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Circulating plasma cells in peripheral blood (cases 1, 2 and 3).
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... cell leukemia (PCL) is defined by an absolute plasma cells (PC) number greater than 2 6 10 9 L 7 1 or a relative number greater than 20% of peripheral white blood cells [1]. PCL represents less than 5% of malignant plasma cell disorders and the outcome of patients with PCL is extremely poor with a median survival less than 1 year in most cases [2 – 4]. The IFM group reported in a series of 40 cases with PCL that 11 patients died within the first month of diagnosis, indicating that cytoreductive therapy is urgently required when the diagnosis is made [4]. Nevertheless, before initiating cytotoxic therapy, including alkylating agents and/or dexamethasone, one must eliminate the diagnosis of reactive plasmacytosis (RP). We here report three cases of RP observed in our department over a 3-year period (Table I). In each case, the number of circulating PC (Figure 1) was superior to 2 6 10 9 L 7 1 in the peripheral blood with anemia, hypergammaglobulinemia on electro- phoresis and the disease mimicked PCL. Careful evaluation revealed that hypergammaglobulinemia was polyclonal and flow cytometry showed that circulating PC was polyclonal and presented a ...
Similar publications
Primary Plasma cell leukaemia (pPCL) is a rare plasma cell (PC) malignancy. The strict criteria for the diagnosis is an absolute PC number greater 2 X 109/L or a plasmocytosis accounting for > 20% of the differential white cell count that does not arise from a pre-existing multiple myeloma. pPCL was associated with aggressive clinic-biological feat...
Primary Plasma cell leukaemia (pPCL) is a rare plasma cell (PC) malignancy. The strict criteria for the diagnosis is an absolute PC number greater 2 X 10(9)/L or a plasmocytosis accounting for > 20% of the differential white cell count that does not arise from a pre-existing multiple myeloma. pPCL was associated with aggressive clinic-biological fe...
Citations
... Marked peripheral blood polyclonal plasmacytosis mimicking PCL can occur in reactive conditions such as viral infections, autoimmune disease, serum sickness or even angioimmunoblastik T-cell lymphoma. In those conditions, plasma cells do not have kappa or lambda light chain restriction and typically disappear with appropriate treatment of the underlying condition[7, 8]. ...
Background
Primary plasma cell leukemia (pPCL) is a rare and highly aggressive plasma cell disorder. Extreme leukocytosis is an infrequent finding in pPCL.
Case presentation
We reported an 82-year-old female patient who presented with marked leukocytosis (61.900/µl) and was diagnosed with pPCL. Plasma cells were found to have t(14;20) and 1q21 amplification. Following partial response after two cycles of bortezomib/dexamethasone combination, central nervous system (CNS) relapse occurred. Due to the advanced age and frailty, no further therapy could be administered. She had a fulminant disease course and died within one month of the CNS involvement.
Conclusion
PCL should be included in the differential diagnosis of leukocytosis.
... An extreme plasma cell count in the peripheral blood of >2000/µl (>2x10 9 /L), or >20 percent of WBCs, characterizes plasma cell leukemia, a seldom occurrence [46]. Inflammatory (reactive) plasma cells are a frequent feature of many infectious and inflammatory ailments and can resemble plasma cell leukemia [47]. ...
... Although they confirmed the presence of variable PC counts in a minor fraction (17%) of myeloma patients, it has not progressed beyond being a prognostic factor (34). Furthermore, limited number of nucleated cells and morphological similarities between normal and clonal cells prevent this technology to be applicable to MRD assessment (35). ...
