Plasmacytoid dendritic cells: physiologic roles and pathologic states

Abstract

Plasmacytoid dendritic cells (PDCs) have perplexed pathologists for decades, undergoing multiple adjustments in nomenclature as their lineage and functions have been characterized. Although PDCs account for less than 0.1% of peripheral blood mononuclear cells, they serve as a principal source of interferon-alpha and are also known as interferon-I producing cells (IPCs). Upon activation in vitro, they can differentiate into dendritic cells, and recent studies have substantiated a potential role in antigen presentation. Thus, PDCs may act as a link between innate and adaptive immunity. Normally found in small quantities in primary and secondary lymphoid organs, PDCs accumulate in a variety of inflammatory conditions, including Kikuchi-Fujimoto lymphadenopathy, hyaline-vascular Castleman disease, and autoimmune diseases, and in certain malignancies such as classical Hodgkin lymphoma and carcinomas. Demonstrating potential for neoplastic transformation reflective of varying stages of maturation, clonal proliferations range from PDC nodules most commonly associated with chronic myelomonocytic leukemia to the rare but highly aggressive malignancy now known as blastic plasmacytoid dendritic cell neoplasm (BPDCN). Formerly called blastic natural killer cell lymphoma or CD4/CD56 hematodermic neoplasm, BPDCN, unlike natural killer cell lymphomas, is not associated with Epstein-Barr virus infection and is generally not curable with treatment regimens for non-Hodgkin lymphomas. In fact, this entity is no longer considered to be a lymphoma and instead represents a unique precursor hematopoietic neoplasm. Acute leukemia therapy regimens may lead to sustained clinical remission of BPDCN, with bone marrow transplantation in first complete remission potentially curative in adult patients.

FIGURE 1.

PDCs in reactive and neoplastic conditions. A, In this reactive lymph node, a PDC nodule (left, indicated by a black arrow) is compared with a neighboring germinal center (right, indicated by a white arrow), the latter having a heterogeneous cellular composition and surrounded by a discrete mantle zone. B, PDCs stain strongly positive for CD123 and are most prominent around high endothelial venules, which as a useful internal control are weakly positive for CD123. C (H&E) and D (CD123), Kikuchi-Fujimoto lymphadenopathy, which on H&E may mimic non-Hodgkin lymphoma, is often associated with loose sheets of PDCs (highlighted by CD123 staining), admixed with histiocytes and immunoblasts. E, Clusters of reactive PDCs in an exceptional case of classical Hodgkin lymphoma. F, PDC nodules in a child with juvenile myelomonocytic leukemia; the abundance of apoptotic bodies may result in a low power appearance resembling “naked” germinal centers. G, High-power view of (E) demonstrates intermediate-sized cells with distinct nuclear membranes and pinpoint nucleoli. H, High-power view of (F) demonstrates uniform intermediate-sized cells with finely dispersed chromatin and inconspicuous nucleoli, admixed with numerous apoptotic bodies. H&E indicates hematoxlin and eosin; PDC, Plasmacytoid dendritic cells.

FIGURE 2.

An unusual example of a “tumor forming” PDC proliferation associated with a myeloid neoplasm, compared with BPDCN. The left column depicts a PDC proliferation in a patient with underlying chronic myelomonocytic leukemia, and the right column depicts a case of BPDCN, both diffusely effacing the underlying lymph node architecture. The distinction can be difficult on histologic examination alone, although the tumor forming PDCs are more round and uniform than the cells of BPDCN. Both are positive for CD123. Both CD56 and TdT (not shown) are usually negative in mature PDC proliferations, although a small subpopulation of PDCs may be CD56⁺, as shown. In contrast, BPDCN is more uniformly positive for CD56 and in almost half of all cases demonstrates TdT positivity. The Ki-67 proliferative index is typically very low (<10%) in mature PDC proliferations and higher (>30%) in BPDCN. BPDCN indicates blastic plasmacytoid dendritic cell neoplasm; PDC, plasmacytoid dendritic cells; TdT, terminal deoxynucleotidyl transferase.