Case 6 -

CD4+/ CD56+ tumors and the TCL-1 oncogene Dan Jones, MD, PhD, UT MD Anderson Cancer Center Houston, TX

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Objectives of the Session: Review a typical case of the CD4+ CD56+ hematodermic tumor. Define the diagnostic criteria and limits of this entity/disease/syndrome. Review the biology and functional immunology of dendritic cells. Assess the role of TCL1 as a diagnostic marker in this entity and its role in pathogenesis. Clinical History: 74-year-old white male, who presented in February 2002 with an indurated skin plaque on the right shoulder, which was excised and then recurred 6 months later at the same site. Bone marrow was normocellular with mild monocytosis (10%). Patient received hyperCVAD chemotherapy and has not had a skin recurrence. Over the last four years, however, the patient has had an increasingly hypercellular bone marrow (60-80% cellular) with marrow monocytosis (up to 23%) and absolute PB monocytosis up to 2.5 x 10(9)/L. Case 6 - Figure 1 Click to view with ImageScope Click to view with a Web-Based Viewer What current and historical entities are related to the CD4+CD56+ hematodermic tumor? Plasmacytoid T-cell lymphoma [1] CD4+/CD56+ acute leukemia [2] Blastoid NK leukemia/lymphoma [3, 4] Blastic NK cell lymphoma [5, 6] Agranular CD4+ CD56+ hematodermic tumor [7] Plasmacytoid dendritic cell neoplasm (DC2oma) [8] What are the typical features and course of CD4+CD56+ hematodermic tumors? Clinical features: Wide range of presentations but commonly as multifocal, often large skin tumors on the extremities, regional lymph node involvement, with at least bone marrow and peripheral blood involvement initially. [2] Generally initial response to acute leukemia-type multiagent chemotherapy. [9, 10] Relapse: >60%, usually with leukemia involvement. [11] Overall median survival dismal, few outliers with longer term survival. Development of subsequent myelomonocytic leukemia is relatively common. [12] Pathologic features: Skin involvement is perivascular to diffuse with minimal epidermotropism. [13] Lymph node involvement is interfollicular to diffuse. Cytologic features range from small lymphoid-appearing cells with blastic chromatin to myeloblast-like large cells with several-distinct nucleoli. Smears may show cytoplasmic vacuoles, and pseudopod-like extensions of the largely agranular cytoplasm. Immunophenotypic features: CD4 and CD56 expression define the entity but can weak/dim in some cases. Strong CD123 expression is more sensitive and specific. CD45RA (also seen in B-cells, and naïve T-cells) and CD43 are positive in nearly all cases. Absence of myeloperoxidase, lysozyme, CD20, CD3 and EBV are the most relative negative stains. TCL1, BDCA1 and CLA are also useful confirmatory markers (discussed below). Variable expression of TdT, CD7, CD99 and CD68 can be seen. Molecular genetic features: AML-MDS-type cytogenetic changes are typical, including trisomy 8, del5q and del13q. [14, 15] Recurrent reciprocal chromosomal translocation have not been identified to date. T-cell receptor gamma or delta rearrangements may be present. [16] Differential diagnosis: Granulocytic / myeloid sarcoma (EMT / chloroma) [17] Particularly CD56+ monocytic leukemias [18] Extranodal NK/T-cell lymphoma, nasal type [19] Large cell lymphoma Evidence that CD4+CD56+ hematodermic tumor may be a dendritic cell neoplasm Shared immunophenotype with plasmacytoid dendritic cells (pDC) [20] including: Uniformly positive for the pDC marker CD123 (IL-3 receptor subunit) and shared expression of CD45RA and TCL1. [21] Variably positive for cutaneous lymphocyte antigen (CLA) [22] and blood dendritic cell antigen 2 protein (BDCA-2). [23] Clinical leukemic/nodal/skin pattern of involvement resembles the migratory pattern of DC. Hematodermic tumor cells can produce IFNa upon virus exposure & stimulate cytokine expression in cocultured T-cells. [24] Hematodermic tumor cells both within a given case and among case series exhibit a range of differentiation states and morphological appearances similar to pDC/DC2. [25] What are plasmacytoid dendritic cells (pDC)? pDC are an interferon-secreting, lymphoid-appearing DC subset that were originally recognized as "plasmacytoid T-cells" and then as " plasmacytoid monocytes". [26] Precursor DC2 subset arises in the bone marrow and circulate as veiled cells. DC2 migrate into lymph node (through HEV) and tissues in response to specific (viral) stimuli and differentiate into "pDC" which regulate the function of lymphocytes, including regulatory T-cells [27] pDC migration across HEV in lymph and to submucosa/dermis is dictated by shift in expression of an array of chemotactic chemokines. pDC can be produced by in vitro maturation of monocytes following FLT3 ligand or cytokine treatment. [28] pDC express the kinase regulator TCL1, [21] which regulates activation of the Akt kinase following cytokine stimuli, in a similar manner as in B-cells [29, 30, 31] and leukemic T-cells. [32] Is the association with myeloid disorders more than coincidental? CMML/AML-M4/M5 are often CD56+ and show a similar pattern of skin and lymph node tropism. DC aggregates have been commonly reported in myelomonocytic tumors in lymph node. [33] CD123+CD68+CD56- pDC/monocytic clusters in bone marrow. [34] Hematodermic tumors with prior MDS/CMML. [35, 36] Hematodermic tumors with concurrent/subsequent MDS/CMML and AML-M4. [37] Clonal relationship established by shared cytogenetic changes in several. Shared TCL1 expression in preceding hematodermic tumor and subsequent AML-M4. Altered pDC phenotype and clonal abnormalities consistent with leukemic DC in AML. [38, 39] Unresolved questions: What should we call this tumor? Which marker profile is most specific? Is variability in marker expression in hematodermic tumors, including TdT, cytoplasmic CD3, CD7 and CD33, indicative of variable maturation or problems with the entity? Should CD4-negative or CD56-negative cases be accepted into the entity? References : Prasthofer EF, Prchal JT, Grizzle WE, Grossi CE. Plasmacytoid T-cell lymphoma associated with chronic myeloproliferative disorder. 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