J Cutan Pathol 2008: 35: 975–977Blackwell Munksgaard. Printed in Singapore

Copyright # Blackwell Munksgaard 2008

Journal of

Cutaneous Pathology

Journal Reviews

CD41/CD561 hematodermic neoplasm(blastic NK-cell lymphoma)

CD41/CD561 hematodermic neoplasm (CD4/CD56 HN) is an aggressive hematopoietic malig-nancy, which has a predilection for the skin andconsists of lineage-negativeCD41 andCD561 blast-like cells (Fig. 1).1 Since originally being described in1994, CD4/CD56 HN, has undergone a plethora ofname changes chronicling the evolution of ourunderstanding of this neoplasm.2 The term blasticnatural killer (NK)-cell lymphoma, agreed upon in the2001 World Health Organization classification oftumors of hematopoietic and lymphoid tissue, wasbased on the distinct cytology and suggested an NK-cell origin because of its CD56 expression.3 In 1999,the French Study Group on cutaneous lymphomassuggested �agranular CD41/CD561 hematodermicneoplasm’ as a descriptive term because of itsuncertain lineage.4 Other more recent studies fromthe non-dermatopathology literature, seven of whichwill be briefly discussed herein, have examined thepotential cell of origin and through functional,immunohistochemical and molecular studies havesuggested a plasmacytoid dendritic cell (pDC) deri-vation.5–11 They provide evidence that CD4/CD56HN is a distinct entity that could more appropriatelybe termed �pDC leukemia/lymphoma’.pDCs, which used to be called plasmacytoid

monocytes, are mononuclear plasmacytoid cellsnormally found clustered in the T-cell-rich interfol-licular areas of lymphoid tissue and are thought to bea first-line of defense against certain pathogens in theinnate immune system. The oldest two articles furtherexamine and define the function of the pDC.Although the in vivo function of pDCs remainshypothetical, one in vitro functional study has shownthat stimulated pDCs differentiate into cells exhibit-ing features of dendritic cells.5 The CD41/CD11c2/CD32 pDCs were isolated from tonsils,rescued fromnormal rapid apoptosis by interleukin-3,and exposed to CD40 ligand resulting in differenti-ation into dendritic cells. The resultant cells expressedmyeloid antigens and had the ability to uptake solubleantigens and phagocytose particles. In addition,another functional study found that pDCs are a main

source of a-interferon.6 pDCs were isolated fromperipheral blood and stimulated to proliferate anddifferentiate. Exposure to viral pathogens showedmore interferon production in the immature pDCs.These functional studies suggest that the pDC isa distinct cell type that functions as interferonproducers in their precursor state while acting asantigen presenters upon terminal differentiation toa mature dendritic cell.

CD4/CD56 HN frequently manifests in skinbefore leukemic involvement is evident; therefore,appropriate markers need to be identified that can beused to distinguish CD4/CD56 HN from theirmorphologic mimickers in paraffin-embedded skinbiopsies. Cutaneous extramedullarymyeloid sarcoma(leukemia cutis) is the most notable mimic of CD4/CD56 HN both histologically and immunopheno-typically because cases of cutaneous acute myelomo-nocytic/monocytic leukemia (c-AML) can express thelineage non-specificmarkers CD4 andCD56. Severalnew immunohistochemical markers may be usefuladjunctive tools in differentiating difficult cases ofCD4/CD56 HN from c-AML. The next five morerecent publications attempt to discover these newimmunohistochemical andmolecular adjunctive toolsto help distinguish and clearly separate CD4/CD56HN from its potential mimickers.

CD123 (IL3Ra), a marker for pDCs, was used toexamine a small series of CD4/CD56 HN andisolated normal pDCs.7 High expression of CD123was identified on all 14 cases of CD4/CD56 HN andall isolated normal pDCs, further supporting thetheory that CD4/CD56 HN line of differentiation isthe enigmatic pDCs. The specificity of CD123 wasverified by examining a variety of controls includingpotential clinicopathologic mimickers such as acuteand chronic myeloid and myelomonocytic leukemias.Only 2 of 30 of the control cases expressed CD123including one c-AML and one chronic myelomono-cytic leukemia involving the skin. Another studycompared the expression of two markers previouslydiscovered on normal pDCs in 26 cases of CD4/CD56 HN and 18 cases of c-AML.8 The first marker,

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TCL1, is a 14-kd cytoplasmic protein that acts as anAKTcoactivator and was found expressed in 90% ofCD4/CD56HNand in only 17%of c-AML.TCL1 isexpressed in a broad variety of B-cell lymphoprolifer-ative disorders and a selective subset of T-celldisorders but is absent in NK-cell lineages. Thesecond marker, cutaneous lymphocyte-associatedantigen (CLA), was expressed in 90% and 78% ofCD4/CD56 HN and c-AML cases, respectively. TheHECA-452 antibody to CLA displayed an unusualperinuclear staining pattern in the CD4/CD56 HN,which was absent in normal lymph node controls andin only a subset of c-AML. Furthermore, CLA that isexpressed onmost cutaneousT-cell lymphomas and isthought to play a role in the homing of lymphocytes tothe skin may explain the cutaneous tropism clinicallyappreciated in CD4/CD56 HN.

