T-cell prolymphocytic leukemia pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Qurrat-ul-ain Abid, M.D.[2], Maria Fernanda Villarreal, M.D. [3]

Overview

T-PLL has the immunophenotype of a mature (post-thymic) T-lymphocyte, and the neoplastic cells are typically positive for pan-T antigens. Clonal TCR gene rearrangements for the γ and δ chains are typically found.It arises from mature (post-thymic) T-cell, which are normally involved in in cell-mediated immunity. On microscopic histopathological analysis, T-cell prolymphocytic leukemia has characteristic findings. In the peripheral blood, T-PLL consists of medium-sized lymphocytes with single nucleoli and basophilic cytoplasm with occasional blebs or projections. Different variants of T-cell lymphocytic leukemias can be differentiated based on the microscopic and gross finding.

Pathophysiology

It is postulated that the originating cell line for this disease is a mature (post-thymic) T-cell. Due to the systemic nature of this disease, leukemic cells can be found in peripheral blood, lymph nodes, bone marrow, spleen, liver, skin.

Molecular Findings

Immunophenotype

T-PLL has the immunophenotype of a mature (post-thymic) T-lymphocyte, and the neoplastic cells are typically positive for pan-T antigens CD2, CD3, and CD7 and negative for TdT and CD1a. The immunophenotype CD4+/CD8- is present in 60% of cases, the CD4+/CD8+ immunophenotype is present in 25%, and the CD4-/CD8+ immunophenotype is present in 15% of cases.

Genetic Findings

Clonal TCR gene rearrangements for the γ and δ chains are typically found. The most frequent chromosomal abnormality is the inversion of chromosome 14, specifcally inv 14(q11;q32). This is found in 80% of cases, while 10% of cases show a reciprocal translocation of chromosome 14 (t(14;14)(q11;q32)). [1]

[2] Also, abnormalities of chromosome 8 are seen approximately 75% of patients, including idic (8p11), t(8;8)(p11-12;q12), and trisomy 8. [3]


 
 
 
 
 
 
 
 
Factors Involved in the Pathophysiology of T-cell Pro-Lymphocytic Leukemia
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genetic Factors
 
 
 
 
 
 
 
 
 
 
 
Association with different Immunophenotypes
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Different types of genetic abnormalities are as follows, mostly involve chromosme 14:[6][10][11][12][13]
  • Inv(14)
  • t(14;14)(q11;q32)
  • t(X;14)(q28;q11) which involves a homolog of TCL1, MTCP1 (mature T cell proliferation 1 gene)

Chromosome 8 defects:[11]

  • idic(8p11)
  • t(8;8)
  • Trisomy 8q
  • Del(12p13)
  • Abnormalities in chromosome 17
  • Deletions in chromosome 6
  • Deletion of TP53 gene[6][7][8][9]
  • Activating mutation in Tyrosine kinase of Jak3[14][15]
  • Deletions or missense mutations at the ataxia telangiectasia mutated (ATM) locus 11q23 [16][17]
 
 
 
 
 
 
 
 
 
 
 
T-cell prolymphocytic leukemia cells express different markers including:
  • CD52(strong association)
  • Pan-T cell markers such as:

    • CD2
    • CD3(might be low or high level)
    • CD7
    • Oncogene TCL1
    • CD4+/CD8-(present in 60% of cases)
    • CD4+/CD8+(present in 25%, unique for T-cell prolymphocytic leukemia)
    • CD4-/CD8+(15% of cases)
    • Negative terminal deoxynucleotidyl transferase (TdT)


    Microscopic Pathology

    Marrow involvement is typically diffuse with morphology similar to what is observed in peripheral blood. In the spleen, the leukemic cell infiltrate both the red pulp and white pulp, and lymph node involvement is typically diffuse through the paracortex. Skin infiltrates are seen in 20% of patients, and the infiltrates are usually dense and confined to the dermis and around the skin appendages.

