T-PLL is a rare disease, representing approximately 2% of all mature lymphocytic leukemias in adults  and 3% of T-cell malignancies overall . T-PLL was initially described in a patient who presented with clinical and morphologic features similar to B-PLL, but in whom the cells were shown to be E-rosette positive, indicating a T-cell phenotype . Following a series of studies by Matutes and coworkers between 1986 and 1991, T-PLL became established as a distinct T-cell malignancy [8, 11, 12].
The most common symptoms at presentation are splenomegaly (73%), followed by lymphadenopathy (53%), hepatomegaly (40%), and cutaneous lesions such as maculopapular rash and focal erythroderma (27%). Serous effusions, predominantly pleural and pericardial, are present in about 15% of patients at presentation and in up to 37% of patients later in the course of the disease . Seventy-five percent of these patients had an elevated white blood cell count (typically > 100 k/mcl) at presentation. T-PLL has a distinctively short prodromal period, with about 63% of patients reporting leukemia-related symptoms for a median of two months prior to diagnosis. This is in contrast with other mature T-cell malignancies such as Sézary Syndrome and T-LGL, which have prodromes with a medium duration of 24-38 months and 9 months, respectively .
Marked morphologic heterogeneity has been observed in cases of T-PLL. Over three quarters of cases show typical prolymphocyte morphology that may be indistinguishable from that of B-PLL, namely medium sized lymphoid cells with moderately condensed nuclear chromatin and prominent central nucleoli. T-prolymphocytes tend to have more intense cytoplasmic basophilia and nuclear irregularity than B-prolymphocytes. In some cases, cytoplasmic protrusions or blebs may be present. In about 20% of T-PLL cases, the cells are smaller with more condensed nuclear chromatin and inconspicuous nucleoli. Such cases were originally referred to as T-CLL, but now are classified as the small cell variant of T-PLL. Less commonly, in about 5% of cases, the cells show markedly irregular nuclei resembling those seen in Sézary cells. While originally labeled as Sézary cell leukemia, these cases are now designated as the cerebriform variant of T-PLL. Both variants were reclassified because they shared the same immunophenotypic and cytogenetic features as typical cases of T-PLL .
The immunophenotype of T-prolymphocytes is consistent with that of a mature post-thymic T-cell. They are negative for CD1a and TdT, but positive for pan T-cell markers such as CD2, CD3, CD5, and CD7. CD7 is expressed with stronger intensity than seen in normal T-cells and other mature T-cell malignancies, but at levels comparable to those seen in T-ALL . Surface expression of CD3 and TCR-α/β may not be detected in up to 20% of cases, but their expression is always seen in the cytoplasm . While most cases (65%) consist of CD4+/CD8- cells, 21% of cases are CD4+/CD8+ and 13% of cases are CD4-/CD8+ . There is variable expression of antigens related to T-cell activation, such as CD25, CD38, and HLA-DR. While not a lymphocyte specific marker, CD52 is more strongly expressed in T-prolymphocytes than in normal T-cells .
While the immunophenotype of our case is predominantly that of a mature T-cell malignancy, the expression of CD117 (c-kit) seems counterintuitive. CD117 is normally expressed by a subset of thymocytes during normal lymphopoiesis which have not yet undergone rearrangement of their T-cell receptor (TCR) genes , playing a vital role in early T-cell development. This marker is also normally expressed by hematopoietic progenitor cells of all lineages . Therefore CD117 serves as a surrogate marker of immaturity, with expression in a subset of precursor T-cell lymphoblastic neoplasms [18, 19]. A review of the literature for the incidence of CD117 expression in mature T-cell malignancies showed CD117 expression restricted to CD4-/CD8+ cases , consistent with the present case.
Many cytogenetic studies have identified several recurrent chromosomal abnormalities in T-PLL. Up to 90% of patients have abnormalities of chromosome 14 that can be demonstrated by FISH. The majority of these abnormalities consist of either inv(14)(q11q32) or t(14;14)(q11;q32) . Inv(14)(q11q32) alone can be detected by conventional cytogenetic studies in more than two-thirds of cases . About 19% of patients have karyotypes showing abnormalities of Xq28, the most common of which is t(X;14)(q28;q11) . Such rearrangements are now considered to be a genetic hallmark of T-PLL and a primary event in its oncogenesis. Both inv(14)(q11q32) or t(14;14)(q11;q32) result in the overexpression of the TCL1 oncogene located on 14q32.1 through its juxtaposition to the TCR-alpha gene on 14q11. When overexpressed, the TCL1 protein binds the D3 phosphoinositide-regulated kinase AKT1 in the cytoplasm, augmenting its transport into the nucleus. This results in increased expression of genes responsible for promoting T-cell proliferation and survival . Likewise, t(X;14)(q28;q11) juxtaposes the MCTP1 (mature T-cell proliferation 1) gene to TCR-alpha gene. MCTP1 is a homologue of TCL1 that also binds to AKT1 [23, 24]. Interestingly, inv(14)(q11q32), t(14;14)(q11;q32), and t(X;14)(q28;q11) have all been detected in expanding T-cell clones from patients with ataxia-telangiectasia. Such clones are usually subclinical and identified as incidental findings several years before lymphoma develops .
Besides the aberrations on chromosome 14, most T-PLL cells usually harbor other secondary chromosomal abnormalities. Unbalanced rearrangements of chromosome 8 are the most common secondary abnormalities and have been reported in up to 80% of cases. Such chromosome 8 abnormalities include trisomy 8q, isochromosome 8(q10), t(8;8)(p12;q11), and translocations with other chromosomes . In addition, c-myc protein amplification has been demonstrated by flow cytometry . Despite their high frequency, the role of these chromosome 8 abnormalities in the pathogenesis of T-PLL remains to be elucidated.
