Background

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy that originates from type I interferon-producing cells of the immune system known as plasmacytoid dendritic cells (pDCs) (Khoury 2018). It accounts for less than 1% of all hematologic malignancies, with an estimated incidence of 0.04 cases per 100,000 individuals (Orazi et al. 2013). The disease typically affects individuals between 60–70 years, with a male-to-female ratio of 3:1 (Orazi et al. 2013; Chaperot 2001).

The clinical presentation is variable, but skin tumors with or without features of leukemia are the most common manifestation, affecting 80–90% of cases. Other commonly affected sites with these abnormal cells include lymph nodes, spleen, central nervous system, and bone marrow (Pagano et al. 2013). Skin lesions usually appear as dark purple, nodular growths that rapidly progress to large tumors without specific distribution (Guru Murthy et al. 2018). In the past, due to the lack of definitive diagnostic criteria, it was often misdiagnosed as cutaneous T-cell lymphoma, leukemia cutis, melanoma, or lupus erythematosus. However, a set of widely accepted criteria have been developed to define it (Sapienza et al. 2019; Julia et al. 2013), including blast cells expressing CD4+ and/or CD56+ in lymph node or bone marrow biopsy, at least one positive plasmacytoid dendritic cell marker (e.g., TCL, CD123, BDCA2, CD303/CD2AP, TCF4), and absence of other lineage-specific markers.

Standard treatment regimens and randomized controlled trials for BPDCN are currently lacking. Both high and low intensity chemotherapy regimens approved for lymphoma, and leukemia have been used to treat, including CHOP for lymphoma, Hyper-CVAD alternating with methotrexate and cytarabine for acute lymphoblastic leukemia, 7 + 3, FLAG-IDA and MICE for acute myeloid leukemia (Pagano et al. 2013). Even though, high intensity regimens used for lymphoblastic leukemia are considered more intense, and have shown marginally better outcomes when compared to myeloid leukemia regimens. Venetoclax, a BCL-2 inhibitor, has been used in combination with high intensity regimens to manage (Agha et al. 2018; Pemmaraju et al. 2015), but it has never been used as substitute to other drugs in regimen. As of today, there is no clear guideline on how to manage BPDCN. However, in 2018, the FDA approved tagraxofusp-erzs (SL-401; ELZONRIS™), a targeted therapy that is specifically designed to target the CD123 receptor on BPDCN cells. Tagraxofusp-erzs has been shown to be effective in treating BPDCN, and it is currently the only FDA-approved treatment for the disease (Pemmaraju et al. 2019). Hematopoietic stem cell transplant when in remission has also been shown to improve progression-free survival (Aoki et al. 2015).

Case presentation

A 49-years-old Arab man presented to our institution in January 2022 with a more than one-year history of gradually worsening widespread, painless multiple skin lesions. The patient had previously undergone a biopsy of the left facial lesion elsewhere in May 2021, which was reported as marginal zone lymphoma (MZL). The immunohistochemistry (IHC) results at that time: neoplastic cells were CD79a, CD19, and PAX5 positive B-cells, with strong BCL-2 expression (anti-apoptosis marker), weakly positive for MUM1 (non-specific), and negative for TdT, BCL6, and CD34 (stem cell marker). The PET scan at that time revealed extensive widespread FDG-avid cutaneous/subcutaneous lesions throughout the body, lymphadenopathy of the nasopharynx, chest, and abdomen, left testicle, and bone marrow. Based on these findings, the patient was diagnosed with stage IV MZL and received 2 cycles of bendamustine and rituximab regimen. Subsequent PET scan revealed an excellent partial response (Deauville score 3). However, after two more cycles, the disease relapsed with new lesions and B symptoms. Excisional lymph node biopsy done at this stage showed diffuse expression of T-cell markers (CD3, CD4, and CD43), and lack of all other B-cell markers (CD19, CD20, CD21), stem cell antigens (CD34), and myeloid markers (myeloperoxidase, CD33) with negative EBER (EBV encoded RNA). The results for T-cell and B-cell gene rearrangement studies were negative Therefore, non-specific T-cell lymphoma was considered, and CHOP (cyclophosphamide, adriamycin, vincristine, prednisolone) chemotherapy was initiated. However, the disease remained refractory, so the patient was referred to our center. Past medical history included diabetes, peripheral neuropathy, hypertension, and depression.

