Classic and Immunoblastoid Variants of Blastic Plasmacytoid Dendritic Cell Neoplasm

Most blastic plasmacytoid dendritic cell neoplasms (BPDCNs) exhibit a lymphoblast or myeloblast-like morphology, but some cases display an immunoblast-like morphology.1–4 The presence of immunoblasts in reported cases suggests that BPDCN, like mantle cell lymphoma, may have classic and immunoblastoid variants. We present our experience with 2 cases of classic morphology and 2 cases of immunoblast morphology. Although this is a small case series, it underscores the challenges of accurately diagnosing BPDCN despite using multiple immunohistochemical panels. However, certain features can serve as helpful clues. The 4 patients were an 18-year-old girl (patient #1), a 26-year-old man (patient #2), a 59-year-old woman (patient #3), and a 39-year-old man (patient #4). Patient #1 complained of fatigue and dizziness for 1.5 years, had a slowly progressing asymptomatic skin rash over the trunk and arms, and recently presented with a fever for a month. She was found to have cytopenia and anemia. Her lactate dehydrogenase (LDH) was normal. Physical examination showed erythematous papules over the back, flanks, and upper limbs without lymphadenopathy or organomegaly. Patient #2 presented with multiple erythematous and purple papules and nodules over the trunk, face, neck, and arms for 4 months. He had a normal full blood count and LDH. Patient #3 complained of a headache for 5 weeks and presented with a large solitary scalp swelling on the forehead that had recently rapidly increased in size. She was found to have a normal full blood count and a raised LDH (833 U/L). Patient #4 complained of a slowly progressing asymptomatic skin rash over the trunk and arms for 3 months. The skin lesions increased in size, became mildly itchy, and clustered as papules and nodules particularly over the flanks (Fig. 1). He had a normal full blood count and raised LDH (2243 U/L).FIGURE 1.: A, Patient #1 reveals multiple erythematous papules and nodules over the trunk. B, One of the erythematous purple nodules in patient #2 is located on the submandibular neck area. C, Patient #3 exhibits a large fungating dark bruised mass over the forehead scalp area. D, Patient #4 shows multiple erythematous papules, plaques, and nodules on the flank area.Histopathologically, skin punch biopsies of patients #1 and #2 showed similar perivascular dermal infiltrates composed of uniform medium-sized cells with round nuclei, small nucleoli, and frequent mitotic figures (Fig. 2). Skin punch biopsies of patients #3 and #4 revealed extensive dermal infiltrates composed of large cells with ample cytoplasm, large vesicular nuclei, prominent central nucleoli, frequent mitotic figures, apoptotic bodies, and tingle body macrophages (Fig. 3). Initially, the lesion of patient #1 was histopathologically confused for myeloid sarcoma, the lesion of patient #2 for NK/T cell lymphoma, and the lesions of patients #3 and #4 with diffuse large B-cell lymphoma.FIGURE 2.: A, B, Skin punch biopsy (patient #1) shows a dense superficial and deep perivascular hematolymphoid dermal infiltrate composed of uniform medium-sized blastoid cells [Hematoxylin and eosin stain (H, E), original magnification ×200, ×600]. C, D, skin punch biopsy (patient #2) reveals that a dense superficial and deep perivascular and interstitial dermal infiltrate consists of similar cells to the lesion in patient #1 (H&E ×200, ×600).FIGURE 3.: A, B, Skin punch biopsy (patient #3) demonstrates diffuse solid sheets replacing the dermis. They are punctuated by starry sky appearance due to frequent apoptotic bodies and tingible body macrophages. The large cells have ample cytoplasm, large vesicular nuclei with prominent central nucleoli, and numerous mitotic figures (H&E ×200, ×600). C, D, Skin punch biopsy (patient #4) shows a solid infiltrate of the mid and deep dermis sparing the epidermis and hair follicles. The infiltrate is composed of large cells with ample cytoplasm, large round to oval vesicular nuclei with prominent central nucleoli, and frequent mitoses, dissecting through the dermal collagen fibers and sparing the sweat ducts (H&E ×100, ×600).The original immunohistochemistry panel used to confirm the initial histopathologic impression included LCA (CD45), CD20, CD3, CD56, myeloperoxidase (MPO), EBER, and Ki67. The tumor cells were positive for CD45, but negative for the other immunomarkers. The tumor cells demonstrated a high Ki67 proliferation index [75% (patient #1), 80% (patient #2), 90% (patient #3), 75% (patient #4)]. An extended panel including CD2, CD4, CD5, CD7, CD8, CD30, ALK, PAX5, CD19, CD79a, CD38, CD138, CD34, CD1a, TdT, CD56, lysozyme, granzyme-B, perforin, and CD117 was conducted to further characterize the hematolymphoid lesions. Plasmacytoid dendritic cell (pDC) immunomarkers were not included because BPDCN was not considered. CD4 and CD56 were expressed by the tumor cells (Fig. 4). CD7 was expressed in the lesions of patients #1 and 2. TdT was focally expressed in the tumor cells of patients #1 and 2, but was negative in the tumor cells of patients #3 and #4. The tumor cells were negative for the remaining immunomarkers.FIGURE 4.: The tumor cells from the lesion of the patients #1, 2, 3, and 4 showed a similar immunoprofile of diffuse and strong staining for LCA (CD45), CD43, CD4, CD56, CD123, TCL1, and bcl2. They expressed c-myc. Inset: The tumor cells show a high Ki67 proliferation index.The histopathologic clues to reconsider BPDCN in the differential diagnosis included an intact epidermis with a grenz zone, spared adnexa, a monotonous cell population without accompanying inflammatory