Testpage4

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Primary Author(s)*

Sara Akhavanfard, M.D., Ph.D.

Ruthann Pfau, Ph.D., FACMG

Cancer Category/Type

HAEM4:Angioimmunoblastic T-cell Lymphoma and Other Nodal Lymphomas of T Follicular Helper Cell Origin

Cancer Sub-Classification / Subtype

Angioimmunoblastic T-cell Lymphoma (AITL)

Definition / Description of Disease

  • A neoplasm of mature T follicular helper (TFH) cells
  • Characterized by systemic disease and a polymorphous infiltrate involving lymph nodes
  • Have prominent proliferation of high endothelial venules (HEVs) and folicular dentritic cells (FDCs)
  • EBV-positive B cells are nearly always present
  • Clinically aggressive and seen mainly in older adults

Synonyms / Terminology

  • Peripheral T-cell Lymphoma
  • Angioimmunoblastic Lymphadenopathy with Dysproteinaemia
  • Immunoblastic Lymphadenopathy
  • Lymphogranulomatosis X

Epidemiology / Prevalence

  • Occurs in middle-aged and elderly individuals[1]
  • Males >> Females[1]
  • One of the most common specific subtypes of PTCL[2][3][4]
    • 15-30% of non-cutaneous T-cell lymphomas
    • 1-2% of all non-Hodgkin lymphomas

Clinical Features[5][6][7][8]

Sign and Symptoms

  • Advanced-stage disease with systemic symptoms
  • Generalized lymphadenopathy
  • Hepathosplenomegaly
  • Polyclonal hypergammagloulinaemia
  • Skin rash, often with pruritus
  • Pleural effusion
  • Arthritis
  • Ascities

Laboratory Findings

  • Circulating Immune Complexes
  • Cold agglutinins with haemolytic anemia
  • Positive rheumatoid factor
  • Positive anti-smooth muscle antibody

Sites of Involvement

  • Primary site: Lymph node
  • Other involved sites: Spleen, Liver, Skin,and Bone marrow[9][10][11][12]

Morphologic Features[13][14]

Pattern-1 (Early involvement)

  • Bare, hyperplastic follicles, with Well-formed germinal centers, often lacking well-defined mantle cuffs[15]
  • Paracortical expansion
  • Marked Vascular Proliferation, associated with perifollicular or atypical lymphoid cells

Pattern-2

  • Remnant of follicles with regressive changes
  • Readily identified neoplastic cells in the expanded paracortex
  • Marked perifollicular expansion of clear cells

Pattern-3

  • Totally or sub-totally effacement of normal architecture
  • Marked vascular proliferation
  • Aggregates of atypical lymphoid cells

Immunophenotype[16][17][18][19][20]

Finding Marker
Positive (universal) CD3, CD2, CD5, CD4, CD10, CXCL13, ICOS, BCL6, PD1(CD279)
Positive (extrafollicular pattern) CD21, CD23, CD35

Chromosomal Rearrangements (Gene Fusions)

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Reference
t(5;9)(q33;q22) ITK / SYK der(5); der(9) [21][22]
t(7;14)(q35;q32.1) TRB/TCL1A der(7); der(14) [23]
t(14;14)(q11;q32.1) / inv(14)(q11q32.1) TRA-TRD/TCL1A der(14) [24][25]
chr(2)(q33.2) CTLA4/CD28 der(2) [26]

Characteristic Chromosomal Aberrations / Patterns

  • Clonal rearrangement in T-Cell receptor gene in 75-90% of AITL cases[27] [28][29]
  • Clonal rearrangement in immunoglobulin genes in 25-30% of AITL cases[27][29]

Genomic Gain/Loss/LOH

Chromosome Number Gain/Loss/Amp/LOH Reference
3,5,21 Trisomy [30]
X Gain [30]
6q Loss [30]
22q Gain [31]
19 Gain [31]
11q13 Gain [31]
13q Loss [31]

Gene Mutations (SNV/INDEL)