At our center, initial physical examination revealed a large seven-centimeter disfiguring tumor on the left side of face (Fig. 1A) and multiple, asymmetric, non-tender, erythematous palpable macules, and deep brown to black nodules (Fig. 1B). Furthermore, diffuse painless, firm, discrete lymphadenopathy, and signs of grade 2 peripheral neuropathy were noted. Other system exams did not reveal any abnormality.

Fig. 1
figure 1

Blastic plasmacytoid dendritic cell neoplasm. A Large facial brownish mass with necrotic patches on the skin. B Forearm brownish palpable macules with necrotic patch (arrow)

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A comprehensive evaluation was performed. Peripheral blood showed normocytic anemia (Hemoglobin 92 g/L; MCV 94.6 fL) with a normal platelet count (205 × 109/L), and mild neutropenia (1.34 × 109/L). Bone marrow examination revealed plasmacytoid dendritic cells with unique finding of signet ring cell morphology (Fig. 2). Concurrent lymph node examination, including IHC using multiple lineage markers, showed neoplastic blastoid cells that were CD123/CD303-positive, co-expressing CD4, TCL1A, strong aberrant expression of CD56 (Fig. 3), and negative for the remaining markers evaluated. T-cell lymphoma was ruled out based on negative CD3, CD5, CD7, and CD8. A B-cell lymphoma was excluded based on negative CD19 and CD20, Hodgkin lymphoma based on negative CD30, stem cell disease [CD34], and myeloid malignancy based on negative CD64, CD68, CD117, and MPO. The PET scan revealed increased abnormal FDG uptake on the left side of the face, skin, and cervical plus inguinal lymph node. Karyotype and FISH panels showed no chromosomal aberrations. New generation sequencing (NGS) revealed a KRAS p.G12D mutation.

Fig. 2
figure 2

Blastic plasmacytoid dendritic cell neoplasm. Cells frequently show previously undescribed signet ring cell morphology (arrow). Bone marrow aspirate, 600× magnification

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Fig. 3
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Blastic plasmacytoid dendritic cell neoplasm. A Extensive skin involvement by tumor 40× magnification; B Tumor cells in lymph node with brisk mitotic activity and a rare cell showing signet ring cell morphology (arrow, 400× magnification); C, D, E and F Tumor cells showing positive immunohistochemical staining for CD4, CD56, CD123 and TCL 1A respectively (lymph node, 400× magnification)

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Considering neuropathy and earlier treatment planned to provide the only FDA-approved drug, the anti-CD123 cytotoxin Tagraxofusp. Due to challenges in procurement of this drug and rapidly proliferating skin lesions we administered Hyper-CVAD (lymphoblastic leukemia regimen) regimen. We had to reduce vincristine dose by fifty percent during cycle one, part one due to severe pain, numbness and mild weakness related to pre-existing neuropathy. Intrathecal chemotherapy was administered for CNS involvement. Excellent clinical response was observed after part one of the first cycle. On the third day of cycle one, part two treatment, we noticed new lesions and an increase in size of earlier regressing skin tumors. We added venetoclax, a BCL-2 inhibitor, on the fourth day of cycle one part two and the patient received it for 2 weeks. CT scan showed a reduction in the size of face lesions, cervical, and inguinal lymph nodes. Unfortunately, pain, numbness and weakness related to neuropathy (Nerve conduction studies show severe polyradiculopathy) worsened so vincristine was completely removed from his protocol during the second cycle, part one and venetoclax continued. New skin lesions began to fade, and the existing ones regressed completely. Subsequent PET scan after cycle 2 confirmed a complete clinical and radiological response as seen in Fig. 4.

