Diagnosis of rare entity CD138 negative plasma cell multiple myeloma: the synergy between laboratory and clinician makes the difference.

Plasma cell multiple myeloma (MM) is a multiform clinical entity characterized by different laboratory hallmarks. This case shows a rare entity of plasma cell myeloma: the entire plasma cell population lack the CD138 expression. In this case, a careful analysis of laboratory finding, particular flow cytometry gating strategies and the use of other ancillary laboratory tests, guide the clinicians to correct diagnosis. The correct evaluation of pre-analytical phase and the correct gating strategy are the necessary conditions to produce robust and solid flow cytometric results. The diagnostic implications of CD138-negative plasma cell are strictly linked to stem cell-like clonogenic features, such as possible more aggressive clinical behaviour and increasing probability of chemotherapy resistance. At this time, clinical laboratory remains the main reference point to MM diagnosis.

Detection of clonal plasma cells in POEMS syndrome using multiparameter flow cytometry.

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein [M-protein], and skin changes) is a rare systemic disorder characterized by various symptoms caused by underlying plasma cell (PC) dyscrasia. Detection of monoclonal PCs is mandatory for the diagnosis of POEMS syndrome; however, the usefulness of EuroFlow-based next-generation flow cytometry (EuroFlow-NGF) in POEMS syndrome for detecting monoclonal PCs in bone marrow (BM) and the gating strategy suitable for flow cytometry study of POEMS syndrome remain unknown. We employed EuroFlow-NGF-based single-tube eight-color multiparameter flow cytometry (MM-flow) and established a new gating strategy (POEMS-flow) to detect the monoclonal PCs in POEMS syndrome, gating CD38 broadly from dim to bright and CD45 narrowly from negative to dim compared to MM-flow. MM-flow detected monoclonal PCs in 9/25 (36.0%) cases, including 2/2 immunofixation electrophoresis (IFE)-negative cases (100%). However, POEMS-flow detected monoclonal PCs in 18/25 cases (72.0%), including 2/2 IFE-negative cases (100%). POEMS-flow detected monoclonal PCs with immunophenotypes of CD19- in 17/18 (94.4%). In six cases where post-treatment samples were available, the size of the clones was significantly reduced after the treatment (P = 0.031). POEMS-flow can enhance the identification rate of monoclonal PCs in POEMS syndrome and become a valuable tool for the diagnosis of POEMS syndrome.

Enhancing diagnostic accuracy of multiple myeloma through ML-driven analysis of hematological slides: new dataset and identification model to support hematologists.

Multiple Myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of plasma cells within the bone marrow. Diagnosing MM presents considerable challenges, involving the identification of plasma cells in cytology examinations on hematological slides. At present, this is still a time-consuming manual task and has high labor costs. These challenges have adverse implications, which rely heavily on medical professionals' expertise and experience. To tackle these challenges, we present an investigation using Artificial Intelligence, specifically a Machine Learning analysis of hematological slides with a Deep Neural Network (DNN), to support specialists during the process of diagnosing MM. In this sense, the contribution of this study is twofold: in addition to the trained model to diagnose MM, we also make available to the community a fully-curated hematological slide dataset with thousands of images of plasma cells. Taken together, the setup we established here is a framework that researchers and hospitals with limited resources can promptly use. Our contributions provide practical results that have been directly applied in the public health system in Brazil. Given the open-source nature of the project, we anticipate it will be used and extended to diagnose other malignancies.

Case of IgG4-related Disease with Crescentic Glomerulonephritis: An Unusual Presentation of the Disease.

IgG4-related disease (IgG4-RD) is a chronic systemic inflammatory  disease, characterized by tissue infiltration of lymphocytes and  IgG4-secreting plasma cells, presenting by fibrosis of different  tissues, which is usually responsive only to oral steroids therapy.  Kidneys are the most commonly involved organs, exhibiting renal  insufficiency, tubulointerstitial nephritis, and glomerulonephritis.  Here, we describe a patient with acute renal insufficiency who  was presented with edema, weakness, anemia and multiple  lymphadenopathies. Kidney and lymph node biopsy showed  crescentic glomerulonephritis in kidneys and lymphoplasmacytic  infiltration in lymph nodes. After a course of treatment with an  intravenous pulse of corticosteroid and cyclophosphamide, the  patient's symptoms subsided, and kidney function improved. DOI: 10.52547/ijkd.7788.

