T-cell prolymphocytic leukemia

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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]

Synonyms and keywords: T-cell chronic lymphocytic leukemia; "Knobby" type of T-cell leukemia; T-prolymphocytic leukemia/T-cell lymphocytic leukemia- Kiel; T-PLL

Overview

T-cell-prolymphocytic leukemia (also known as T-PLL) is a rare, mature T-cell leukemia with aggressive behavior and predilection for blood, bone marrow, lymph nodes, liver, spleen, and skin. T-cell prolymphocytic leukemia was first described by Catovsky in 1973. There is no classification system for T-cell prolymphocytic leukemia. The inversion of chromosome 14 (14q11) has been associated with the development of T-cell prolymphocytic leukemia. T-cell prolymphocytic leukemia is very rare, and it represents 2% of all small lymphocytic leukemias in adults. T-cell prolymphocytic leukemia is more commonly observed among young adult patients aged between 30 to 40 years old. Males are slightly more affected with are more commonly affected with T-cell prolymphocytic leukemia than females. Laboratory findings consistent with the diagnosis of T-cell prolymphocytic leukemia, include: high lymphocyte count (> 100 x 109/L), anemia, thrombocytopenia, and negative HTLV-1 serology. There are no specific imaging findings associated with T-cell prolymphocytic leukemia. Prognosis is generally poor, and the median survival time of patients with T-cell prolymphocytic leukemia is approximately 7 months. The mainstay of therapy for T-cell prolymphocytic leukemia is alemtuzumab (anti-CD52). However, T-cell prolymphocytic leukemia is often resistant to therapy. Autologous and allogeneic stem cell transplants is the mainstay of therapy for patients who achieve remission.

Historical Perspective

  • 40 years ago, in 1973, Catovsky first described four cases of T-cell prolymphocytic leukemia.[1][2]
  • In 1994, Harris a pathologist from Boston and his colleagues made an effort to classify T-cell prolymphocytic leukemia.[3]

Classification

  • T-cell prolymphocytic leukemia classification is based on its morphology. [4][5][6]
Morphological Variant Percentage of total number
Typical T-cell prolymphocytic leukemia 75 percent
Small cell variant 20 percent
Cerebriform (Sézary cell-like) variant 5 percent

Pathophysiology

  • T-cell prolymphocytic leukemia is a uncommon T- cell malignancy.
  • T-cell prolymphocytic leukemia arises from mature (post-thymic) T-cell, which is normally involved in in cell-mediated immunity.[7]
  • Factors which play role in the parthenogenesis of these cells are:
    • Immunophenotypic factors:
    • Genetic factors:[8][9][10][11]
      • Abnormalities in chromosome 14
      • Abnormalities in chromosome 8
      • Mutations in tumor suppressor gene 11q23, at the ataxia telangiectasia mutated (ATM) locus.
  • It is a relatively aggressive malignancy, characterized by marked lymphocytosis and involving peripheral blood, liver, spleen and bone marrow.
  • The inversion of chromosome 14 (14q11) has been associated with the development of T-cell prolymphocytic leukemia.
  • Patients with T-cell prolymphocytic leukemia have TCR gene rearrangements for the γ and δ chains.
  • Mutations of chromosome 8 are seen in approximately 75% of patients.
 
 
 
 
 
 
 
 
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:[8][12][13][14][15]
  • 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:[13]

  • idic(8p11)
  • t(8;8)
  • Trisomy 8q
  • Del(12p13)
  • Abnormalities in chromosome 17
  • Deletions in chromosome 6
  • Deletion of TP53 gene[8][9][10][11]
  • Activating mutation in Tyrosine kinase of Jak3[16][17]
  • Deletions or missense mutations at the ataxia telangiectasia mutated (ATM) locus 11q23 [18][19]
 
 
 
 
 
 
 
 
 
 
 
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)


    • On gross pathology, characteristic findings of T-cell prolymphocytic leukemia, include:[4]
    • No remarkable findings
    • On microscopic histopathological analysis, characteristic findings of T-cell prolymphocytic leukemia, include:[4]
    • The immunophenotype CD4+/CD8- (present in 60% of cases)
    • The immunophenotype CD4+/CD8+ (present in 25%)
    • The immunophenotype CD4-/CD8+ (15% of cases) Different variants of T-cell Lymphocytic leukemias can be differentiated based on microscopic and gross finding.[20][21]
    Morphological Variant Gross Findings Microscopic Findings
    Typical T-cell

    prolymphocytic

    leukemia

    • Medium-sized lymphoid cells
    • Densely packed chromatin
    • Prominent nucleolus with blisters on surface
    Small cell variant
    • Small cells
    • Dense chromatin
    • Minute electron microscopically visible nucleolus
    Cerebriform

    (Sézary cell-like)

    variant

    • Asymmetrical nuclear outline
    • Cerebriform nucleus

    Causes

    • Common causes of T-cell prolymphocytic leukemia, include:[4]
    • Genetic mutations (e.g. Trisomy 8, chromosomal abnormalities)

    Differentiating T-cell Prolymphocytic Leukemia from Other Diseases

    Epidemiology and Demographics

    • T-cell prolymphocytic leukemia is very rare, and it represents 2% of all small lymphocytic leukemias in adults.
    • The incidence of T-cell prolymphocytic leukemia increases with age; the median age at diagnosis is 65 years.[4]
    • Patients with ataxia telangiectasia and T-cell prolymphocytic leukemia are young adults; the median age at diagnosis is 30 years.
    • Males are slightly more affected with T-cell prolymphocytic leukemia than females.
    • There is no racial predilection for T-cell prolymphocytic leukemia.

    Risk Factors

    • There are no risk factors associated with the development of T-cell prolymphocytic leukemia.[4]

    Screening

    There is insufficient evidence to recommend routine screening for T-cell prolymphocytic leukemia.

