BLASTIC PLASMACYTOID DENDRITIC NEOPLASM
The patient is a 25-year old Oriental woman who presented with a rapid onset multiple purple papules on her trunk and upper eyelid ecchymoses. One of the skin lesions on her chest was biopsied.
Histological sections show a dense infiltrate of atypical monomorphic medium to large cells filling the dermis. The neoplastic cells have indistinct grey-blue cytoplasm and feature ovoid and slightly irregular nuclei, fine chromatin and inconspicuous nucleoli. There is a Grenz zone and hemorrhage in the papillary dermis. Mitotic figures are easily identified.
Immunohistochemical stains demonstrate that the neoplastic cells are immunoreactive to CD45(+), CD43(+), CD4(+) and CD56(+). They are negative for other myeloid and monocytic markers (MPO, lysozyme, CD117, CD34, CD13 and CD68, CD163, respectively). Ki-67 proliferation index is increased at over 70%. The large cells are negative for B- and T- cell markers (CD20, CD79a, Pax-5, and CD2, CD3, CD5, CD8 stains, respectively). TdT is negative. Markers of the blastic plasmacytoid dendritic cells (CD123 and TCL-1) are positive.
DIAGNOSIS: BLASTIC PLASMACYTOID DENDRITIC NEOPLASM
Blastic plasmacytoid dendritic neoplasm (BPCDN) is a rare and clinically aggressive hematopoietic malignancy, formerly known as Blastic NK-cell lymphoma and agranular CD4+CD56+ hematodermic neoplasm. The 2008 World Health Organization classification has re-grouped it with the category of acute myeloid leukemia (AML). The young age of our patient is unusual, as the tumor classically affects older individuals with a median age of 65 years. It is one of the true emergencies in the dermatologic practice as the patients initially present to a dermatologist with a solitary or multiple erythematous painful nodules, tumors, plaques, or bruise-like lesions. A prompt biopsy and an immediate referral for bone marrow biopsy and peripheral blood flow cytometric analysis to rule out a systemic dissemination is a key.
Immunophenotypically, BPCDN is characterized by overexpression of CD4, CD43 and CD56, as well as the hematopoietic precursor–associated antigens CD38 and HLA-DR. The neoplastic cells are almost always negative for lineage-specific antigens for B-cells (CD20, CD79a, PAX5), granulocytes (myeloperoxidase, CD117, and lysozyme), monocytes, EBV, CD10 and cytotoxic molecules (granzyme B1, TIA1, and perforin). Because of the significant overlap with other hematopoietic neoplasms, the diagnosis of BPCDN requires an extensive immunohistochemical panel to exclude expression of the myeloid, lymphoid and monocytic markers and to document presence of plasmacytoid dendritic cell-associated antigens. The latter include CD123 (the interleukin-3 receptor α chain), T-cell leukemia/lymphoma 1 (TCL-1), blood dendritic cell antigen-2 (BDCA-2), and CD2-associated protein (CD2AP).
Cutaneous myeloid sarcoma is the main consideration in the diagnostic work-up of an early skin lesion of BPCDN. While the myeloid markers are usually negative in BPCDN, CD33 may be expressed and CD68 is positive in up to half of the cases. CD43 is positive in both conditions, and CD34 may be absent in myeloid sarcoma with monocytic differentiation. To complicate the matters further, MLL rearrangements characteristic of AML (such as MLL-MLLT1 and MLL-ENL) have been reported in BPCDN. With the monocytic differentiation being common in myeloid sarcoma, it may express CD4, CD56, and even CD123, although the intensity of staining with CD123 is much higher in BPCDN. TCL-1 tends to be a more specific blastic plasmacytoid dendritic cell marker. The diagnosis of AML is further supported by the presence of myeloperoxidase and diffuse cytoplasm pattern of staining with CD68, which is dotlike and cytoplasmic in BPDCN. CD11c is negative in BPCDN and may be helpful to confirm a monocytic variant of AML.