Secondary plasma cell leukaemia (PCL) with plasmablastic morphology.

A 71-year-old female with relapsed IgA lambda myeloma developed progressive cytopenia. The peripheral blood film showed 5% blastoid cells. Flow cytometry analysis was indicative of plasma cells. The bone marrow smear was packed with plasmablasts. Target CD138-cell FISH and molecular karyotyping identified a complex genome. NGS identified high-risk mutations. Bone marrow histology confirmed myeloma with no evidence of acute leukaemia. The patient was diagnosed with plasmablastic progression of myeloma and secondary PCL. Secondary PCL patients have a poor prognosis. It is essential to recognize this subtype and explore a novel treatment approach.

Lymphoplasmocytic plaque in children: A report of an atypical location.

Lymphoplasmocytic plaque in children (LPC) is a rare and distinctive skin disorder primarily affecting the pediatric population. Characterized by its unique histopathological features, the condition manifests as well-defined plaques with a predominance of lymphocytes and plasma cells infiltrating the dermis. Despite its limited prevalence, recognizing this entity is crucial for accurate diagnosis and appropriate management of affected patients. We report the case of a 10-year-old male presenting with LPC in the extensor surface of the upper arm, a rarely reported location, treated with both topical and intralesional corticosteroids resulting in partial improvement.

Colonic adenomatous polyp with florid presence of monoclonal lambda Russell bodies: Case report and etiopathogenic hypothesis.

Russell bodies (RBs) are round eosinophilic intracytoplasmic inclusions formed by condensed immunoglobulins in mature plasma cells, which are called Mott cells. These cells are rarely found in the gastric tract, with even less cases reported in the colorectal region. There are still many questions about this event, as it is still unknown the relationship between the agents reported of increasing the probability of appearance of these cells and the generation of RBs. In this case report we describe the fifth patient presenting an infiltration of Mott cells in a colorectal polyp, being the second case with a monoclonal origin without a neoplastic cause, and the first one monoclonal for lambda. A comparison with previously similar reported cases is also done, and a possible etiopathogenic hypothesis proposed.

Circulating plasma cells as a predictive biomarker in Multiple myeloma: an updated systematic review and meta-analysis.

BACKGROUND: Circulating plasma cells (CPCs) are defined by the presence of peripheral blood clonal plasma cells, which would contribute to the progression and dissemination of multiple myeloma (MM). An increasing number of studies have demonstrated the predictive potential of CPCs in the past few years. Therefore, there is a growing need for an updated meta-analysis to identify the specific relationship between CPCs and the prognosis of MM based on the current research status. METHODS: The PubMed, Embase, and Cochrane Library databases were screened to determine eligible studies from inception to November 5, 2023. Publications that reported the prognostic value of CPCs in MM patients were included. Hazard ratios (HRs) with 95% confidence intervals (CIs) of overall survival (OS) and progression-free survival (PFS) were extracted to pool the results. Subgroup analyses were performed based on region, sample size, cut-off value, detection time, initial treatment, and data type. The association between CPCs level and clinicopathological characteristics, including the International Staging System (ISS), Revised-ISS (R-ISS), and cytogenetic abnormalities were also evaluated. Statistical analyses were conducted using STATA 17.0 software. RESULTS: Twenty-two studies with a total of 5637 myeloma patients were enrolled in the current meta-analysis. The results indicated that myeloma patients with elevated CPCs were expected to have a poor OS (HR = 2.19, 95% CI: 1.81-2.66, p < 0.001) and PFS (HR = 2.45, 95% CI: 1.93-3.12, p < 0.001). Subgroup analyses did not alter the prognostic role of CPCs, regardless of region, sample size, cut-off value, detection time, initial treatment, or data type. Moreover, the increased CPCs were significantly related to advanced tumour stage (ISS III vs. ISS I-II: pooled OR = 2.89, 95% CI: 2.41-3.46, p < 0.001; R-ISS III vs. R-ISS I-II: pooled OR = 3.65, 95% CI: 2.43-5.50, p < 0.001) and high-risk cytogenetics (high-risk vs. standard-risk: OR = 2.22, 95% CI: 1.60-3.08, p < 0.001). CONCLUSION: Our meta-analysis confirmed that the increased number of CPCs had a negative impact on the PFS and OS of MM patients. Therefore, CPCs could be a promising prognostic biomarker that helps with risk stratification and disease monitoring.