With the introduction of more effective novel therapies, the prognosis of multiple myeloma (MM) has improved significantly over the past decade, resulting with a significant proportion of patients achieving durable remissions that may reach even more than 10 years. Several studies demonstrated that the real prognostic value of complete remission (CR) relies on sustained undetectable minimal residual disease (MRD). Additionally, advances in MRD detection methods used for the detection of clonal plasma cells (cPC) inside or outside the bone marrow have also improved the value of MRD. The use of peripheral blood for MRD detection could be an effective method that overcomes the spatial heterogeneity and invasive intervention with recurrent bone marrow aspirations. During the last two decades, many groups have investigated the role of circulating plasma cells (CPCs) at diagnosis. As also presented by multiple groups during the recent ASH 2021 annual meeting, CPCs are becoming recognized as an independent prognostic factor. In addition, measurement of post-induction residual plasma cells in the stem cell graft is identified as another option for MRD assessment. Earlier studies in the era of less intensive induction regimens attempts to analyze the level of CPC contamination in the graft was shown to contribute to myeloma relapse and progression. According to these recent results, higher graft purity has been found to be in concordance with deeper responses. As expected, graft minimal residual disease (gMRD) may reflect the efficacy of induction as an additional response assessment tool. Although gMRD is a non-invasive approach, it has not gained sufficient support for routine use. In view of the hurdles related to monoclonal protein assessments, high-sensitivity cellular component measurement continues to possess its value as an end point for therapeutic efficacy. In this review, we will present a structural framework for MRD testing in peripheral blood stem cell autografts in MM and review the clinical integration into MM management.
... Conventional cytology is a simple and inexpensive technique that can be applied in any clinical laboratory and although it is not able to identify clonality of circulating plasma cells, the new definition can be considered as a starting point for further investigation. The incapacity to establish clonality is a limitation in the rare case of polyclonal circulating plasma cells in some patients with MM [34,35] and could be readily resolved with flow cytometry immunotyping [33]. ...
Primary plasma cell leukemia (PCL) has a consistently ominous prognosis, even after progress in the last decades. PCL deserves a prompt identification to start the most effective treatment for this ultra-high-risk disease. The aim of this position paper is to revisit the diagnosis of PCL according to the presence of circulating plasma cells in patients otherwise meeting diagnostic criteria of multiple myeloma. We could identify two retrospective series where the question about what number of circulating plasma cells in peripheral blood should be used for defining PCL. The presence of ≥5% circulating plasma cells in patients with MM had a similar adverse prognostic impact as the previously defined PCL. Therefore, PCL should be defined by the presence of 5% or more circulating plasma cells in peripheral blood smears in patients otherwise diagnosed with symptomatic multiple myeloma.
... The passing criteria (before 1974) did not consider the investigation of PC clonality, as the first primitive electric cell sorting device was reported only up to 1965 [60]. It is important to distinguish the cause of reactive plasmacytosis by PC phenotype determination, as it can mimic PCL in patients with a variety of infections (such as Staphylococcal sepsis) or neoplastic conditions [61,62]. ...
Long non-coding RNAs (lncRNAs) are functional RNAs longer than 200 nucleotides. Due to modern genomic techniques, the involvement of lncRNAs in tumorigenesis has been revealed; however, information concerning lncRNA interplay in multiple myeloma (MM) and plasma cell leukemia (PCL) is virtually absent. Herein, we aimed to identify the lncRNAs involved in MM to PCL progression. We investigated representative datasets of MM and PCL patients using next-generation sequencing. In total, 13 deregulated lncRNAs (p < 0.00025) were identified; four of them were chosen for further validation in an independent set of MM and PCL patients by RT-qPCR. The obtained results proved the significant downregulation of lymphocyte antigen antisense RNA 1 (LY86-AS1) and VIM antisense RNA 1 (VIM-AS1) in PCL compared to MM. Importantly, these two lncRNAs could be involved in the progression of MM into PCL; thus, they could serve as promising novel biomarkers of MM progression.
... Another limitation of the current diagnostic definition of PCL is that it does not take into consideration plasma cell clonality, which can be characterized using multiparametric flow cytometry 6 . Establishing the presence of a malignant clonal population is important as reactive plasmacytosis can occur due to a variety of infections, neoplastic or inflammatory conditions [7][8][9][10] . ...