    In the peripheral blood, T-PLL consists of medium-sized lymphocytes with single nucleoli and basophilic cytoplasm with occasional blebs or projections. The nuclei are usually round to oval in shape, with occasional patients having cells with a more irregular nuclear outline that is similar to the cerebriform nuclear shape seen in Sézary syndrome.[19] A small cell variant comprises 20% of all T-PLL cases, and the Sézary cell-like (cerebriform) variant is seen in 5% of cases.[19]

    Morphological Variant Microscopic Findings
    Typical T-cell

    prolymphocytic

    leukemia

    Small cell variant
    • Small cells
    • Dense chromatin
    • Minute electron microscopically visible nucleolus
    Cerebriform

    (Sézary cell-like)

    variant

    References

    1. Brito-Babapulle V, Catovsky D (1991). "Inversions and tandem translocations involving chromosome 14q11 and 14q32 in T-prolymphocytic leukemia and T-cell leukemias in patients with ataxia telangiectasia". Cancer Genet. Cytogenet. 55 (1): 1–9. PMID 1913594.
    2. Maljaei SH, Brito-Babapulle V, Hiorns LR, Catovsky D (1998). "Abnormalities of chromosomes 8, 11, 14, and X in T-prolymphocytic leukemia studied by fluorescence in situ hybridization". Cancer Genet. Cytogenet. 103 (2): 110–6. PMID 9614908.
    3. Sorour A, Brito-Babapulle V, Smedley D, Yuille M, Catovsky D (2000). "Unusual breakpoint distribution of 8p abnormalities in T-prolymphocytic leukemia: a study with YACS mapping to 8p11-p12". Cancer Genet. Cytogenet. 121 (2): 128–32. PMID 11063795.
    4. Sud A, Dearden C (April 2017). "T-cell Prolymphocytic Leukemia". Hematol. Oncol. Clin. North Am. 31 (2): 273–283. doi:10.1016/j.hoc.2016.11.010. PMID 28340878.
    5. Jaffe E.S., Harris N.L., Stein H., Vardiman J.W. (eds): World Health Organization Classification of Tumors. Pathology and Genetics of Tumours of Haemopoietic and Lymphoid Tissues. IARC Press: Lyon 2001
    6. 6.0 6.1 6.2 Brito-Babapulle V, Catovsky D (August 1991). "Inversions and tandem translocations involving chromosome 14q11 and 14q32 in T-prolymphocytic leukemia and T-cell leukemias in patients with ataxia telangiectasia". Cancer Genet. Cytogenet. 55 (1): 1–9. PMID 1913594.
    7. 7.0 7.1 Hetet G, Dastot H, Baens M, Brizard A, Sigaux F, Grandchamp B, Stern MH (2000). "Recurrent molecular deletion of the 12p13 region, centromeric to ETV6/TEL, in T-cell prolymphocytic leukemia". Hematol. J. 1 (1): 42–7. doi:10.1038/sj/thj/6200008. PMID 11920168.
    8. 8.0 8.1 Brito-Babapulle V, Hamoudi R, Matutes E, Watson S, Kaczmarek P, Maljaie H, Catovsky D (July 2000). "p53 allele deletion and protein accumulation occurs in the absence of p53 gene mutation in T-prolymphocytic leukaemia and Sezary syndrome". Br. J. Haematol. 110 (1): 180–7. PMID 10930996.
    9. 9.0 9.1 Costa D, Queralt R, Aymerich M, Carrió A, Rozman M, Vallespí T, Colomer D, Nomdedeu B, Montserrat E, Campo E (November 2003). "High levels of chromosomal imbalances in typical and small-cell variants of T-cell prolymphocytic leukemia". Cancer Genet. Cytogenet. 147 (1): 36–43. PMID 14580769.
