T-cell Prolymphocytic Leukemia Involving Lymph Node and Other Tissues

T-cell Prolymphocytic Leukemia Involving Lymph Node and Other Tissues
Tariq Muzzafar, MBBS
L. Jeffrey Medeiros, MD
Key Facts
Terminology
  • T-PLL is aggressive disease characterized by
    • Numerous small/medium-sized T prolymphocytes
    • Involvement of blood, bone marrow, spleen, liver, and skin
Clinical Issues
  • Median age: ˜ 62 years; male predominance
  • T-PLL is widespread at time of initial diagnosis
  • Median WBC: 40 × 109/L (range: 1.6-621)
  • Poor prognosis
Microscopic Pathology
  • Features of T-PLL in H&E stained tissue sections
    • Small to medium-sized cells
    • Nucleoli identified in subset of cells
    • Oil immersion often needed to appreciate nucleoli
  • Lymph node
    • Paracortical or diffuse replacement of architecture
  • Cytologic features best observed in PB and BM smears
    • Typical, small cell, and cerebriform variants
Ancillary Tests
  • Pan-T-cell antigens(+), TCR-αβ(+), CD52(+)
  • CD4(+), CD8(-) or CD4(+), CD8(+)
  • Chromosome rearrangements in T-PLL
    • inv(14)(q11q32) or t(14;14)(q11;q32): ˜ 70% cases
    • t(X;14)(q28;q11): < 10% cases
Top Differential Diagnoses
  • Adult T-cell leukemia/lymphoma (ATLL)
  • Sézary syndrome/mycosis fungoides
  • Blastic plasmacytoid dendritic cell neoplasm
  • T-cell large granular lymphocytic leukemia
Low-power magnification of a lymph node involved by T-cell prolymphocytic leukemia (T-PLL). The nodal architecture is effaced. The neoplastic cells extend through the capsule into fat image.
Lymph node involved by T-PLL. The neoplastic cells are small to medium-sized, and nucleoli are not prominent. Four mitotic figures image are present in this field.
TERMINOLOGY
Abbreviations
  • T-cell prolymphocytic leukemia (T-PLL)
Synonyms
  • T-chronic lymphocytic leukemia
    • Has been used for small cell variant of T-PLL
Definitions
  • Aggressive leukemia characterized by
    • High number of small to medium-sized prolymphocytes
    • Involvement of peripheral blood (PB), bone marrow (BM), spleen, and liver ± other sites
    • Mature T-cell lineage
ETIOLOGY/PATHOGENESIS
Environmental Exposure
  • No known role for radiation or carcinogenic agents
Infectious Agents
  • No known role for any virus
Role of Inheritance
  • No familial clustering of cases has been reported
  • Patients with ataxia-telangiectasia (AT) are at increased risk for T-PLL
Ataxia-Telangiectasia Mutated (ATM) Gene Mutations in T-PLL
  • AT patients have germline mutations in ATM gene at chromosome 11q23
    • ˜ 10% of AT homozygotes develop malignancy, particularly lymphomas or T-PLL
    • Suggests ATM as candidate tumor suppressor gene in pathogenesis of T-PLL
    • AT patients can develop T-cell clones without evidence of T-PLL
      • May be subsequently followed by overt T-PLL
  • In patients without AT, ATM mutations occur in 60-70% of T-PLL cases
  • ATM-deficient transgenic mice have increased frequency of T-cell neoplasms
Chromosomal Rearrangements in T-PLL
  • inv(14)(q11q32) or t(14;14)(q11;q32) result in
    • TCRα/δ gene at 14q11 juxtaposed with TCL-1 gene at 14q32
      • Results in T-cell leukemia-1 (TCL-1) gene activation and expression
    • t(X;14)(q28;q11) results in
      • TCRα gene juxtaposed with MTCP-1 gene at Xq28
      • MTCP-1 is homologous with TCL-1
  • TCL-1 and MTCP-1 in transgenic mouse models induce lymphoma
    • Long latency suggests that other oncogenic events are required for lymphomagenesis
Tcl-1 Protein Overexpression in T-PLL
  • Tcl-1 is not expressed by normal mature T cells but is expressed in 70-80% of cases of T-PLL