cell infiltrates, rimming of individual adipocytes by tumor cells, and the absence of tumor necrosis and angioinvasion. Immunohistochemical clues included negative lineage-specific antigen markers and the coexpression of CD4 and CD56. The immunomarker panel was extended to include CD123 and TCL1. Other pDC immunomarkers, such as TCF4, CD303, and CD304, are not available in our laboratory. All lesions from the 4 patients expressed CD123 and TCL1 (Fig. 4). CD43, bcl2, and c-myc were added to the panel. The tumor cells expressed bcl2, CD43, and c-myc [≥70% of the tumor cells expressed c-myc in patients #1 and 2, and ≥90% in patients #3 and #4]. The final integrated diagnosis was BPDCN with classic morphology (patients #1 and 2) and with immunoblastic morphology (patients #3 and #4). BPDCN, previously known as CD4+ CD56+ hematodermic neoplasm to highlight its coexpression of CD4 and CD56, is a rare aggressive malignancy.5 It is now established to originate from pDCs.5 Classic BPDCN presents with variable dermal infiltrates composed of monomorphous medium-sized cells with small nuclei and inconspicuous nucleoli.5 Typically, it coexpresses CD4 and CD56 along with at least 1 pDC markers such as CD123, TCL1, TCF4, CD303, or CD304.6,7 It also commonly stains positive for CD45, CD43, bcl2, and TdT and may variably stain for CD2, CD5, CD7, CD10, CD38, CD68, bcl6, MUM1, CD79a, and CD117.5,7 The tumor cells lack specific lineage antigens. They do not stain for CD3, CD20, PAX5, CD19, CD14, CD16, CD34, lysozyme, MPO, granzyme-B, and perforin.5–7 Approximately 10%–30% of BPDCNs present with immunoblastic and pleomorphic cells, some displaying a starry sky appearance, and express c-myc.1–5 The case reported by Aran et al1 showed immunoblastoid cells. The absence of CD56 and TdT raised the possibility of mature plasmacytoid dendritic cell proliferation (MPDCP), but the presence of high mitoses, apoptotic bodies, and Ki67 favored BPDCN. However, the status of c-myc expression was not mentioned in their case. It would be interesting to compare the c-myc expression in their case with our cases and with the cases reported by Yu et al, Chang et al, and Kurt et al, all of which expressed c-myc.2–4 Two of our cases displayed classic morphology, whereas 2 cases exhibited large immunoblastic cells. All 4 cases had a similar immunoprofile. Like our case, the case by Chang et al also expressed CD56 and focally TdT. However, the cases reported by Yu et al and Kurt et al did not show CD56 and TdT expression. All immunoblastoid BPDCNs expressed CD4, but with varying CD56 and TdT expression.1–5 Similar to our cases, the patients with immunoblastoid variants in the authors' studies were elderly. Unfortunately, the authors did not provide information on the follow-up status of their patients, except for Chang et al.’s patient who died after 42 months despite treatment. In comparison, although all lesions in our series had a similar immunophenotype and bone marrow involvement during the disease course, the 2 young patients with classic morphology showed improvement with treatment, whereas the older patients with immunoblastoid morphology died within 3 months (patient #3) and 4 months (patient #4) despite treatment. Immunoblastoid variants may represent divergent subclones with poorer clinical outcome. Although BPDCN has a variable immunoprofile, a strong coexpression of CD4 and CD56 in cutaneous hematolymphoid neoplasms is a clue to consider it in the differential diagnosis.6,7 These cases emphasize that although BPDCN classically presents with monomorphic lymphoblast or myeloblast-like cells, the findings of large immunoblasts or pleomorphic cells should not divert pathologists from considering BPDCN in cutaneous hematolymphoid lesions. Adding at least 1 pDC marker to the immunohistochemical panel and, thereafter, adding CD123, bcl2, TdT, and c-myc are essential for patients' management. BPDCN can be easily missed because it is rare and has variable overlapping immunohistopathologic patterns. The most important differential diagnosis is acute myeloid leukemia. Patients with acute myeloid leukemia, particularly with monocytic and monoblastic differentiation, can coexpress CD4, CD56, and CD123.1,6 The expression of CD56 with some T-cell markers may suggest extranodal NK/T cell lymphoma.1 TdT staining may lead to confusion with lymphoblastic lymphoma. A new set of immunohistochemical criteria for the diagnosis of BPDCN was established. This included the expression of CD123 and 1 pDC marker such as TCF4, TCL1, CD303, or CD304, in addition to CD4 and/or CD56, and absent expression of T-cell, B-cell, NK, and myeloid lineage markers.6 The combination of expected positive and negative immunomarkers should confirm the diagnosis of BPDCN and rule out look-alike simulators.6 The negative CD56 and TdT may raise the possibility of MPDCP associated with a myeloid neoplasm.1,6 Patients with acute myeloid leukemia or other myeloproliferative disorders may harbor tumoral accumulation of clonally expanded pDCs.6 The presence of separate aggregates of cells that are demarcated from the leukemic cells by their low-grade morphology and low Ki67 (<10%) helps distinguish MPDCP from BPDCN.1,6 In conclusion, specific histopathologic features and immunohistochemical profiles are helpful clues to consider BPDCN as one of the differential diagnoses in cutaneous hematolymphoid lesions, even in cases with immunoblastoid or pleomorphic morphology. It remains to be determined whether immunoblastoid morphology, along with c-myc expression, and variable CD56 and TdT expression indicate a variant of BPDCN with distinct clinical behavior and therapeutic implications.