    10. Maljaei SH, Brito-Babapulle V, Hiorns LR, Catovsky D (June 1998). "Abnormalities of chromosomes 8, 11, 14, and X in T-prolymphocytic leukemia studied by fluorescence in situ hybridization". Cancer Genet. Cytogenet. 103 (2): 110–6. PMID 9614908.
    11. 11.0 11.1 Pekarsky Y, Hallas C, Isobe M, Russo G, Croce CM (March 1999). "Abnormalities at 14q32.1 in T cell malignancies involve two oncogenes". Proc. Natl. Acad. Sci. U.S.A. 96 (6): 2949–51. PMC 15875. PMID 10077617.
    12. Stern MH, Soulier J, Rosenzwajg M, Nakahara K, Canki-Klain N, Aurias A, Sigaux F, Kirsch IR (September 1993). "MTCP-1: a novel gene on the human chromosome Xq28 translocated to the T cell receptor alpha/delta locus in mature T cell proliferations". Oncogene. 8 (9): 2475–83. PMID 8361760.
    13. Hu Z, Medeiros LJ, Fang L, Sun Y, Tang Z, Tang G, Sun T, Quesada AE, Hu S, Wang SA, Pei L, Lu X (May 2017). "Prognostic significance of cytogenetic abnormalities in T-cell prolymphocytic leukemia". Am. J. Hematol. 92 (5): 441–447. doi:10.1002/ajh.24679. PMID 28194886.
    14. Bergmann AK, Schneppenheim S, Seifert M, Betts MJ, Haake A, Lopez C, Maria Murga Penas E, Vater I, Jayne S, Dyer MJ, Schrappe M, Dührsen U, Ammerpohl O, Russell RB, Küppers R, Dürig J, Siebert R (April 2014). "Recurrent mutation of JAK3 in T-cell prolymphocytic leukemia". Genes Chromosomes Cancer. 53 (4): 309–16. doi:10.1002/gcc.22141. PMID 24446122.
    15. Kiel MJ, Velusamy T, Rolland D, Sahasrabuddhe AA, Chung F, Bailey NG, Schrader A, Li B, Li JZ, Ozel AB, Betz BL, Miranda RN, Medeiros LJ, Zhao L, Herling M, Lim MS, Elenitoba-Johnson KS (August 2014). "Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia". Blood. 124 (9): 1460–72. doi:10.1182/blood-2014-03-559542. PMC 4148768. PMID 24825865.
    16. Stilgenbauer S, Schaffner C, Litterst A, Liebisch P, Gilad S, Bar-Shira A, James MR, Lichter P, Döhner H (October 1997). "Biallelic mutations in the ATM gene in T-prolymphocytic leukemia". Nat. Med. 3 (10): 1155–9. PMID 9334731.
    17. Vorechovský I, Luo L, Dyer MJ, Catovsky D, Amlot PL, Yaxley JC, Foroni L, Hammarström L, Webster AD, Yuille MA (September 1997). "Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia". Nat. Genet. 17 (1): 96–9. doi:10.1038/ng0997-96. PMID 9288106.
    18. 18.0 18.1 Graham RL, Cooper B, Krause JR (2013). "T-cell prolymphocytic leukemia". Proc (Bayl Univ Med Cent). 26 (1): 19–21. PMC 3523759. PMID 23382603.
    19. 19.0 19.1 Matutes E, Garcia Talavera J, O'Brien M, Catovsky D (1986). "The morphological spectrum of T-prolymphocytic leukaemia". Br. J. Haematol. 64 (1): 111–24. PMID 3489482.
    20. Matutes E, Brito-Babapulle V, Swansbury J, Ellis J, Morilla R, Dearden C, Sempere A, Catovsky D (December 1991). "Clinical and laboratory features of 78 cases of T-prolymphocytic leukemia". Blood. 78 (12): 3269–74. PMID 1742486.
    21. Ravandi F, O'Brien S (December 2005). "Chronic lymphoid leukemias other than chronic lymphocytic leukemia: diagnosis and treatment". Mayo Clin. Proc. 80 (12): 1660–74. doi:10.4065/80.12.1660. PMID 16342661.

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