Gene Mutation Oncogene/Tumor Suppressor/Other Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) Prevalence (COSMIC/TCGA/Other)
IDH2 R172S; R172G;R172K Tumor Suppressor LOF 20-30%[32][22][33][34]
TET2 Widely distributed Tumor Suppressor LOF 50-80%[35][33]
DNMT3A W305* Tumor Suppressor LOF 20-30%[22][33]
RHOA G17V; G17E; C16R; T19I; D120Y Tumor Suppressor LOF 60-70%[36][37][38]
FYN L174R; R176C; Y531H Oncogene GOF up to 5-10%[39][38]
PLCG1 S345F; G869E Oncogene GOF up to 5-10%[39][22]
CD28 D124V; D124E; T195P Oncogene GOF up to 5-10%[39][40]
TNFRSF21 S428fs*S1 Tumor Suppressor LOF [22]
CCND3 Q280* Tumor Suppressor LOF [22]
SAMSN1 R153* Tumor Suppressor LOF [22]

Epigenomics (Methylation)

  • Frequent mutation in epigenetic modifiers like: [22][33][34][35]
    • IDH2 (20-30%)
    • TET2 (50-80%)
    • DNMT3A (20-30%)

Genes and Main Pathways Involved

Molecular Features Pathway Pathophysiologic Outcome
FYN, PLCG1, and CD28 mutations T-cell receptor signaling pathway[22][38][39][40] Increased proliferation and survival
IDH2, TET2, and DNMT3A mutations Histone modification and chromatin remodeling[22][33][34][35] Abnormal gene expression program

Diagnostic Testing Methods

  • Clinical, morphological, and immunophenotypic findings are generally sufficient for diagnosis
  • IDH2 R172 mutations are specific to AITL
  • T-Cell receptor and immunoglobulin genes rearrangement detection by karyotyping and FISH analysis

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

  • Overall prognosis is poor[41][42]
  • Median survival < 3 years, even with aggressive treatment[41][42]
  • Male sex, mediastinal lymphadenopathy, and anemia adversely affect the survival[41]

Suggested Treatment Regimens based on NCCN Guideline Version 1.2020 (TCEL-B 3 of 5)

Second-line therapy (with intention to transplant) and subsequent therapy:

  • Clinical Trial preferred
  • Preferred regimens
    • Single Agents (alphabetical order)
      • Belinostat
      • Brentuximab Vedotin for CD30+ AITL
      • Romidepsin
    • Combination Regimens
      • DHAP(Dexamethasone, Cisplatin, Cytarabine)
      • ESHAP (Etoposide, Methylprednisolone, Citarabine, Cisplatin)
      • GDP (Gemcitabine, Dexamethasone, Cisplatin)
      • GemOx (Gemcitabine, Oxaliplatin)
      • ICE (Ifosfamide, Carboplatin, Etoposide)
  • Other recommended regimens
    • Single Agents (alphabetical order)
      • Bendamustine
      • Gemcitabine
      • Lenalidomide
      • Pralatrexate

Second-line or initial palliative intent therapy (no intention to transplant) and subsequent therapy:

  • Clinical Trial preferred
  • Preferred regimens
    • Single Agents (alphabetical order)
      • Belinostat
      • Brentuximab Vedotin for CD30+ AITL
      • Romidepsin
  • Other recommended regimen (alphabetical order)
    • Alemtuzumab
    • Bendamustine
    • Bertezomib (categort 2B)
    • Cyclophosphamide and/or Etoposide (IV or PO)
    • Cyclosporine
    • Gemcitabine
    • Lenalidomide
    • Pralatrexate
    • Radiation therapy

Other Information

N/A

Links

HAEM4:Angioimmunoblastic T-cell Lymphoma and Other Nodal Lymphomas of T Follicular Helper Cell Origin

References

(use "Cite" icon at top of page)

