Abstract
Case Presentation
An 88-year-old gentleman with no significant past and family history, presented with an erythematous indurated plaque-like lesion on the right leg since 3 to 4 months along with few lesions on the abdomen and chest. He had no itching sensation in the region.
On examination, indurated erythematous plaques were noted. There was no ulceration of the skin. All laboratory investigations done were within normal limits. He was treated with topical steroids but it yielded no response.
Subsequently, he underwent a skin biopsy from the lesional area. Grossly, skin biopsy measured 0.5 x 0.5 x 0.2 cm.
On microscopic examination, skin biopsy showed thinned out atrophic epidermis with a well-defined Grenz zone in the papillary dermis (Figure 1A).
Skin biopsy showing (A) thinned out atrophic epidermis with a well-defined Grenz zone in the papillary dermis. (B) There was pandermal infiltrate of diffuse sheets of neoplastic round cells intermediate in size. The cells had pleomorphic convoluted nuclei with coarse chromatin and inconspicuous nucleoli (Figure 1C). Mitosis was brisk (inset). (D) Dense dermal sclerosis was noted.
There was pandermal infiltrate of diffuse sheets of neoplastic round cells intermediate in size (Figure 1B) along with dense dermal sclerosis (Figure 1D). The cells had pleomorphic convoluted nuclei with coarse chromatin and inconspicuous nucleoli (Figure 1C). Mitosis was brisk (inset). The follicular units are also surrounded and focally infiltrated by the neoplastic cells. Epidermotropism was absent.
Q) Based on the Above Clinical and Histomorphological Findings, What Are Your Differential Diagnoses?
The following differentia diagnoses were considered: Primary cutaneous T cell lymphoma (PCTL) Diffuse large B cell lymphoma (DLBCL) leg type Myeloid sarcoma Metastatic melanoma Plasmacytoma Merkel cell carcinoma Metastatic disease with an unknown primary
Q) In Order to Proceed With the Diagnosis, What Are the Investigations You Will Order?
In the initial panel of immunohistochemistry, the neoplastic cells expressed Bcl2 (Figure 2A), Bcl6 (Figure 2B), LCA (Figure 2C), and were negative for CK (Figure 2D), CD20 (Figure 2E), CD3 (Figure 2F), CD10, cMyc, MUM1.
The neoplastic cells expressed Bcl2 (A), Bcl6 (B), LCA (C), and were negative for CK (D), CD20 (E), CD3 (F).
Based on these findings, the differentials of PCTL, DLBCL leg type, metastatic disease, Merkel cell carcinoma were ruled out.
Q) What Was the Next Panel of IHCs to Follow?
As both CD3 and CD20 were negative, a possibility of Myeloid sarcoma, CD20 negative lymphomas—like plasmablastic lymphoma, ALK+ DLBCL as well as CD3 negative lymphomas like anaplastic large cell lymphoma with downregulation of CD3 were considered.
An extensive panel of IHC markers was applied.
The neoplastic cells were positive for CD123 (Figure 3A), CD4 (Figure 3B), CD56 (Figure 3C), while being negative for CD79a (Figure 3D), TdT (Figure 3E), CD138 (Figure 3F) as well as PAX5, S100, ALK1. CD30, P16, and EBER by in situ hybridization were also negative.
The neoplastic cells were positive for CD123 (A), CD4 (B), CD56 (C), while being negative for CD79a (D), TdT (E), CD138(F).
Thus, plasmablastic lymphoma, ALK+ DLBCL, metastatic melanoma were ruled out.
Q) How Did You Proceed Further With the Diagnosis?
The above histomorphology and IHC findings along with the age of the patient and clinical presentation of plaque-like lesions behoved us to rule out the possibility of a dendritic cell neoplasm.
The next panel of IHC markers yielded the following results—the neoplastic cells were positive for CD43 (Figure 4A) and CD68 (Figure 4B) while being negative for MPO (Figure 4C), CD163 (Figure 4D), and CD117 (Figure 4E). KI67 index was 40% (Figure 4F).
The neoplastic cells were positive for CD43(A), CD68(B) while being negative for MPO (Figure 4C), CD163 (Figure 4D), and CD117 (Figure 4E). KI67 index was 40% (Figure 4F).
Q) What Is Your Diagnosis of This Skin Biopsy?