    Natural History, Complications and Prognosis

    • The majority of patients with T-cell prolymphocytic leukemia are symptomatic at the time of diagnosis.
    • Early clinical features include fever, fatigue, and lymphadenopathy.
    • If left untreated, patients with T-cell prolymphocytic leukemia may progress to develop multiple organ failure.
    • Common complications of T-cell prolymphocytic leukemia, include:[4]
    • Prognosis is generally poor, and the median survival time of patients with T-cell prolymphocytic leukemia is approximately one to two years.[4]
    • Patients with CD45RO+/CD45RA- immunophenotype tend to have a more indolent course.
    • It seems following factors are associated with worse prognosis:
      • Increased expression of TCL1
      • Increased activity of the serine-threonine kinase AKT

    Diagnosis

    Diagnostic Study of Choice

    • There are no established criteria for the diagnosis of T-cell prolymphocytic leukemia. Patients with T-cell prolymphocytic leukemia are diagnosed by clinical presentation, pathology evaluation of the peripheral blood and bone marrow. Flow cytometry and immunostains should be performed to diagnose a T cell immunophenotype.

    History and Symptoms

    • Symptoms of T-cell prolymphocytic leukemia may include the following:[4][22]

    Physical Examination

    • Patients with T-cell prolymphocytic leukemia usually appear pale and malnourished.
    • Physical examination may be remarkable for:[4]

    Laboratory Findings

    • Laboratory findings consistent with the diagnosis of T-cell prolymphocytic leukemia, include:[4]
    • High lymphocyte count (> 100 x 109/L)
    • Anemia
    • Thrombocytopenia
    • Negative human T lymphotropic virus (HTLV) serology
    • Peripheral Blood Smear demonstrated predominance of lymphocytes:
      • Typical variant:
        • Medium-sized lymphocytes
        • Condensed chromatin and a visible nucleolus
        • Round nucleus
        • Slightly basophilic cytoplasm
        • Cytoplasmic protrusion
      • Small cell variant
        • Small tumor cells with condensed chromatin
        • Small nucleolus visible by electron microscopy
      • Cerebriform (Sézary cell-like) variant
        • Irregular nuclear outline
        • Similar to cerebriform nucleus of Sézary cells seen in mycosis fungoides

    Electrocardiogram

    There are no ECG findings associated with T-cell prolymphocytic leukemia.

    X-ray

    There are no x-ray findings associated with T-cell prolymphocytic leukemia. However, an x-ray may be helpful in the diagnosis of complications of T-cell prolymphocytic leukemia, which include pleural effusion and lung involvement.

    Echocardiography or Ultrasound

    There are no echocardiography findings associated with T-cell prolymphocytic leukemia.

    Ultrasound may be helpful in the diagnosis of T-cell prolymphocytic leukemia. Findings on an ultrasound suggestive of/diagnostic of T-cell prolymphocytic leukemia include hepatomegaly and splenomegaly.

    CT scan

    CT scan may be helpful in the diagnosis of T-cell prolymphocytic leukemia. Findings on an CT scan suggestive of/diagnostic of T-cell prolymphocytic leukemia include hepatomegaly and splenomegaly.

    MRI

    There are no MRI findings associated with T-cell prolymphocytic leukemia.

    Other Imaging Findings

    There are no specific imaging findings associated with T-cell prolymphocytic leukemia.[4]

    Other Diagnostic Studies

    Flow cytometry and immunohistopathology must be done to diagnose T-cell prolymphocytic leukemia.

    Treatment

    Medical Therapy

    • The mainstay of therapy for T-cell prolymphocytic leukemia, include:[4][23]
    • T-cell prolymphocytic leukemia is often resistant to therapy.

    Surgery

    • Autologous and allogeneic stem cell transplants is the mainstay of therapy for patients who achieve remission.

    Primary Prevention

    • There are no established measures for the primary prevention of T-cell prolymphocytic leukemia.

    Secondary Prevention

    • There are no established measures for the secondary prevention of T-cell prolymphocytic leukemia.

    References

    1. ↑ Catovsky D, Galetto J, Okos A, Galton DA, Wiltshaw E, Stathopoulos G (August 1973). "Prolymphocytic leukaemia of B and T cell type". Lancet. 2 (7823): 232–4. PMID 4124423.
    2. ↑ 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.
    3. ↑ Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, Delsol G, De Wolf-Peeters C, Falini B, Gatter KC (September 1994). "A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group". Blood. 84 (5): 1361–92. PMID 8068936.
    4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 Graham RL, Cooper B, Krause JR (2013). "T-cell prolymphocytic leukemia". Proc (Bayl Univ Med Cent). 26 (1): 19–21. PMC 3523759. PMID 23382603.
    5. ↑ Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD, Jaffe ES (May 2016). "The 2016 revision of the World Health Organization classification of lymphoid neoplasms". Blood. 127 (20): 2375–90. doi:10.1182/blood-2016-01-643569. PMC 4874220. PMID 26980727.
    6. ↑ 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.
    7. ↑ 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.
    8. ↑ 8.0 8.1 8.2 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.
    9. ↑ 9.0 9.1 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.
    10. ↑ 10.0 10.1 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.
    11. ↑ 11.0 11.1 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.
    12. ↑ 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.
    13. ↑ 13.0 13.1 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.
    14. ↑ 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.
    15. ↑ 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.
    16. ↑ 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.
    17. ↑ 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.
    18. ↑ 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.
    19. ↑ 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.
    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.
    22. ↑ 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.
    23. ↑ Robak T, Robak P (April 2007). "Current treatment options in prolymphocytic leukemia". Med. Sci. Monit. 13 (4): RA69–80. PMID 17392661.
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