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Blastic Plasmacytoid Dendritic Cell Neoplasm: Cytopathologic Findings

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematopoietic neoplasm, which in the past was also known variously as blastic NK cell lymphoma, agranular CD4+ natural killer cell leukemia, and CD4+/CD56+ hematodermic
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  R  EVIEW  A RTICLE Blastic Plasmacytoid Dendritic Cell Neoplasm: EvolvingInsights in an Aggressive Hematopoietic Malignancy Witha Predilection of Skin Involvement Shweta Gera, MD, *  Mhair S. Dekmezian, †   Madeleine Duvic, MD,  ‡  Jaime A. Tschen, MD,§  Francisco Vega, MD, PhD,¶ and Jeong Hee Cho-Vega, MD, PhD§  Abstract:  Blastic plasmacytoid dendritic cell neoplasm (BPDCN)derived from precursors of plasmacytoid dendritic cells is a very rare,unique, and highly aggressive immature hematopoietic malignancy,more frequently occurring among healthy elderly adults. BPDCN can be characterized by a striking predilection for cutaneous involvement,which is often detected incidentally by dermatologists and is dif  󿬁 cult to clinically distinguish it from other primary skin lesions and histologically from leukemia/lymphoma cutis. Thus, histologicaldiagnosis of cutaneous biopsies is crucial to correctly classify thisentity. Most patients eventually progress to acute myeloid leukemiaand are generally not curable. Here, we present 2 cases of classicBPDCN and discuss the origin of tumor and literature-based characteristic clinical and morphological features, evolving immu-nomarkers, and molecular genetic aspects of this neoplasm. Key Words:  blastic plasmacytoid dendritic cell neoplasm, CD4+/ CD56+ hematodermic neoplasm, blastic natural killer cell lymphoma,TCL-1, CD123, BCL11A(  Am J Dermatopathol   2014;36:244  –  251) INTRODUCTION Blastic plasmacytoid dendritic cell neoplasm (BPDCN)has undergone multiple adjustments in the nomenclature and was formerly called blastic natural killer (NK) cell lymphomaor CD4+/CD56+ hematodermic neoplasm. 1 This is a very rareand aggressive neoplasm among the elderly adults with nosigni 󿬁 cant medical history and is no longer considered to beas a lymphoma and instead unique immature hematopoieticneoplasm. Recent phenotypic and functional characterizationof both normal plasmacytoid dendritic cells (PDCs) and neo- plastic cells showed many features in common, suggestingderivation from PDC precursors and the tumor is renamed as BPDCN. 2,3 In majority of the BPDCN cases, skin isinvolved at the initial presentation, preceding bone marrowor peripheral blood involvement.The skin lesions of BPDCN present as solitary or multiple bruise-like erythematous papules/plaques or tumorsand are often clinically diagnosed as a vasculitis or traumatic purpura. The histological features also often overlap withthose of leukemia/lymphoma of the skin. Thus, cutaneous biopsies are crucial to correctly classify cases. Despite the fact that the BPDCN tends to be limited to the skin initially, the prognosis is very poor and most patients eventually progressto acute myeloid leukemia. 4 In this review, the 2 classical cases of BPDCN weexperienced provided characteristics of this neoplasm clini-cally and histopathologically, and a literature-based reviewalso can reveal evolving insights, in particular, in the srcin of tumor, the diagnostic immunomarkers, and the molecular and therapeutic progresses for this unique neoplasm. CASE PRESENTATIONCase 1 Clinical Findings An 87-year-old white man initially noticed an erythematous papule on the right cheek over 2 years before this presentation. Hehad never tried any systemic therapy or local treatment for the lesion.The patient  ’ s past medical history was unremarkable and he waslargely asymptomatic. The  󿬁 rst skin biopsy from the right cheek lesion did not yield a correct pathological diagnosis. He remained untreated. One year later, he subsequently developed numerous addi-tional facial lesions that became con 󿬂 uent (Fig. 1A), and multiplenew pink plaques developed on the trunk (Fig. 1B). Several addi-tional skin biopsies from the right cheek, right preauricular, and theleft eyebrow lesions con 󿬁 rmed a diagnosis of BPDCN. Pathology Findings All biopsies from different time points and from different