  1. ↑ 1.0 1.1 L, de Leval; et al. (2010). "Advances in the understanding and management of angioimmunoblastic T-cell lymphoma". PMID 19961485.
  2. ↑ M, Vences; et al. (2013). "To name or not to name: Criteria to promote economy of change in Linnaean classification schemes". PMID 26042291.
  3. ↑ T, Rüdiger; et al. (2002). "Peripheral T-cell lymphoma (excluding anaplastic large-cell lymphoma): results from the Non-Hodgkin's Lymphoma Classification Project". PMID 11863096.
  4. ↑ J, Vose; et al. (2008). "International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes". PMID 18626005.
  5. ↑ A, Dogan; et al. (2003). "Angioimmunoblastic T-cell lymphoma". PMID 12780782.
  6. ↑ F, Lachenal; et al. (2007). "Angioimmunoblastic T-cell lymphoma: clinical and laboratory features at diagnosis in 77 patients". PMID 17873758.
  7. ↑ N, Mourad; et al. (2008). "Clinical, biologic, and pathologic features in 157 patients with angioimmunoblastic T-cell lymphoma treated within the Groupe d'Etude des Lymphomes de l'Adulte (GELA) trials". doi:10.1182/blood-2007-08-105759. PMC 2343588. PMID 18292286.CS1 maint: PMC format (link)
  8. ↑ W, Siegert; et al. (1995). "Angioimmunoblastic lymphadenopathy (AILD)-type T-cell lymphoma: prognostic impact of clinical observations and laboratory findings at presentation. The Kiel Lymphoma Study Group". PMID 8664186.
  9. ↑ L, de Leval; et al. (2010). "Advances in the understanding and management of angioimmunoblastic T-cell lymphoma". PMID 19961485.
  10. ↑ A, Dogan; et al. (2003). "Angioimmunoblastic T-cell lymphoma". PMID 12780782.
  11. ↑ M, Federico; et al. (2013). "Clinicopathologic characteristics of angioimmunoblastic T-cell lymphoma: analysis of the international peripheral T-cell lymphoma project". doi:10.1200/JCO.2011.37.3647. PMC 3532394. PMID 22869878.CS1 maint: PMC format (link)
  12. ↑ N, Mourad; et al. (2008). "Clinical, biologic, and pathologic features in 157 patients with angioimmunoblastic T-cell lymphoma treated within the Groupe d'Etude des Lymphomes de l'Adulte (GELA) trials". doi:10.1182/blood-2007-08-105759. PMC 2343588. PMID 18292286.CS1 maint: PMC format (link)
  13. ↑ A, Attygalle; et al. (2002). "Neoplastic T cells in angioimmunoblastic T-cell lymphoma express CD10". PMID 11781247.
  14. ↑ M, Rodriguez-Justo; et al. (2009). "Angioimmunoblastic T-cell lymphoma with hyperplastic germinal centres: a neoplasia with origin in the outer zone of the germinal centre? Clinicopathological and immunohistochemical study of 10 cases with follicular T-cell markers". PMID 19329936.
  15. ↑ Hj, Ree; et al. (1998). "Angioimmunoblastic lymphoma (AILD-type T-cell lymphoma) with hyperplastic germinal centers". PMID 9630171.
  16. ↑ A, Attygalle; et al. (2002). "Neoplastic T cells in angioimmunoblastic T-cell lymphoma express CD10". PMID 11781247.
  17. ↑ L, de Leval; et al. (2007). "The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells". PMID 17284527.
  18. ↑ Dm, Dorfman; et al. (2006). "Programmed death-1 (PD-1) is a marker of germinal center-associated T cells and angioimmunoblastic T-cell lymphoma". doi:10.1097/01.pas.0000209855.28282.ce. PMC 3137919. PMID 16819321.CS1 maint: PMC format (link)
  19. ↑ Kl, Grogg; et al. (2005). "Angioimmunoblastic T-cell lymphoma: a neoplasm of germinal-center T-helper cells?". doi:10.1182/blood-2005-03-1083. PMC 1895208. PMID 16079436.CS1 maint: PMC format (link)
  20. ↑ G, Roncador; et al. (2007). "Expression of two markers of germinal center T cells (SAP and PD-1) in angioimmunoblastic T-cell lymphoma". PMID 17640856.
  21. ↑ B, Streubel; et al. (2006). "Novel t(5;9)(q33;q22) fuses ITK to SYK in unspecified peripheral T-cell lymphoma". PMID 16341044.
  22. ↑ 22.0 22.1 22.2 22.3 22.4 22.5 22.6 22.7 22.8 22.9 M, Wang; et al. (2017). "Angioimmunoblastic T cell lymphoma: novel molecular insights by mutation profiling". doi:10.18632/oncotarget.14846. PMC 5392284. PMID 28148900.CS1 maint: PMC format (link)
