The patient was a 51-year-old male who presented with a 1.5-year history of a progressive nodular and plaque-like eruption manifesting an exclusively truncal distribution. The clinical exam revealed multiple back lesions. There was no lymphadenopathy, splenomegaly or hepatomegaly. The largest, which measured 9 x 5 cm, was the initial lesion and was followed by others over the ensuing months (Figures 1A-C). The application of topic steroids followed by a 10-day course of doxycycline did not result in any improvement. He denied fever, chills and weight loss. His past medical history was unremarkable. His workup to date does not disclose any evidence of extracutaneous dissemination.
Light Microscope Findings
A biopsy was performed. There was an extensive pandermal infiltrate of monotonous appearing cells that had a lymphoblastic-like appearance (Figures 2 and 3). The cells were in the 7 to 9 µm range, showing round to oval nuclei with a finely dispersed chromatin (Figure 4). Nucleoli were not conspicuous. Scattered mitoses were identified. Epidermotropism was not identified. There was a paucity of other inflammatory cell elements.
The cells were extensively positive for CD4, CD56 (Figure 5), CD123 (Figure 6), HLADR and TCL1 oncogene (Figure 7). Significant staining was not observed for lysozyme, CD11c, myeloperoxidase, CD3, CD20, MXA and CD2.
A germ line configuration was observed both in regards to evidence of T cell receptor and heavy chain immunoglobulin gene rearrangement.
The clinical presentation and biopsy findings in this case were diagnostic of blastic plasmacytoid dendritic cell neoplasm. The positivity of this neoplasm for CD56 led hematopathologists to initially consider this neoplasm under the rubric of CD56+ Natural killer (NK) cell lymphomas. Its uniqueness lied in the positivity of this apparent NK lymphoma/leukemia for CD4. Most NK neoplasms are without positivity for CD4 and CD8 or rarely, although rarely these tumors can be CD8 positive. This tumor fell under the designation of blastic NK-like T cell lymphoma.
In the revised World Health Organization-European Organization for Research and Treatment of Cancer classification, blastic NK-cell lymphoma was considered a clinically aggressive T cell neoplasm; skin involvement typically occurred concurrently with leukemic dissemination. A blastic cytomorphology and expression of CD56 were held to be evidence of an NK-precursor cell origin. The designation of this neoplasm as CD4+CD56+ hematodermic neoplasm was by Kato and colleagues in 2001; although it was not until 2002 when a new cell of origin was proposed for this aggressive neoplasm, namely one of plasmacytoid dendritic cell origin for this neoplasm was proposed.
Consequently, the term blastic NK-like T cell lymphoma was first supplanted by the term CD4+CD56+ hematodermic neoplasm and now more recently blastic plasmacytoid dendritic cell tumor. In those neoplasms categorized as true NK lymphomas, there is a frequent association with Epstein-Barr virus (EBV), especially in Asian patients with nasopharyngeal involvement; EBV has not been pathogenetically implicated in CD4+CD56+ hematodermic neoplasms. At further variance with the classic NK lymphomas/leukemias, is the agranular nature of the tumor, with the absence of granzyme B and T cell intracellular antigen (TIA) cytotoxic protein expression. Most patients die within 12 months of initial presentation. Elderly patients are characteristically affected, and there is a male predominance. Disseminated disease is common involving peripheral blood and lymph nodes and bone marrow. The prognosis is grim with most patients succumbing to disease within 12 months of presentation.1,2
While the dominant literature addressing CD4+CD56+ malignancies is in the context of CD4+CD56+ hematodermic neoplasm/blastic plasmacytoid dendritic cell neoplasm, there are other hematological malignancies that may express this particular phenotypic profile including myelofibrosis, anaplastic large cell lymphoma and leukemia cutis. It should be emphasized that the expression of other pan T cell markers, however, does not exclude a diagnosis of CD4+CD56+ hematodermic neoplasm. In particular while CD4+CD56+ hematodermic neoplasms are typically CD2 and CD7 negative, CD7 and focal CD2 positivity can be seen in this neoplasm. The classic immunohistocemical stains for identifying plasmacytoid dendritic cells are BDCA-2, CD123 and TCL1. CD123 represents the alpha chain of the interleukin (IL)-3 receptor. This 60 to 70 kDa transmembrane protein binds to IL-3 with low affinity by itself, and when associated with CD131 (common beta chain) binds IL-3 with high affinity.3
Biopsies typically show a striking effacing non-epitheliotropic mononuclear cell infiltrate exhibiting variable angiocentricity. The cells have a lymphoid-like appearance and are of medium size (ie, in the 9 µm size range). The chromatin is more finely dispersed than a mature lymphocyte. The cells demonstrate conspicuous nucleoli. In foci of angiocentric infiltration, red cell extravasation is observed.
The infiltrate expresses CD4 CD56+ and CD123+. As well, there is positivity for cutaneous lymphocyte antigen. Other markers that may be positive include CD2, CD7, MXA, CD83 and TCL1. The cells do express granzyme and TIA. TCR clonality studies revealed a germ line configuration and/or a polyclonal T cell population. Markers of myeloid differentiation including CD11c, lysozyme, myeloperoxidase, CD14 and CD68 are negative. A few cases of purported CD4+ CD56+ hematodermic neoplasm do not express CD4. The vast majority of cases reported in the literature, however, describe CD4 staining.
Although the clinical course in the vast majority of cases of blastic plasmacytoid dendritic cell neoplasm is poor, cases presenting in the skin without evidence of extracutaneous disease at the time of presentation may have a potentially indolent course and/or a less aggressive clinical course compared to the more classic presentation of blastoid plasmablastic dendritic cell neoplasm.4,5
The cases of primary cutaneous blastic plasmacytoid dendritic cell neoplasm affect a young age group compared to the more common multi-organ variant. Of the few reported cases in the literature, the patients have undergone polychemotherapy with a hyper-CVAD regimen and obtained a remarkable clinical response with regression of skin lesions. Bekkenk et al6 suggested that patients younger than age 40, presentation with skin lesions, high TdT expression and an aggressive acute leukemia protocol treatment have a superior prognosis.
Dr. Magro is the director of dermatopathology at the Weill Cornell Medical College in Manhattan, NY, and is board certified in anatomic pathology, dermatopathology and cytopathology.
1. Angelot-Delettre F, Garnache-Ottou F. Blastic plasmacytoid dendritic cell neoplasm. Blood. 2012;120(14):2784.