anatomic sites demonstrated similar histopathological features:a diffuse or nodular monomorphic population of medium-sized  blastoid cells involving dermis and subcutaneous adipose tissue but sparing the epidermis and dermal adnexa (Figs. 2A  –  E). Characteris-tic extravasated red blood cells dispersed within the tumor could beresponsible for the bruise-like, erythematous clinical presentation.Other in 󿬂 ammatory components were minimal. Angiocentricityand necrosis were not noted in any of biopsies. Cytologically, theneoplastic cells were medium-sized cells with  󿬁 ne chromatin, vesic-ular, and indistinct nucleoli, resembling lymphoblasts. The From the *Department of Pathology, St. Luke ’ s Roosevelt Hospital, New York, NY;  † Baylor College of Medicine, Houston, TX;  ‡ Department of Derma-tology, University of Texas MD Anderson Cancer Center, Houston, TX;§St. Joseph Dermatopathology, Houston, TX; and ¶Department of Hematopathology, University of Texas MD Anderson Cancer Center,Houston, TX.The authors declare no con 󿬂 icts of interest.Reprints: Jeong Hee Cho-Vega, MD, PhD, St. Joseph Dermatopathology,6909 Greenbrier St, Houston, TX 77005 (e-mail:© 2013 Lippincott Williams & Wilkins 244  |  Am J Dermatopathol     Volume 36, Number 3, March 2014  cytoplasm was variably abundant and lacked granules. Occasionalmitotic  󿬁 gures were noted.The immunophenotyping demonstrated that the neoplastic cellswere positive for CD4 (Fig. 2F), CD56 (Fig. 2G), T-cell leukemia-1(TCL-1) (Fig. 2H), CD123 (IL-3 receptor   a  chain) (Fig. 2I), BCL11a(Fig. 2J), TdT (variably positive), BCL-6 (weak), and BCL2. Theneoplastic cells were negative for CD3 (Fig. 2K), CD20, epithelialmembrane antigen, CD30, myeloperoxidase, and lysozyme.Bone marrow  󿬂 ow cytometry revealed less than 1% of CD4+,CD56+, and CD123+ cells, but morphological correlation did not indi-cate any neoplastic involvement. The immunophenotyping (CD2, CD3,CD4, CD8, TCL1, CD56, TdT, and CD34) performed on bone marrow biopsy also revealed no tumor involvement. Flow cytometry of the peripheral blood again con 󿬁 rmed no evidence of tumor involvement. Staging, Treatment, and Follow-up Clinical staging demonstrated only skin-limited disease. cyclo- phosphamide, Hydroxydaunorubicine, Oncovin, Predenisone (CHOP)treatment had been initially recommended but the patient declined  because of his age. The patient started with methotrexate at a dose of 20 mg per week for a total of 2 weeks. After completion of 2 weeks of treatment, the facial lesions almost completely disappeared and the patches on the chest and back had partially cleared. However,8 months after chemotherapy, the patient progressed to acute myeloid leukemia as detected in a peripheral blood smear (Fig. 2L). He refused any further aggressive diagnostic or therapeutic procedures and asked for hospice care. Case 2 Clinical Findings An 87-year-old white man presented with several sparse,indurated, smooth purpuric plaques on the left anterior chest, left abdomen, and right mid forearm (clinical photographs never taken), FIGURE 1.  Multiple erythematous papules/plaques are foundon the face (A). Scattered subtle erythematous patches areadmixed with numerous seborrheic keratosis on the back (B). FIGURE 2.  The initial biopsy (A) was from an erythematouspapule on the right cheek in October 2008. The second biopsy was fromthe new papule on the right cheek in March 2009 (B). Two more biopsies were from the right preauricular area (C) and the lefteyebrow (D) in July 2009. All skin biopsies demonstrated similar histopathological features of diffuse or nodular and monomorphictumor cell infiltrate involving dermis and subcutaneous adipose tissue but sparing the epidermis (grenz zone) and dermal adnexa.Characteristic extravasated red blood cells dispersed within the tumor (E). Other inflammatory component was minimal. Cyto-logically, the neoplastic cells were medium-sized with variably abundant and nongranular cytoplasm, fine nuclear chromatin, andoften vesicular and indistinct nucleoli, resembling lymphoblasts (E). Tumor cells were positive for CD4 (F), CD56 (G), TCL-1 (H),CD123 (I), and BCL11A (J). Tumor cells were negative for CD3 (K, except reactive T cells) and CD20 (not shown). Peripheral bloodsmear demonstrated many blasts, morphologically