  23. ↑ Mf, Cosimi; et al. (1990). "Rearrangements on chromosomes 7 and 14 with breakpoints at 7q35 and 14q11 in angioimmunoblastic lymphadenopathy and IBL-like T-cell lymphoma". PMID 2284141.
  24. ↑ B, Schlegelberger; et al. (1990). "Inv(14)(q11q32) in one of four different clones in a case of angioimmunoblastic lymphadenopathy". PMID 2293883.
  25. ↑ E, Leich; et al. (2007). "Tissue microarray-based screening for chromosomal breakpoints affecting the T-cell receptor gene loci in mature T-cell lymphomas". PMID 17582237.
  26. ↑ Hy, Yoo; et al. (2016). "Frequent CTLA4-CD28 gene fusion in diverse types of T-cell lymphoma". doi:10.3324/haematol.2015.139253. PMC 5013939. PMID 26819049.CS1 maint: PMC format (link)
  27. ↑ 27.0 27.1 Ad, Attygalle; et al. (2007). "Distinguishing angioimmunoblastic T-cell lymphoma from peripheral T-cell lymphoma, unspecified, using morphology, immunophenotype and molecular genetics". PMID 17448026.
  28. ↑ L, de Leval; et al. (2010). "Advances in the understanding and management of angioimmunoblastic T-cell lymphoma". PMID 19961485.
  29. ↑ 29.0 29.1 Bt, Tan; et al. (2006). "The frequency of B- and T-cell gene rearrangements and epstein-barr virus in T-cell lymphomas: a comparison between angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified with and without associated B-cell proliferations". doi:10.2353/jmoldx.2006.060016. PMC 1867616. PMID 16931587.CS1 maint: PMC format (link)
  30. ↑ 30.0 30.1 30.2 B, Schlegelberger; et al. (1994). "Detection of aberrant clones in nearly all cases of angioimmunoblastic lymphadenopathy with dysproteinemia-type T-cell lymphoma by combined interphase and metaphase cytogenetics". PMID 7919378.
  31. ↑ 31.0 31.1 31.2 31.3 C, Thorns; et al. (2007). "Chromosomal aberrations in angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma unspecified: A matrix-based CGH approach". PMID 17044049.
  32. ↑ Ra, Cairns; et al. (2012). "IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma". doi:10.1182/blood-2011-11-391748. PMC 3293643. PMID 22215888.CS1 maint: PMC format (link)
  33. ↑ 33.0 33.1 33.2 33.3 33.4 O, Odejide; et al. (2014). "A targeted mutational landscape of angioimmunoblastic T-cell lymphoma". doi:10.1182/blood-2013-10-531509. PMC 4260974. PMID 24345752.CS1 maint: PMC format (link)
  34. ↑ 34.0 34.1 34.2 C, Wang; et al. (2015). "IDH2R172 mutations define a unique subgroup of patients with angioimmunoblastic T-cell lymphoma". doi:10.1182/blood-2015-05-644591. PMC 4600014. PMID 26268241.CS1 maint: PMC format (link)
  35. ↑ 35.0 35.1 35.2 F, Lemonnier; et al. (2012). "Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters". PMID 22760778.
  36. ↑ M, Sakata-Yanagimoto; et al. (2014). "Somatic RHOA mutation in angioimmunoblastic T cell lymphoma". PMID 24413737.
  37. ↑ Hy, Yoo; et al. (2014). "A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma". PMID 24584070.
  38. ↑ 38.0 38.1 38.2 T, Palomero; et al. (2014). "Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas". doi:10.1038/ng.2873. PMC 3963408. PMID 24413734.CS1 maint: PMC format (link)
  39. ↑ 39.0 39.1 39.2 39.3 Sh, Lee; et al. (2015). "A highly recurrent novel missense mutation in CD28 among angioimmunoblastic T-cell lymphoma patients". doi:10.3324/haematol.2015.133074. PMC 4666342. PMID 26405154.CS1 maint: PMC format (link)
  40. ↑ 40.0 40.1 J, Rohr; et al. (2016). "Recurrent activating mutations of CD28 in peripheral T-cell lymphomas". doi:10.1038/leu.2015.357. PMC 5688878. PMID 26719098.CS1 maint: PMC format (link)
  41. ↑ 41.0 41.1 41.2 N, Mourad; et al. (2008). "Clinical, biologic, and pathologic features in 157 patients with angioimmunoblastic T-cell lymphoma treated within the Groupe d'Etude des Lymphomes de l'Adulte (GELA) trials". doi:10.1182/blood-2007-08-105759. PMC 2343588. PMID 18292286.CS1 maint: PMC format (link)
  42. ↑ 42.0 42.1 J, Vose; et al. (2008). "International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes". PMID 18626005.

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

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