CD4+/CD56+ hematodermic neoplasm (blastic NK‐cell lymphoma)

CD41/CD561 hematodermic neoplasm (CD4/ CD56 HN) is an aggressive hematopoietic malignancy, which has a predilection for the skin and consists of lineage-negativeCD41 andCD561 blastlike cells (Fig. 1). Since originally being described in 1994, CD4/CD56 HN, has undergone a plethora of name changes chronicling the evolution of our understanding of this neoplasm. The term blastic natural killer (NK)-cell lymphoma, agreed upon in the 2001 World Health Organization classification of tumors of hematopoietic and lymphoid tissue, was based on the distinct cytology and suggested an NKcell origin because of its CD56 expression. In 1999, the French Study Group on cutaneous lymphomas suggested agranular CD41/CD561 hematodermic neoplasm’ as a descriptive term because of its uncertain lineage. Other more recent studies from the non-dermatopathology literature, seven of which will be briefly discussed herein, have examined the potential cell of origin and through functional, immunohistochemical and molecular studies have suggested a plasmacytoid dendritic cell (pDC) derivation. They provide evidence that CD4/CD56 HN is a distinct entity that could more appropriately be termed pDC leukemia/lymphoma’. pDCs, which used to be called plasmacytoid monocytes, are mononuclear plasmacytoid cells normally found clustered in the T-cell-rich interfollicular areas of lymphoid tissue and are thought to be a first-line of defense against certain pathogens in the innate immune system. The oldest two articles further examine and define the function of the pDC. Although the in vivo function of pDCs remains hypothetical, one in vitro functional study has shown that stimulated pDCs differentiate into cells exhibiting features of dendritic cells. The CD41/ CD11c2/CD32 pDCs were isolated from tonsils, rescued fromnormal rapid apoptosis by interleukin-3, and exposed to CD40 ligand resulting in differentiation into dendritic cells. The resultant cells expressed myeloid antigens and had the ability to uptake soluble antigens and phagocytose particles. In addition, another functional study found that pDCs are a main source of a-interferon. pDCs were isolated from peripheral blood and stimulated to proliferate and differentiate. Exposure to viral pathogens showed more interferon production in the immature pDCs. These functional studies suggest that the pDC is a distinct cell type that functions as interferon producers in their precursor state while acting as antigen presenters upon terminal differentiation to a mature dendritic cell. CD4/CD56 HN frequently manifests in skin before leukemic involvement is evident; therefore, appropriate markers need to be identified that can be used to distinguish CD4/CD56 HN from their morphologic mimickers in paraffin-embedded skin biopsies. Cutaneous extramedullarymyeloid sarcoma (leukemia cutis) is the most notable mimic of CD4/ CD56 HN both histologically and immunophenotypically because cases of cutaneous acute myelomonocytic/monocytic leukemia (c-AML) can express the lineage non-specificmarkers CD4 andCD56. Several new immunohistochemical markers may be useful adjunctive tools in differentiating difficult cases of CD4/CD56 HN from c-AML. The next five more recent publications attempt to discover these new immunohistochemical andmolecular adjunctive tools to help distinguish and clearly separate CD4/CD56 HN from its potential mimickers. CD123 (IL3Ra), a marker for pDCs, was used to examine a small series of CD4/CD56 HN and isolated normal pDCs. High expression of CD123 was identified on all 14 cases of CD4/CD56 HN and all isolated normal pDCs, further supporting the theory that CD4/CD56 HN line of differentiation is the enigmatic pDCs. The specificity of CD123 was verified by examining a variety of controls including potential clinicopathologic mimickers such as acute and chronic myeloid and myelomonocytic leukemias. Only 2 of 30 of the control cases expressed CD123 including one c-AML and one chronic myelomonocytic leukemia involving the skin. Another study compared the expression of two markers previously discovered on normal pDCs in 26 cases of CD4/ CD56 HN and 18 cases of c-AML. The first marker,