Primary plasma cell leukemia (pPCL) is an aggressive plasma cell disorder with a guarded prognosis. The diagnosis is confirmed when peripheral blood plasma cells (PCs) exceed 20% of white blood cells or 2000/μL. Emerging data demonstrates that patients with lower levels of circulating (PCs) have the same adverse prognosis, challenging the clinical disease definition, but supporting the adverse impact of circulating PCs. The cornerstone of treatment consists of combination therapy incorporating a proteasome inhibitor, an immunomodulatory agent, steroids, and/or anthracyclines and alkylators as part of more-intensive chemotherapy, followed by consolidative autologous hematopoietic cell transplantation in eligible patients and then maintenance therapy. Monoclonal antibodies are also currently being evaluated in this setting with a strong rationale for their use based on their activity in multiple myeloma (MM). Due to limited therapeutic studies specifically evaluating pPCL, patients with pPCL should be considered for clinical trials. In contrast to MM, the outcomes of patients with pPCL have only modestly improved with novel therapies, and secondary PCL arising from MM in particular is associated with a dismal outlook. Newer drug combinations, immunotherapy, and cellular therapy are under investigation, and these approaches hopefully will demonstrate efficacy to improve the prognosis of pPCL.
... These counts already proved critical for the differential diagnosis between MM and PCL [18,110]. In addition, they confirmed the presence of variable PC counts in a minor fraction (17%) of all MM patients [30], which (frequently) cannot be accurately discriminated from normal/reactive plasmablasts [111] due to both the limited number of nucleated cells evaluated (i.e., <500 cells) and their morphological similarities [112], particularly among patients that show low numbers of circulating PC. Because of these limitations and the clear clinical utility of CTPC detection and quantitation in blood, conventional immunocytochemistry-based approaches were subsequently adopted. ...
Cancer dissemination and distant metastasis most frequently require the release of tumor cells into the blood circulation, both in solid tumors and most hematological malignancies, including plasma cell neoplasms. However, detection of blood circulating tumor cells in solid tumors and some hematological malignancies, such as the majority of mature/peripheral B-cell lymphomas and monoclonal gammopathies, has long been a challenge due to their very low frequency. In recent years, the availability of highly-sensitive and standardized methods for the detection of circulating tumor plasma cells (CTPC) in monoclonal gammopathies, e.g., next-generation flow cytometry (NGF), demonstrated the systematic presence of CTPC in blood in virtually every smoldering (SMM) and symptomatic multiple myeloma (MM) patient studied at diagnosis, and in the majority of patients with newly-diagnosed monoclonal gammopathies of undetermined significance (MGUS). These methods set the basis for further detailed characterization of CTPC vs. their bone marrow counterpart in monoclonal gammopathies, to investigate their role in the biology of the disease, and to confirm their strong impact on patient outcome when measured both at diagnosis and after initiating therapy. Here, we review the currently available techniques for the detection of CTPC, and determine their biological features, physiopathological role and clinical significance in patients diagnosed with distinct diagnostic categories of plasma cell neoplasms.
... In the context of blood smear analysis some extra domain-specific challenges arise. The first challenge is that some blood cell subtypes are rare in occurrence, for example, the authors in [2], were able to collect only three samples of reactive plasmacytosis in three years. Hence, having a sufficient number of blood smears containing such rare types for training a deep network might take many years. ...
Peripheral Blood Smear (PBS) analysis is a vital routine test carried out by hematologists to assess some aspects of humans’ health status. PBS analysis is prone to human errors and utilizing computerbased analysis can greatly enhance this process in terms of accuracy and cost. Recent approaches in learning algorithms, such as deep learning, are data hungry, but due to the scarcity of labeled medical images, researchers had to find viable alternative solutions to increase the size of available datasets. Synthetic datasets provide a promising solution to data scarcity, however, the complexity of blood smears’ natural structure adds an extra layer of challenge to its synthesizing process. In this work, we propose a methodology that utilizes Locality Sensitive Hashing (LSH) to create a novel balanced dataset of 2500 synthetic blood smears. This dataset, which was automatically annotated during the generation phase, will be made public for research purposes and covers 17 essential categories of blood cells. We proved the effectiveness of the proposed dataset by utilizing it for training a deep neural network, this model got a very high accuracy score of 98.72% when tested with the well known ALL-IDB dataset. The dataset also got the approval of 5 experienced hematologists to meet the general standards of making thin blood smears .
