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










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

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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