Fig. 4
figure 4

A, B Axial PET-CT increased tracer uptake left facial lesion (arrows) and complete resolution of same post treatment respectively. C, D coronal PET-CT, increased tracer uptake in cervical and inguinal lymph node (arrows) and complete resolution of same post-treatment

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The patient presented six weeks later with relapse and bone marrow transplant was deferred. We procured and initiated tagraxofusp but had to discontinue its use on the fourth day due to grade 3 liver toxicity (AST: 403IU/L, ALT: 153IU/L). Further management became difficult due to the rapid progression of skin lesions, liver toxicity, seizures, and cytopenias. Eventually, the patient succumbed in September 2022, seventeen months after the initial diagnosis of malignancy.

Discussion

This case report highlights a number of issues in the diagnosis and treatment of this cancer. Diagnosis can be challenging due to its rarity and the overlap of clinical and morphological features with other hematological malignancies involving skin. Clinical and morphological suspicion is crucial in directing the specialized cell marker studies required to confirm the diagnosis (CD123, BDCA2, CD303/CD2AP, TCF4) (Orazi et al. 2013). Additionally, the blastic pDCs were frequently of signet ring cell shape on the aspirate smears, a feature that is hitherto undescribed.

Treatment remains challenging, but high-intensity regimens such as Hyper-CVAD, which includes vincristine, are now being considered as the standard of care (Chaperot 2001; Pagano et al. 2013; Montero et al. 2017). However, the development of new-onset neuropathy or worsening of pre-existing neuropathy can significantly limit the use of these regimens. In this particular case, the patient’s vincristine dose had to be reduced by fifty percent during cycle one and completely omitted during cycle two due to the manifestation of significant neuropathy. As the disease relapsed during the latter part of cycle one treatment, we were faced with the need to select a drug that could sustain remission with minimal side effects. Venetoclax, a BCL-2 inhibitor, emerged as the most promising alternative due to its demonstrated favorable outcomes when combined with high-intensity regimens (Pemmaraju et al. 2015; Agha et al. 2018). In a similar context, venetoclax has been successfully used as a substitute for vinorelbine, a member of the same drug class as vincristine, in the management of diffuse large B-cell lymphoma (DLBCL), exhibiting excellent safety and favorable outcomes (Hatzl et al. 2021). Although no reported cases of BPDCN utilizing venetoclax as a substitute for vincristine exist to date, our patient demonstrated a maintained response for an additional six weeks before experiencing disease relapse during a treatment break while preparing for a stem cell transplant from a fully matched related donor.

We also attempted the use of tagraxofusp, a CD123-directed cytotoxin and the first FDA-approved treatment for BPDCN. However, its administration was limited due to rapid onset grade 3 hepatotoxicity, thrombocytopenia, and peripheral edema (Pemmaraju et al. 2019). Despite the challenges encountered in procuring the drug, the patient could only receive a partial dose. Nevertheless, the patient's survival for a duration of seventeen months slightly exceeds the reported overall survival in similar cases (Wang et al. 2018). Despite surviving better than reported cases, the patient experienced significant psychological distress due to skin lesions. The only time he felt blissful was during the 6 weeks he did not have any skin lesions. This was the only time in his entire 17-month journey that he felt relieved.

Conclusion

In conclusion, accurate diagnosis and modified treatments are crucial to address the challenges of BPDCN. Misdiagnoses underscore the need for heightened awareness and comprehensive evaluations. We suggest lowering the threshold for complete re-evaluation when immunohistochemical marker studies are ambiguous and minimal or no response to standard chemotherapy regimens is observed. Vincristine limitations due to neuropathy prompted the use of venetoclax as a substitute, showing promise. However, the patient's relapse highlights the aggressive nature of the disease, necessitating further research on BCL-2 inhibitors as replacements and bridging therapy to stem cell transplant. The lone indication, high side effect profile, and difficulty in procuring Tagraxofusp, the only FDA-approved drug for BPDCN, may limit its usage in real-world settings. More studies are needed to see the drug's true adaptability in real-world patients. Enhancing treatment options and outcomes for this rare neoplasm remains a vital goal.