Case of the Month

Answer to November's Case of the Month.

C. CD3

All others are typically positive in blastic plasmacytoid dendritic cell neoplasm (BPDCN), but can also be positive in other neoplasms, including acute myeloid leukemia.

BPDCN is a rare, clinically aggressive hematologic malignancy characterized by clonal expansion of precursors to plasmacytoid dendritic cells and with frequent cutaneous involvement (as seen in this case). The pattern of cutaneous involvement may include isolated areas with a purplish nodule or bruise-like papule. Alternatively, more disseminated purplish nodules/papules/macules may be present. Bone marrow involvement with associated cytopenias is also common and becomes increasingly likely with disease progression. Leukemic dissemination may also be present at diagnosis (1). Lymph nodes are involved in 40–50 percent of cases.

The male:female ratio is approximately 3:1. Patients are typically elderly, but can be any age (2). A subset of cases may develop in relation to other myeloid neoplasms, especially chronic myelomonocytic leukemia (3). Regardless of presentation, the prognosis of BPDCN remains poor, with median survival of one to two years.

Histologically, a diffuse, monotonous proliferation of medium-sized, blast-like cells with relatively scant, greyish-blue cytoplasm is appreciated. The nuclei have irregular contours with fine chromatin and one or several small nucleoli. There is typically extensive involvement of the dermis with extension into the subcutaneous fat but relative sparing of the epidermis. Lymph node involvement tends to be interfollicular with sparing of the B-cell nodules. Bone marrow involvement may range from interstitial to massive replacement. The bone marrow also frequently shows myelodysplastic features, particularly of the megakaryocytic lineage (4).

Several immunophenotypic markers are characteristic of BPDCN (5):

• Positive: CD4, CD45RA, CD56, CD123, CD43, TCL1, CD303
• Subset of cases: CD7, CD2 (rare), CD33, TdT, CD68 (small cytoplasmic dots), CD5, CD36, CD38, CD79a, CD117
• Negative: CD3, CD13, CD16, CD19, CD20, lysozyme, myeloperoxidase, EBER

CD34 is typically negative by immunohistochemistry but may be positive by flow cytometry (6). Other recently described markers that may be useful include the transcription factor TCF4, which drives plasmacytoid dendritic cell development (7). In a subset of cases, negativity for CD4 or CD56 may occur and create further diagnostic challenge. S100 is positive in a subset of cases, including pediatric patients (2). In general, an extensive panel of stains may be required to confirm the diagnosis, due to potential overlap with other entities. Differential diagnoses to consider include:

• Mature plasmacytoid dendritic cell proliferations, which may also be seen in chronic myelomonocytic leukemia and involve the skin. These show a mature morphology, low Ki67 proliferation rate, and are negative for CD56, but may express a range of other atypical antigens in the setting of a primary marrow disorder (1).
• B- or T-cell lymphoblastic lymphoma. These typically express more B or T lineage markers in addition to TdT. CD10 is often positive and Ki67 proliferation rate is very high. In addition, clonal rearrangement of IG or TCR loci would be helpful.
• Acute myeloid leukemia or myeloid sarcoma. These typically show MPO or lysozyme, CD13, and additional myeloid markers, but significant overlap with monocytic tumors expressing CD4, CD56, and CD123 may occur. BPDCN may also show CD68, but in a dot-like pattern.
• In some cases of acute leukemia, definitive lineage cannot be assigned and may fall into one of the categories of acute leukemias of ambiguous lineage.

Molecular studies demonstrate germline TCR and immunoglobulin loci, although an associated T cell clone may be present in some cases. A subset of patients exhibits a complex karyotype, with recurrent abnormalities in chromosomes 5q, 12p, 13q, 6q, 15q, and 9 described (8). TET2 appears to be the most commonly mutated gene, with mutations in NRAS, ATM, MET, KRAS, IDH2, and KIT also reported (9).

The prognosis of the disease is poor. Patients may respond initially to therapy, but have subsequent relapse and disease resistance. The overall mean survival ranges from 10–22 months. Active areas of investigation include a better understanding of disease mechanisms and potential treatment strategies.

Courtesy of PathologyOutlines.com. Case by Gabriel Lerner (Boston University School of Medicine, Boston, Massachusetts, USA), Lija Joseph, Bethany Tierno, Rebecca Shore, and Murat Anamur (Lowell General Hospital, Lowell, Massachusetts, USA); discussion by Genevieve M. Crane, Cleveland Clinic, Cleveland, Ohio, USA.