Although CD3 and CD5 are usually negative, BPCDN is positive for CD4 and may show expression of T-cell associated antigens CD2 and CD7. Therefore, BPCDN may mimic peripheral T-cell lymphoma involving the skin. CD56 may be detected in both. However, mature T cell lymphoma does not have a blastic appearance of PBCDN. If TdT is expressed in conjunction with the T-cell markers, then a distinction from cutaneous T-cell lymphoblastic leukemia/lymphoma (T-ALL/LBL) becomes important. Classically, T-ALL is either CD4 negative, or double positive for both CD4 and CD8, while BPCDN lacks CD8. If the immunohistochemical profile leaves uncertainty, then TCR gene rearrangement studies should be pursued: a clonal rearrangement is present in both PTCL and T-ALL, but is absent in BPDCN.
T-cell markers and CD56 are also expressed in extranodal NK/T-cell lymphoma, nasal type, which often involves the skin outside of the sinonasal tract and has blastic morphology, just like BPCDN. However, extranodal NK/T-cell lymphoma lacks CD4 and is consistently positive for EBV latent membrane protein 1 and cytotoxic markers. The histologic sections classically show angiocentric and angiodestructive pattern.
Lastly, plasmacytoid dendritic cells may undergo hyperplasia and accumulate in both the lymph nodes and the extranodal sites in patients with chronic myelomonocytic leukemia. This is an expansion of benign cells that appear mature on histology and lack CD56.
In summary, blastic plasmacytoid dendritic neoplasm is a rare and highly aggressive hematopoietic malignancy. It has been recognized as a distinct entity relatively recently. Its pathogenesis is not well understood, and a standard therapeutic regimen is yet to be established. Most cases of BPCDN carry complex chromosomal abnormalities, but no single chromosomal change has been established as diagnostic of this condition. Similarly, there is no reliable prognostic marker that we could use and/or targeted therapy. Despite the intensive multiagent chemotherapy, the patients uniformly have a rapid and fatal progression despite the transient response. Younger age, TdT expression by the tumor cells and stem cell transplantation may offer better survival in some patients.
- Chapter 50. Blastic plasmacytoid dendritic neoplasm. In: Jaffe ES, Harris NL, Vardiman JW, Campo E, Arber DA, Eds. Hematopathology, Elsevier Saunders Publishers, St. Louis, MO, USA, 2010, p.789 – 798.
- Swerdlow SH, Campo E, Harris NL, Jaffe ES, et al, Eds. (2008). WHO classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France, International Agency for Research on Cancer, p. 146-147.
- Laribi K, Denizon N, Besançon A, Farhi J, Lemaire P, Sandrini J, Truong C, Ghnaya H, Baugier de Materre A. Blastic Plasmacytoid Dendritic Cell Neoplasm: From Origin of the Cell to Targeted Therapies. Biol Blood Marrow Transplant. 2016 Aug;22(8):1357-67.
- Lee JM, Kim IS, Lee JN, Park SH, Kim HH, Chang CL, Lee EY, Kim HR, Oh SH, Song SA. Acute Myeloid Leukemia With MLL Rearrangement and CD4+/CD56+ Expression can be Misdiagnosed as Blastic Plasmacytoid Dendritic Cell Neoplasm: Two Case Reports. Ann Lab Med. 2016 Sep;36(5):494-7.
- Pagano L, Valentini CG, Grammatico S, Pulsoni A. Blastic plasmacytoid dendritic cell neoplasm: diagnostic criteria and therapeutical approaches. Br J Haematol. 2016 Jul;174(2):188-202.
- Cutaneous leukemic infiltrates and precursor cell neoplasms. In: Calonje EJ, Brenn T, Lazar A, McKee P, eds. McKee’s Pathology of the Skin: Expert Consult. 2 Vol Set, 4 edition. Philadelphia, PA: Saunders; 2011:35: 1414 – 1416.
- Shi Y, Wang E. Blastic plasmacytoid dendritic cell neoplasm: a clinicopathologic review. Arch Pathol Lab Med. 2014 Apr;138(4):564-9.