There is a growing need for an updated meta-analysis to identify the specific relationship between CPCs and the prognosis of MM based on the current research status.Our meta-analysis revealed that a high CPCs level was significantly associated with worse OS and PFS in MM patients.CPCs could be a promising predictive biomarker that helps with risk stratification and disease monitoring.

Smoldering multiple myeloma: taking the narrow over the wide path?

ABSTRACT: Smoldering multiple myeloma (MM) is an asymptomatic clonal plasma cell condition considered as a premalignant entity that may evolve over time to symptomatic MM. Based on a "poorly defined" risk of progression, some well-intended investigators proposed prospective interventional trials for these individuals. We believe this may be a harmful intervention and favor a close "wait and watch" approach and rather enroll these patients in dedicated observational biological studies aiming to better identify patients who will evolve to MM, based on their plasma cells' biology, including genomics, epigenetics, and the immune microenvironment.

Different evasion strategies in multiple myeloma.

Multiple myeloma is the second most common malignant hematologic malignancy which evolved different strategies for immune escape from the host immune surveillance and drug resistance, including uncontrolled proliferation of malignant plasma cells in the bone marrow, genetic mutations, or deletion of tumor antigens to escape from special targets and so. Therefore, it is a big challenge to efficiently treat multiple myeloma patients. Despite recent applications of immunomodulatory drugs (IMiDS), protease inhibitors (PI), targeted monoclonal antibodies (mAb), and even hematopoietic stem cell transplantation (HSCT), it remains hardly curable. Summarizing the possible evasion strategies can help design specific drugs for multiple myeloma treatment. This review aims to provide an integrative overview of the intrinsic and extrinsic evasion mechanisms as well as recently discovered microbiota utilized by multiple myeloma for immune evasion and drug resistance, hopefully providing a theoretical basis for the rational design of specific immunotherapies or drug combinations to prevent the uncontrolled proliferation of MM, overcome drug resistance and improve patient survival.

Myelomatous pleural effusion in multiple myeloma- A rare presentation.

Multiple myeloma is a malignant plasma cell condition that mostly affects the skeletal system and bone marrow. Pleural effusions are uncommon and typically result from other conditions coexisting with multiple myeloma. Malignant myelomatous pleural effusions are rare complications of multiple myeloma, occurring in less than 1% of patients and are associated with poor prognosis having mean survival of less than 4 months. The present case report is a 41-year-old multiple myeloma patient who developed bilateral pleural effusion at a disease relapse. Chemotherapeutic regimen of cyclophosphamide, bortezomib, and dexamethasone given. Despite a positive response to treatment, the patient's condition worsened over the course of following month and he eventually passed away. Myelomatous pleural effusion indicates poor prognosis and early consideration helps in quick diagnosis and initiation of treatment which may help in improving prognosis.

Chronic sclerosing sialadenitis of the bilateral submandibular glands in childhood - a diagnostic dilemma.

Chronic sclerosing sialadenitis (CSS), currently included in the group of immunoglobulin G4 (IgG4)-related diseases, is an under-recognized inflammatory lesion that afflicts mostly the submandibular gland of 40-60 years adults. To our knowledge, only one case of CSS located in the submandibular gland has been reported in childhood to date. We present a case of CSS in a 5-year-old male child. He presented with bilateral submandibular swellings that clinically resembled discrete lumps, suspected to be tumors. The completely resected tumors composed predominantly of dense lymphoplasmacytic inflammatory infiltrate rich in IgG4-positive cells [77-90 IgG(+) cells per high-power field; IgG4(+)∕IgG(+) cells ratio of 42.77%]. We discuss the peculiarities of this case, and we also review the literature on CSS.