... This is a limitation as large amounts of polyclonal cPCs can be observed in some patients with severe infections, mononucleosis and serum sickness. 18,19 Given these current drawbacks in the management of pPCL, MFC can easily overcome some of these aforementioned issues of lower sensitivity and lack of clonal assessment of cPCs by morphological assessment of a PB smear. This study demonstrates that the MFC cutoff of ≥200 cPCs/μL identifies most patients (77%) with ≥5% cPCs by morphological assessment of a PB smear. ...
The diagnosis of primary plasma cell leukemia (pPCL) has been made by quantifying circulating plasma cells (cPCs) morphologically on a peripheral blood (PB) smear. However, this technique is not sufficiently sensitive. Multiparametric flow cytometry (MFC) provides a readily available and highly sensitive method to identify and quantify cPCs that could complement PB smear assessment. However, an optimal quantitative cutoff for cPCs by MFC to identify pPCL has not been established. Thus, a total of 591 patients newly diagnosed multiple myeloma (NDMM) patients who had their PB samples evaluated morphologically by PB smear, and immunophenotypically by MFC prior to beginning therapy were evaluated. The presence of ≥200 cPCs/μL by MFC (N = 25 or 5% of the total population) was chosen to identify patients with ≥5% cPCs by PB smear with a specificity of 99% and a sensitivity of 77%. For patients with ≥200 cPCs/μL by MFC compared to the remainder of the cohort, the median Time to next therapy (TTNT) was 18 vs 30 months and the median OS was 38 vs 70 months respectively. Thus, MFC assessment of PB can be utilized in conjunction with the morphological assessment of a PB smear to aid in improving the identification of pPCL among NDMM patients.
... Some studies use only one of the original two requirements to define PCL, and several recent studies question whether a lower threshold of total plasma cells might better risk classify a subgroup of MM patients. Moreover, advances in flow cytometry allow better characterization and clonality assessment of plasma cell populations [1,[11][12][13][14][15][16]. The morphology and immunophenotype of the malignant PCs in PCL, MM, and sPCL are not distinguishable. ...
... Cell sorting, flow cytometry, and immunohistochemistry were in their absolute nascence with the first primitive electric cell sorting device being reported in 1965 [18]. Yet, we know that high amounts of circulating plasma cells are not limited to PCL, but are also observed in severe infections, mononucleosis, and serum sickness [14,15]. Furthermore, there have been case reports of benign polyclonal plasmacytosis in other diseases, such as renal amyloidosis [16]. ...
Purpose of Review
We discuss current topics on the definition of plasma cell leukemia and the distinction between plasma cell leukemia and multiple myeloma. Moreover, we review the latest literature on how to treat plasma cell leukemia.
Recent Findings
Plasma cell leukemia is clinically and genetically distinct from multiple myeloma. Plasma cell leukemia is defined by the observation in blood of more than 20% clonal plasma cells by differential count of the leucocytes or by counting more than 2 × 10⁹ per liter circulating clonal plasma cells. However, patients with lower levels of circulating plasma cells have the same adverse prognosis, which challenges the disease definition. Survival has improved after implementation of high-dose chemotherapy with stem-cell support, bortezomib, and lenalidomide in the treatment; yet, the prognosis remains poor. The results of allo-transplants have been disappointing.
Summary
The diagnostic criteria of PCL are currently discussed in the international myeloma community. Despite some improvement in survival, the prognosis remains adverse. New, more targeted treatment modalities, including immunotherapies, will hopefully improve the outcome in the near future.