    • Tcl-1 dysregulation via chromosomal rearrangement is unique to T-PLL
  • Normal functions of Tcl-1
    • Role in normal T-cell physiology is not well understood
    • Tcl-1 protein product is β barrel protein normally located in cytoplasm
    • Engagement of T-cell receptor (TCR) leads to recruitment of Tcl-1 and Akt to membrane
      • Tcl-1 forms activation complexes with Akt and TCR kinases
    • Tcl-1 binds with Akt and regulates its activity, possibly promoting Akt transphosphorylation
      • Akt is serine threonine kinase involved in Akt/PI3K pathway
      • PI3K has central role in intracellular signaling for numerous growth factors
  • In T-PLL, Tcl-1 may augment TCR responsiveness or perhaps substitute for TCR engagement
    • Tcl-1 dysregulation may drive early clonal expansion or promote growth advantage
    • Possibly most important in early stages of pathogenesis of T-PLL
    • With clonal evolution, other molecular abnormalities may drive proliferation
CLINICAL ISSUES
Epidemiology
  • Incidence
    • Rare
      • ˜ 2% of mature lymphocytic leukemias in patients > 30 years
  • Age
    • Median: ˜ 62 years
  • Gender
    • Male predominance
      • Male:Female ratio reported up to ˜ 3:1
  • Ethnicity
    • No ethnic predisposition or geographical clustering
Site
  • T-PLL is usually widespread at time of diagnosis
  • Peripheral blood and bone marrow involved in virtually all patients
  • Splenomegaly in ˜ 75% patients
  • Hepatomegaly in ˜ 50%
  • Lymphadenopathy in ˜ 25-50%
  • Skin lesions in ˜ 25%
  • Serous effusions in ˜ 15%; more common at relapse
  • CNS, conjunctiva, and lung are rarely involved
Presentation
  • Most patients present with evidence of aggressive disease
  • Leukocytosis and absolute lymphocytosis in peripheral blood
    • Rapidly rising leukocyte count
  • Thrombocytopenia in 45%; anemia in 25% of patients
    • Due to bone marrow failure &/or hypersplenism
  • Splenomegaly can be massive
    • > 10 cm below costal margin in many patients
    • Can cause local mass-type symptoms or hypersplenism
  • Lymphadenopathy is usually generalized
  • Skin involvement is variable
    • Symmetrical rash with petechial/purpuric features
    • Facial involvement with swelling
    • Diffuse infiltrative erythema and nodules may occur
    • Erythroderma is unusual
    • Skin rash after established diagnosis is followed by aggressive clinical course
  • “Smoldering” T-PLL in ˜ 25% of patients
    • These patients are asymptomatic or relatively well at initial diagnosis
    • Moderate and relatively stable levels of absolute lymphocytosis in peripheral blood
    • Patients may have prolonged indolent phase
      • Median duration: 33 months; rarely can be > 5 years
    • In almost all patients, disease eventually progresses
      • Manifested by rapid increase in absolute lymphocyte counts
    • Demographic features similar to patients in overt aggressive phase
    • Treatment does not affect duration of indolent phase or risk of progression
Laboratory Tests
  • Complete blood count
    • Absolute lymphocytosis with features consistent with prolymphocytes
      • > 100 × 109L in ˜ 50% of patients
      • Median in series at MD Anderson Cancer Center (MDACC); Houston, Texas; USA: 40 × 109/L (range: 1.6 – 621)
    • Thrombocytopenia in 45%; anemia in 25% of patients
      • Due to bone marrow failure &/or hypersplenism
Treatment
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Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on T-cell Prolymphocytic Leukemia Involving Lymph Node and Other Tissues

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