compatible with acute monoblastic leukemia (L). Am J Dermatopathol     Volume 36, Number 3, March 2014  Blastic Plasmacytoid Dendritic Cell Neoplasm   2013 Lippincott Williams & Wilkins  |  245  which were incidentally noticed by a routine follow-up dermatolo-gist. The initial clinical impression was to rule out traumatic purpuraor a vasculitis. This patient also was otherwise asymptomatic. Pathology Findings A skin biopsy was performed from the right anterior chest lesion. Morphological and immunophenotypical features were verysimilar to those found in case 1. A deep skin punch biopsy revealed diffuse and nodular dense monomorphous dermal in 󿬁 ltrates of medium-sized blastoid cells with epidermal sparing and a subepider-mal Grenz zone as well as sparing of the adnexal structures(Figs. 2A, B). Extravasated red blood cells within the tumor alsowere present. Cytologically, the tumor cells were medium-sized blas-toid cells with vesicular nuclei (Fig. 3C). Rare mitoses wereobserved. Angiocentricity was not identi 󿬁 ed either, but perivascular distribution was seen in the mid-dermis.The tumor cells were positive for CD4 (Fig. 3D), CD56(Fig. 3E), TCL-1 (Fig. 3F), TdT (variably positive) (Fig. 3G),CD123 (Fig. 3H), and BCL11A (Fig. 3I). The tumor cells werenegative for CD3 and CD20. Staging, Treatment, and Follow-up Comprehensive staging was performed, demonstrating skin-limited disease. A peripheral blood smear and bone marrow biopsydemonstrated no evidence of neoplastic involvement. Subsequently,the skin lesions disseminated over nearly the entire body of the patient.After CHOP treatment, the skin lesions improved temporarily,although 8 months later, he also progressed to acute myeloid leukemia. This was con 󿬁 rmed by an increase in myeloid blasts ina peripheral blood smear (not shown). This patient also refused anaggressive treatment, and he died 1 month later. PDC: The Origin of BPDCN Starting in 1994, multiple previous reports under either nameof blastic NK-cell tumor  3,5  –  21 or CD4+/CD56+ hematodermic neo- plasm 22  –  38 showed that this neoplasm did not neatly  󿬁 t with other tumors in the various lymphoma classi 󿬁 cations. One study further demonstrated that the tumor cell lineage was closer to myelomono-cytic cells than to NK-cells and suggested a very immature cell for which the exact nature remained to be determined. 3 The  󿬁 nding of  FIGURE 3.  A biopsy (A) was from the chest lesion and demonstrated similar histopathological features of those found in case 1. A diffuse or nodular and monomorphic tumor cell infiltrate involved the dermis but spared the epidermis (Grenz zone) and dermaladnexa (A and B). Characteristic extravasated red blood cells dispersed within the tumor (C). Other inflammatory componentwas minimal. Cytologically, the neoplastic cells were also similar to those found in case 1, resembling lymphoblasts (C). Neoplasticcells were positive for CD4 (D), CD56 (E), TCL-1 (F), TdT (G, variable), CD123 (H), and BCL11A (I). Gera et al   Am J Dermatopathol     Volume 36, Number 3, March 2014 246  |    2013 Lippincott Williams & Wilkins  CD123 antigen expression by the tumor cells provided a basis for thediscovery of the likely cell of srcin for neoplasm. Few normal cellsexpress the CD123 antigen, which is present mainly on dendriticcells (DCs) and strongly displayed on precursor DCs. Several dis-tinct names by different groups, therefore, were attributed to CD123 + DCs; however, the current consensus term for these cells now seemsto be PDC, and the tumor has been renamed as BPDCN in 2008. 2 Although both the PDCs and conventional (CDCs) or myeloid DCs are believed to arise from common CD34+ hematopoietic stemcells (Fig. 4A), 39,40 the precise relationship between PDCs and CDCs FIGURE 4.  