Although conventional cytogenetics revealed a normal karyotype, a comprehensive panel of FISH probes detected an isolated deletion of the (p13) region of chromosome 12. As a result of limited resolution, this deletion cannot be visualized using standard cytogenetic techniques (i.e. karyotyping) and requires FISH for detection. It is present in nearly half of T-PLL cases , but has always been accompanied by the well characterized aberrations of either chromosomes 14, X, or 8 [1, 12, 28, 29]. Considering that abnormalities of 14q11 [i.e. t(14;14)(q11;q32), inv(14)(q11q32), t(X;14)(q28;q11)] and chromosome 8 [i.e. i(8)(q10), t(8;8)(p12;q11)] are each present in up to 90% and 80% of T-PLL patients, respectively [1, 23], we believe that the present case is the first report of a patient with an isolated deletion of the 12(p13) region. A review of the literature for T-PLL cases lacking the common abnormalities of chromosomes 14, X, and 8 showed an overrepresentation of CD4-/CD8+ T-PLL cases like ours [12, 30]. Therefore our case may represent a subset of T-PLL cases in which alternative pathways are likely responsible for its pathogenesis. The minimal region of 12(p13) deletion contains the CDKN1B gene, which encodes the cell cycle regulatory protein p27KIP1 [27, 31]. Decreased expression of this protein results in stabilization of cyclinD-CDK4/6 complexes and facilitates cell cycle progression , which was shown to be sufficient for the development of T-PLL in mouse models .
The most important differential diagnosis in the pediatric age group is T-ALL. T-ALL typically presents as a mediastinal mass with an immunophenotype consistent with late cortical thymocytes (i.e. positive for TdT, CD1a, cytoplasmic CD3, CD4, and CD8). T-ALL cells may range from small, round cells with high N/C ratios, relatively condensed chromatin and inconspicuous nucleoli to larger cells with abundant basophilic cytoplasm, irregular nuclear contour, dispersed chromatin and one or more distinct nucleoli . It is this cytologic heterogeneity that may pose a challenge in differentiating T-ALL from T-PLL in a child, since it may overlap with the T-PLL cytologic spectrum. Furthermore, as previously mentioned, rare cases of T-PLL will aberrantly express CD117, a marker more commonly seen in up to 11% of T-ALL cases. Importantly, T-ALL cases that express CD117 also carry activating mutations of the FLT3 receptor tyrosine kinase (i.e., CD135), the genetic abnormality most commonly seen in AML . In contrast, our case did not express CD135 by flow cytometry and no mutations were detected by PCR (data not shown), arguing against a diagnosis of T-ALL.
The WHO categorizes T-cell and NK-cell neoplasms into broad clinically defined groups such as leukemic or disseminated, nodal, extranodal, and cutaneous . The most common mature T-cell malignancy in children is anaplastic lymphoma kinase (ALK) positive anaplastic large cell lymphoma (ALCL), account for up to 30% of lymphomas in the pediatric age group. It has been suggested that a majority of non-ALCL T-cell/NL-cell lymphomas in children tend to be derived from components of the innate immune system such as cytotoxic T or NK cells . Consistent with this, CD4-/CD8+ T-cell lymphomas were observed in young transgenic mice models of T-PLL . Therefore it appears that evolutionary primitive components of the immune system are featured more often in pediatric hematologic malignant neoplasms, and conversely tumors of the adaptive immune system, a more mature component of the immune system, are exceptionally rare in children . The frequency of non-anaplastic mature T-cell lymphomas in children is too low for performing large scale clinical trials. Therefore not much is known about their prognosis and optimal choice of therapy.
Standard T-cell ALL induction therapy was not effective in this case. FLACC regimen was effective in achieving remission status while definitive therapy is most likely with stem cell transplantation. This case illustrates that the diagnosis of T-PLL should be entertained in all children with T-ALL and alternative induction regimens such as the one used in this case should be entertained early in the course of treatment.
FLACC regimen is highly immunosuppressive. Reactivation of CMV should be considered in all cases where evidence of prior CMV exposure is present. This may happen in spite of standard prophylactic use of valacyclovir, and periodic monitoring of peripheral blood CMV viral load may be appropriate. Those children with no evidence of prior CMV exposure should receive CMV-negative blood products and screened periodically for new exposure. Similarly, although pentamidine was used to prevent PCP pneumonitis, it was ineffective in this case. Trimethoprim/sulfisoxazole, although may lead to prolonged neutropenia, may be more effective and should be considered.
To our knowledge, the present case is the first report of T-PLL in a child. The lack of underlying ataxia-telangiectasia makes this a case of sporadic T-PLL, which is even more intriguing. While T-ALL is the more commonly seen T-cell malignancy in the pediatric age group, this case highlights the importance of keeping mature T-cell malignancies in the differential diagnosis. Furthermore, the regimen successfully used in this case may provide a valuable option for clinicians attempting to treat rare cases of pediatric mature T-cell malignancies. The isolated deletion 12(p13) in our case highlights the importance of alternative mechanisms of T-PLL leukemogenesis that needs to be further investigated. Finally, additional studies are necessary to determine the prognostic significance of CD117 expression in mature T-cell malignancies and its restriction to CD4-/CD8+ cases.