Increased frequency of oral plasma cell mucositis/plasma cell gingivitis after the COVID-19 pandemic: a 23-year retrospective analysis and review of diagnostic challenges relating to this condition.

OBJECTIVE: Oral plasma cell mucositis (PCM) or localized plasma cell gingivitis (PCG) is an idiopathic inflammatory condition often associated with hypersensitivity reactions. This study aimed to evaluate the frequency and features of PCM/PCG in a large biopsy service over a time period of more than 20 years. STUDY DESIGN: The biopsy archives at University of Florida College of Dentistry were searched from 2000 through the first quarter of 2023 for cases of oral PCM or PCG. Case data were aggregated and analyzed. RESULTS: A total of 107 cases were included. Between 2000 and 2019, PCM/PCG was diagnosed in 0.03% of all biopsy cases. Starting in 2020 through 2023, the percentage of biopsies diagnosed as PCM/PCG increased threefold to 0.10% of all biopsy cases, and the mean patient age increased by 3 years. There were no statistically significant differences between cases diagnosed from 2000 to 2019 and those from 2020 to 2023 regarding age, sex, location, or histology. CONCLUSIONS: A significant increase in PCM/PCG was identified in this study at one institution coinciding with the start of the COVID-19 pandemic. Further investigation is recommended to determine if this is a widespread phenomenon and identify possible etiologic mechanisms.

Diagnosis and management of smouldering myeloma: A British Society for Haematology Good Practice Paper.

Multiple myeloma is a bone marrow-based plasma cell tumour that develops from asymptomatic pre-cursor conditions smouldering myeloma and monoclonal gammopathy of uncertain significance and all are characterised by the presence of a monoclonal protein in the blood. Diagnosis and distinction between these conditions is based on blood tests, the bone marrow biopsy and cross sectional imaging. There are various risk stratification models that group patients with smouldering myeloma into risk groups based on risk of progression to symptomatic disease. Management is mainly observational for patients with smouldering myeloma although clinical trials for high-risk disease may be available. Restaging is required if evidence for progression.

Idiopathic multicentric Castleman disease (iMCD)-idiopathic plasmacytic lymphadenopathy: A distinct subtype of iMCD-not otherwise specified with different clinical features and better survival.

Idiopathic multicentric Castleman disease (iMCD) is subclassified into iMCD-thrombocytopenia, anasarca, reticulin fibrosis, renal dysfunction, organomegaly (TAFRO) and iMCD-not otherwise specified (NOS) according to the Castleman Disease Collaborative Network (CDCN) consensus criteria. With a deeper understanding of iMCD, a group of patients with iMCD-NOS characterised by polyclonal hypergammaglobulinaemia, plasmacytic/mixed-type lymph node histopathology and thrombocytosis has attracted attention. This group of patients has been previously described as having idiopathic plasmacytic lymphadenopathy (IPL). Whether these patients should be excluded from the current classification system lacks sufficient evidence. This retrospective analysis of 228 patients with iMCD-NOS identified 103 (45.2%) patients with iMCD-IPL. The clinical features and outcomes of patients with iMCD-IPL and iMCD-NOS without IPL were compared. Patients with iMCD-IPL showed a significantly higher inflammatory state but longer overall survival. No significant difference in overall survival was observed between severe and non-severe patients in the iMCD-IPL group according to the CDCN severity classification. Compared with lymphoma-like treatments, multiple myeloma-like and IL-6-blocking treatment approaches in the iMCD-IPL group resulted in significantly higher response rates and longer time to the next treatment. These findings highlight the particularities of iMCD-IPL and suggest that it should be considered a new subtype of iMCD-NOS.

Plasmablastic lymphoma: current knowledge and future directions.