A, A simplified illustrationhighlights distinct DC subsets includingPDCs in humans. The different subsetsrespond to self and foreign antigen chal-lenges and exhibit different functionalspecialization. These subtypes can becharacterized based on their tissue distri-bution, cell surface markers, and tran-scriptional programs. B, An illustration of PDC role in allergic contact dermatitis.Topical allergen application triggersmigration of Langerhans cells (LCs) fromthe epidermis through the afferent lym-phatics toward regional skin-draininglymph nodes. In the T-cell–rich paracorticalarea of the lymph node, LCs encounter naive T cells and activate these throughinteraction between major histocompati-bility complex (MHC)–peptide and T-cellreceptor. Hapten-specific T cells expandand generate effector or memory functionand will go into the circulation. Upon re-exposure to the allergen, epidermal cellsrelease pro-inflammatory cytokines andchemokines, which will recruit hapten-specific T cells. The frequency of IFN- a -secreting PDCs is also increased in theinflammatory lesion and participates tolocal inflammation. Infiltrating T cellsrelease inflammatory cytokines, IFN- g , andIL-4, which stimulate keratinocytes to pro-duce chemokines, amplifying cellular infil-tration. These infiltrating cells migrate intodermal and epidermal compartments. Ulti-mately, inflammation characterized by, for example, edema and spongiosis reach itsmaximum at 24–48 hours after allergenexposure. 69 C, Normal morphology of PDC.Compared with a monoblast (arrowhead),one PDC (arrow) shows a round-to-ovoideccentric nucleus with a subtle indentation,fine or reticular chromatin, and moderatelyabundant nongranular cytoplasm thatstains faintly basophilic in Giemsa. D and E, A nodular proliferation of PDCs in a bonemarrow biopsy of chronic myelomonocyticleukemia. The proliferating PDCs are cyto-logically bland and morphologically maturecells (E), distinct from the neoplasm of their blastic counterparts. Am J Dermatopathol     Volume 36, Number 3, March 2014  Blastic Plasmacytoid Dendritic Cell Neoplasm   2013 Lippincott Williams & Wilkins  |  247  or myeloid DCs remains controversial. There is considerable plas-ticity in DC lineages, and PDC could be derived from either myeloid or lymphoid precursors. 41 Similar to evolving nomenclature of   “ BPDCN, ”  this enig-matic cell also has been renamed several times in previous yearsand has been listed as  “ lymphoblasts ” , 42 “ T cell-associated plasmacells ” , 43 “  plasmacytoid T-cells ” , 44 or   “  plasmacytoid monocytes ” . 45 Upon stimulation with CD40 ligand and interleukin, plasmacytoid cells develop long dendrites in culture and the term  “  plasmacytoid dendritic cell ”  was adopted. 46 The plasmacytoid cells tend to pro-duce large amounts of type I interferon (IFN-I) and express lower levels of major histocompatibility complex (MHC) class II compared with dendritic cells in culture, which lose their capacity to produceIFN-I and up regulate MHC class I and II. 47 The PDCs are rare mononuclear cells that make up less than0.1% of peripheral blood mononuclear cells and have been found to be the primary source of IFN- a . They are believed to play a role inantigen presentation, providing a link between innate and adaptiveimmunity. PDCs accumulate in a variety of in 󿬂 ammatory conditions,including infection (tuberculosis, toxoplasmosis), sarcoidosis, Kikuchi-Fujimoto lymphadenopathy, hyaline-vascular Castleman disease, and autoimmune diseases. Although PDCs are normally also very rare inskin, their accumulation has been described in in 󿬂 ammatory skin con-ditions such as systemic lupus erythematosus, lichen planus, psoriasis,and contact dermatitis (Fig. 4B), possibly via the triggering of Toll-likereceptor 9 (TLR9), and subsequent IFN production. 48,49 In addition,PDCs also in 󿬁 ltrate in a variety of malignancies including melanoma,various carcinomas, cutaneous T-cell lymphoma, classical Hodgkinlymphoma, and primary cutaneous marginal zone B-cell lymphomaand may be involved in antitumor immunity. 4,50,51 The normal morphology of a PDC is between that of a smalllymphocyte and a monocyte, with a round-to-ovoid nucleus that can be indented or eccentric,  󿬁 ne or reticular chromatin, and moderately abundant nongranular cytoplasm that stains eosino- philic in hematoxylin/eosin or faintly basophilic in Giemsa (Fig. 4C).There can be abundant rough endoplasmic reticulum parallel to the plasma membrane mimicking that of plasma cells, giving rise to theterm  “  plasmacytoid. ” 50 The immunophenotypes of PDC and BPDCN overlap sub-stantially, also shown in 2 of our reported cases. Positivity is usualwith CD123, CD68, BCL11A, T-cell leukemia 1 (TCL1), cutaneouslymphocyte  –  associated antigen, CD2AP, and blood dendritic cellantigen-2 (BDCA-2). The