Thus, a final diagnosis of Blastic Plasmacytoid Dendritic Cell Neoplasm was offered.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a clinically aggressive tumor derived from the precursors of plasmacytoid dendritic cells (PDCs, also called professional type I interferon producing cells or plasmacytoid monocytes), with a high frequency of cutaneous and bone marrow involvement and leukemic dissemination. 1
Q) What Is the Etiopathogenesis and Epidemiology of This Disease?
Etiology of BPDCN is unknown, but its association with myelodysplastic syndrome (MDS) in some cases may suggest a related pathogenesis. There is no association with EBV. 1
The incidence of BPDCN in the general population is not defined. The prevalence of BPDCN is difficult to estimate because of the constantly changing nomenclature and lack of precise defining criteria prior to the 2008 WHO classification. 1 The few available data reported that its overall incidence is extremely low, accounting from 0.44% of all hematological malignancies to 0.7% of cutaneous lymphomas. 2
Q) What Is the Clinical Presentation of BPDCN?
The male-to-female ratio is 3.3:1. Most patients are elderly, with a mean age of diagnosis being 61 to 67 years. No racial or ethnic predilection is known. Most common site of involvement is the skin (involved in 64% to 100% of cases), followed by bone marrow and peripheral blood (in 60%–90%) and lymph node (in 40%–50%). Patients usually present with asymptomatic solitary or multiple lesions.
Three types of presentation are most commonly observed: isolated purplish nodule type (around two-thirds of cases), isolated bruise-like papule type (as was in our case) -Disseminated type with purplish nodules and/or papules and/or macules. It is the most characteristic clinical presentation. Isolated nodules are preferentially found on the head and lower limbs and can be >10 cm in diameter.
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Q) What Is the Prognosis?
Following initial response to chemotherapy, relapses invariably occur, involving skin and other sites, including soft tissue and the CNS.
In most cases, a fulminant leukemic phase ultimately develops.
About 10% to 20% of cases of BPDCN are associated with or develop into other myeloid neoplasms, most commonly chronic myelomonocytic leukemia, but also MDS or acute myeloid leukemia, Myeloid sarcoma, T cell lymphoblastic leukemia/lymphoma, NK/T cell lymphoma/leukemia, some mature T cell lymphoma/leukemias are the most frequent morphological mimickers of BPDCN and show some overlapping features.
Thus, it is a diagnosis of exclusion.
For the diagnosis of BPDCN, the tumor should be negative for myelomonocytic, NK, T, and B lineage markers (CD34, CD8, MPO, PAX5, CD20, CD79a, EBV, and T cell receptor protein). But the expression of CD33, CD2, CD3, CD7, S100, CD38, and CD10 may be observed in few cases. CD68 immunoreactivity is detected in most of the BPDCN cases which was similar to our case.
Several IHC markers (TCL-1, BDCA-2, CD2AP) are defined for the differentiation of BPDCN from its mimickers. TCL-1 is expressed in 90% of BPDCN and also seen in a broad variety of B cell lymphoproliferative disorders and some T cell disorders but absent in NK cell lineages. BDCA-2 is a specific marker of normal PDC and seen in a certain proportion of BPDCN.
Recently TCF4, transcriptional factor, has emerged as reliable marker.
Flow cytometry analysis, cytogenetics, and clonality studies may also help in the diagnosis and in the exclusion of mimickers. Literature reveals that the median survival is about 12 to 14 months. 3
Q) What Is the Management Protocol of This Disease?
There is no consensus on therapy. Several treatment regimens including therapies for nonHodgkin lymphoma, ALL and AML have been used as an alternative therapy. Multiagent chemotherapy regimens as in ALL are the most accepted application for these patients. The disease often goes with relapses after chemotherapy and it becomes resistant to the previous drugs. 3
Aggressive management including allogeneic bone marrow transplantation should be considered immediately, as it is currently the only option associated with long-term survival.
New drugs that target epigenetic changes, signaling pathways, or antigens expressed by tumor cells are showing promising results and may pave the way for prospective studies using targeted therapies for mostly elderly patients with a poor prognosis who are unable to receive intensive chemotherapy. 4
Conclusion
BPDCN is a rare disease with a poor prognosis, which is underdiagnosed and underreported. Flow cytometry has led to a better characterization of this pathology. Cytogenetics and molecular biology have enabled a better understanding of the pathophysiology of this disease.
Footnotes
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.