2	PDRM2, STAT3
17q	gain	q21.2q31	PRDX4, ZFX, ELN
9q	gain	q22-34
7q	LOH	11.22q23
Xp	gain	p22.11
8p	loss

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Characteristic Chromosomal Patterns

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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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Gene Mutations (SNV / INDEL)

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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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• STAT3
• SOCS1
• TET2
• DNMT3A
• KMT2D

INCLUDE THESE IN THE STANDARD TABLE WITH PREVALENCES. WHO BOOK STATES THAT STAT3 IS ABSENT, SO IT WILL BE IMPORTANT TO RECONCILE.

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Epigenomic Alterations

• Not described

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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• JAK-STAT

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Genetic Diagnostic Testing Methods

• No pathognomonic diagnostic markers (molecular or otherwise)
• Imaging (PET/CT)
• Endoscopy
• Morphological and immunophenotypic characterization
• T-cell receptor gene rearrangement studies demonstrate clonality, which can help distinguish from inflammatory disorders of the intestines (Crohn's disease, ulcerative colitis, celiac disease)
• STAT3-JAK2 rearrangement in CD4+ cases may be detected by conventional cytogenetic analysis, FISH may detect JAK2 rearrangement, and NGS may detect rearrangement if available in panel

Familial Forms

• Not described

Additional Information

• N/A

Links

• HAEM4:Intestinal T-cell Lymphoma

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: “Indolent T-cell lymphoma of the gastrointestinal tract”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/6/2024, https://ccga.io/index.php/HAEM5:Indolent_T-cell_lymphoma_of_the_gastrointestinal_tract.