latter 2 markers are transmembrane gly-coproteins, which are involved in antigen internalization and pre-sentation. Expression of cutaneous lymphocyte  –  associated antigen,which binds to E-selectin on skin endothelial cells, may be respon-sible for skin tropism of both PDCs and their blastic counterpart.Strong expression of the CD123 is also common in both in contrast to no expression in CDCs. CD62L, an L-selectin, allows the PDCs toenter through high endothelial venules into lymphoid tissue, wherethey are relatively abundant (Fig. 4B). BCL11A, a transcription fac-tor, is differentially expressed during B-cell development and strongly expressed in PDCs. 52 Peripheral blood PDCs also showexpression of chemokine receptors CCR2, CCR5, CCR7, CXCR3,and CXCR4 that may be involved as well in leukocyte migration. 50 Heterogeneity among PDC fractions has been described both inmouse and human blood. 53 Thus, subsets expressing CD2, CD5,or CD7 may translate into phenotypic heterogeneity among BPDCNcases. 53 PDCs themselves have been described to form  “  benign nod-ules ”  of cytologically bland and morphologically mature cells, oftenin association with chronic myelomonocytic or atypical chronicmyeloid leukemia, distinct from the neoplasms of their blastic coun-terparts (Figs. 4D, E). Unlike BPDCN, these may regress upontherapy for the underlying myeloid neoplasm. Differentiation between the 2 neoplasms can be con 󿬁 rmed immunophenotypically by PDC markers, and Ki-67;  “  benign tumor   –  forming ”  PDCs havea comparatively lower proliferative index. 4 A phenotypic and functional link at molecular level betweenBPDCN cells and PDC subpopulation has been also reported. 25,54 Acomparison of gene expression pro 󿬁 le between BPDCN and cutane-ous myelomonocytic leukemia also revealed higher expression of various PDC-related genes in BPDCN than in the leukemia cutis. 30 Clinical Presentation and Association WithMyeloid Disorders We performed a reference search including 181 cases from 39reports since 1998 and con 󿬁 rmed the clinical  󿬁 ndings reported byothers (Table 1). In this list, all reports designated as 43 cases of  blastic or blastoid NK-cell lymphomas (BNKCL), 5  –  21 86 casesof CD4+/CD56+ hematodermic neoplasms, 22  –  38 and 52 cases of BPDCNs 55  –  59 were included. The authors are well aware that a com- prehensive review of historical cases is problematic because theformer category of BNKCL could also include examples of lympho- blastic leukemias/lymphomas or primitive hematopoietic malignan-cies of uncertain lineage, which may biologically behave differently.This is probably the reason why some differences between entities of BNKCL and others are noted in Table 1 and 2. All these previouslyreported BNKCL might warrant reclassi 󿬁 cation based on more spe-ci 󿬁 c PDC markers that were not previously available for testing.In analyzing the reported cases, this neoplasm primarilyaffects elderly adults ( . 60 years old, 64%), although 17 patients(3%) were 10 years younger at diagnosis. The male/female ratiowas 3.8:1. Over half of cases show skin-limited lesion at the initial presentation.The follow-up period ranged from 3 weeks to 98 months in152 cases. Most patients received combined chemotherapy or combination chemotherapy and radiotherapy. Systemic relapses TABLE 1.  Summary of Literature-Based Clinical Features BNKCN CD4+/CD56+ HN BPDCN  No. of cases 43 (17) 5  –  21 86 (17) 22  –  38 52 (5) 55  –  59 M:F ratio 4.4:1 2.3:1 4.7:1Age (%) , 10 2/43 (4) 6/86 (20) 1/52 (1)10  –  30 7/43 (16) 4/86 (4) 030  –  60 13/43 (30) 18/86 (20) 10/52 (19) . 60 21/43 (48) 58/86 (67) 41/52 (78)Staging (%)Skin only 9/36 (25) 43/75 (57) 29/43 (67)Skin + others 27/36 (75) 32/75 (42) 14/43 (32)Skin involvement (%)Multiple 35/37 (94) 39/63 (61) 24/35 (68)Single 2/37 (5) 24/63 (38) 11/35 (31)Relapse (%)Skin 4/15 (26) 7/33 (21) 0Systemic 11/15 (73) 26/33 (78) 1/1 (100)Follow-up (%)Alive 11/37 (29) 24/86 (27) 16/29 (55)Dead 26/37 (70) 62/86 (72) 13/29 (44) BNKCN, blastic NK-cell neoplasm; CD4+/CD56+ HN, CD4+CD56 + hematoder-mic neoplasm; BPDCN, blastic plasmacytoid dendritic cell neoplasm. Gera et al   Am J Dermatopathol     Volume 36, Number 3, March 2014 248  |    2013 Lippincott Williams & Wilkins
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