Indolent T-cell Lymphoproliferative Disorder of the Gastrointestinal Tract

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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)*

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

Cancer Category/Type

Cancer Sub-Classification / Subtype

Definition / Description of Disease[1]

  • 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

Synonyms / Terminology

  • N/A

Epidemiology / Prevalence[2]

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

Clinical Features

  • 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[3]

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[1][4]

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%

Chromosomal Rearrangements (Gene Fusions)[5]

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)

Characteristic Chromosomal Aberrations / Patterns

Genomic Gain/Loss/LOH[1]

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

Gene Mutations (SNV/INDEL)[6]

  • 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.

Epigenomics (Methylation)

  • Not described

Genes and Main Pathways Involved[5]

  • JAK-STAT

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 [5]

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

  • 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[5]
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[7][8]
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[4] but seen in type 2 refractory celiac disease, EATL and MEITL
  • Prognosis[2]
    • Indolent, but chronic relapsing clinical course
  • Therapeutic Implications
    • Generally unresponsive to therapy[1]
      • The potential use of JAK-STAT inhibitors such as tofacinib and AZD1480 has not been formally tested

Familial Forms

  • Not described

Other Information

  • N/A

Links

References

  1. ↑ 1.0 1.1 1.2 1.3 E, Margolskee; et al. (2013). "Indolent small intestinal CD4+ T-cell lymphoma is a distinct entity with unique biologic and clinical features". doi:10.1371/journal.pone.0068343. PMC 3701677. PMID 23861889.CS1 maint: PMC format (link)
  2. ↑ 2.0 2.1 Am, Perry; et al. (2013). "Indolent T-cell lymphoproliferative disease of the gastrointestinal tract". doi:10.1182/blood-2013-07-512830. PMC 3837508. PMID 24009234.CS1 maint: PMC format (link)
  3. ↑ K, Hirakawa; et al. (1996). "Primary gastrointestinal T-cell lymphoma resembling multiple lymphomatous polyposis". PMID 8780585.
  4. ↑ 4.0 4.1 M, Cheminant; et al. (2019). "NKp46 is a diagnostic biomarker and may be a therapeutic target in gastrointestinal T-cell lymphoproliferative diseases: a CELAC study". PMID 30448772.
  5. ↑ 5.0 5.1 5.2 5.3 A, Sharma; et al. (2018). "Recurrent STAT3-JAK2 fusions in indolent T-cell lymphoproliferative disorder of the gastrointestinal tract". doi:10.1182/blood-2018-01-830968. PMC 5958657. PMID 29592893.CS1 maint: PMC format (link)
  6. ↑ Cr, Soderquist; et al. (2020). "Genetic and phenotypic characterization of indolent T-cell lymphoproliferative disorders of the gastrointestinal tract". doi:10.3324/haematol.2019.230961. PMC PMC7327650 Check |pmc= value (help). PMID 31558678.CS1 maint: PMC format (link)
  7. ↑ Sy, Tan; et al. (2013). "Type II EATL (epitheliotropic intestinal T-cell lymphoma): a neoplasm of intra-epithelial T-cells with predominant CD8αα phenotype". PMID 23399895.
  8. ↑ G, Mutzbauer; et al. (2018). "SYK expression in monomorphic epitheliotropic intestinal T-cell lymphoma". PMID 29052597.

Notes

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