A third study examined the expression of the blooddendritic cell antigen 2 (BDCA-2) in a small series ofCD4/CD56HN andNK-cell lymphomas.9 BDCA-2is a cell surface protein that has been shown to bea specific marker for pDCs by flow cytometry and infrozen tissue. Although not entirely worked out, it hasbeen proposed that the function of BDCA-2 isinvolved in regulating production of interferon andantigen uptake. The investigators developed theirown antibody reagent and tested the biochemicalspecificity by immunoprecipitation, immunoblottingand dual immunohistochemical staining for CD123andBDCA-2 of normal pDCs in control tissue. Ten of19 (55%) of CD4/CD56 HN cases showed immuno-reactivity for BDCA-2, where as no expression wasidentified in six cases ofNK-cell lymphoma. Since thisstudy, other investigators have further supported thehigh specificity of BDCA-2 in CD4/CD56 HN.12

Interestingly, a statistically significant number of theCD4/CD56 HN cases expressed BDCA-2 and CD7

but lacked TdT. This was the same pattern found onnormal pDCs in lymphoid tissue. The cases of CD4/CD56 HN with a CD71/TdT2 phenotype, com-pared with a CD72/TdT1 phenotype, had a signif-icantly worse prognosis. The above findings suggestthat CD4/CD56 HN is derived from a spectrum ofmaturing pDCs. The CD4/CD56 HN cases witha TdT1/CD72/BDCA-22 phenotype likely rep-resents a more immature clonal population of pDCsthat may behave in a more aggressive manner.The purpose of a recent study was to determine the

�cell of origin’ or line of differentiation of pDCs bymarking normal, reactive and neoplastic pDCs withimmunohistochemical markers including signalingmolecules, transcription factors and Toll-like recep-tors from the different hematologic cell lines.10

Regardless of the nature of the pDCs, they expressedsome B-cell-associated markers. However, myeloidand monocytic markers were also present and manyimportant B-cell markers were absent. It is thereforestill uncertain whether pDCs arise from committedlymphoid or myeloid precursors. Three markers(BCL11A, CD2AP and ICSBP/IRF8) were foundto be expressed in all cases of CD4/CD56HN. Thesethreemarkerswere present in subsets of normal B cellsbut, importantly, absent in cases of c-AML. A novelmarker, CD2AP (CD2-associated protein), was a veryselective marker of pDCs because it was only weaklyexpressed in 1 of 24 cases of c-AML. CD2AP wasweakly expressed in the mantle B cells in somesamples. Thus CD2AP, although not entirely specificfor pDCs, may potentially be another useful adjunc-tive tool in distinguishing difficult cases of CD4/CD56 HN from their morphologic and phenotypicmimickers.Because of the clinical, morphological and immu-

nophenotypical conspicuous resemblance between

Fig. 1. Hematoxylin-eosin-stained tissue sec-

tions from a solitary skin tumor in which the

tumor cells displayed immunoexpression for

CD4 and CD56 without any myeloid or

monocytic marker coexpression. A) Unre-

markable epidermis with a Grenz zone

separating a diffuse infiltrate of mononu-

clear cells within the superficial and deep

dermis. Focally, a leukemic spread of single-

file pattern of infiltration between collagen

bundles can be appreciated (32). B and C)

The mononuclear cells are intermediate in

size with fine chromatin and focally prom-

inent nucleoli consistent with a blast-like

morphology. The nuclei are occasionally

eccentrically placed and indented with

surrounding scant to moderate amounts of

cytoplasm (320 and 340).

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CD4/CD56 HN (n ¼ 5) and c-AML (n ¼ 6), inves-tigators have also used a genetic approach todistinguish these tumors using gene expression pro-filing (GEP) and comparative genomic hybridization(CGH).11 Unsupervised hierarchical clustering of theGEP data separated cases into two groups, even aftergenes encoding proteins used for diagnosis wereexcluded. c-AML cases displayed increased expres-sion of myelomonocytic proteins such as SIGLEC3(CD33) and CD14, while CD4/CD56 HN displayedincreased expression of proteins considered to beprototypic for pDCs including TCL1a, CD123 andToll-like receptors 9 and 10. Importantly, the cases ofCD4/CD56 HN lacked expression of the Toll-likereceptors considered prototypic for dendritic cells ofmyelomonocytic origin. This gene-expression profilefurther supports the plasmacytic dendritic cell line ofdifferentiation of CD4/CD56 HN. CGH providedfurther support that CD4/CD56HN and c-AML aredistinct entities. CGH found no recurrent alterationsin c-AML, while the cases of CD4/CD56 HNdisplayed recurrent chromosomal deletions of variousregions on chromosomes 4, 9 and 13. These findingsprovide evidence that there are significant differencesbetweenCD4/CD56HNand c-AMLand thatCD4/CD56 hematodermic neoplasms are of pDC origin.In conclusion, CD4/CD56HN is a relatively newly

described entity with an aggressive clinical course thatappears to arise fromapDC thatwill be included in theupcoming WHO classification of tumors of hemato-poietic and lymphoid tissue (exact terminology awaitspublication of this monograph). Various immunohis-tochemical and molecular studies have supportedCD4/CD56 HN as a distinct entity from variouscutaneous extramedullary myeloid sarcomas, whichshare overlapping clinical and morphologic features.Diagnosis relies on the pathologist’s familiarity withthis entity and including it in the differential diagnosisof blastic tumors. In the appropriate clinical setting,evaluation of newer markers, including CD123,TCL1, CLA, BDCA-2 and CD2AP, should assist inestablishing a definitive diagnosis of these pDC tumors.

Joshua Weaver MD1

Eric D. Hsi MD2

1Department of Anatomic Pathology L25, and2Department of Hematopathology, Pathology andLaboratory Medicine Institute, Cleveland Clinic,

Cleveland, OH, USAe-mail: weaverj3@ccf.org

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