Plasmablastic lymphoma (PBL) is an aggressive non-Hodgkin lymphoma associated with HIV infection and immunodeficiency. However, PBL can also be seen immunocompetent individuals in recent studies. PBL was characterized by distinct clinical and pathological features, such as plasmablastic morphology and universal expression of plasma cell markers. The clinicopathologic features were different between HIV-negative and HIV-positive patients. Gene expression analysis identified the unique molecular feature in PBL, including frequent c-MYC rearrangement and downregulation of BCR signaling pathway. Despite the recent advances in the treatment of PBL, the prognosis of PBL patients remains dismal. The objectives of this review are to summarize the current knowledge on the epidemiology, molecular profiles, clinical and pathological features, differential diagnosis, treatment strategies, prognostic factors, and potential novel therapeutic approaches in PBL patients.

Imaging flow cytometric detection of del(17p) in bone marrow and circulating plasma cells in multiple myeloma.

BACKGROUND: Detection of del(17p) in myeloma is generally performed by fluorescence in situ hybridization (FISH) on a slide with analysis of up to 200 nuclei. The small cell sample analyzed makes this a low precision test. We report the utility of an automated FISH method, called "immuno-flowFISH", to detect plasma cells with adverse prognostic risk del(17p) in bone marrow and blood samples of patients with myeloma. METHODS: Bone marrow (n = 31) and blood (n = 19) samples from 35 patients with myeloma were analyzed using immuno-flowFISH. Plasma cells were identified by CD38/CD138-immunophenotypic gating and assessed for the 17p locus and centromere of chromosome 17. Cells were acquired on an AMNIS ImageStreamX MkII imaging flow cytometer using INSPIRE software. RESULTS: Chromosome 17 abnormalities were identified in CD38/CD138-positive cells in bone marrow (6/31) and blood (4/19) samples when the percent plasma cell burden ranged from 0.03% to 100% of cells. Abnormalities could be identified in 14.5%-100% of plasma cells. CONCLUSIONS: The "immuno-flowFISH" imaging flow cytometric method could detect del(17p) in plasma cells in both bone marrow and blood samples of myeloma patients. This method was also able to detect gains and losses of chromosome 17, which are also of prognostic significance. The lowest levels of 0.009% (bone marrow) and 0.001% (blood) for chromosome 17 abnormalities was below the detection limit of current FISH method. This method offers potential as a new means of identifying these prognostically important chromosomal defects, even when only rare cells are present and for serial disease monitoring.

Retrospective Case Series of Cocaine-Associated Plasma Cell Orificial Mucositis.

Importance: Plasma cell orificial mucositis (PCOM) associated with cocaine use is an emerging, rare condition that has become a concern in Spain in recent years. Limited knowledge exists regarding this novel condition. Objectives: To delineate the clinicopathologic characteristics of this emerging entity and establish a novel approach in the differential diagnosis of cocaine-associated lesions. Design, Setting, and Participants: A descriptive, retrospective, multicenter case series of 10 patients diagnosed with cocaine-associated PCOM was conducted in Spain from April 2020 to March 2023. Main Outcomes and Measures: Patient demographic, clinical, histopathologic, and treatment data were collected. Results: A total of 10 patients (6 [60%] male; median [range] age, 45.5 [36-66] years) presenting with exudative ulcerated plaques were identified for this study. The lesions had raised and erythematous edges over the nostril and a median (range) evolution time of 9 (2-24) months. Septal or palate perforations were observed in 4 (40%) of the patients. Biopsies revealed a dense inflammatory infiltrate of plasma cells in the dermis without atypia and with eosinophils. All patients reported recent cocaine use. Three urine tests detected cocaine but found no presence of amphetamines or opiates. Six patients improved with corticosteroid therapy. Up to 60% of patients were lost to follow-up. Conclusions and Relevance: This case series describes the clinicopathologic characteristics of PCOM, an emerging entity associated with cocaine use in Spain, and demonstrates a novel approach in the differential diagnosis of cocaine-associated lesions. To date, cocaine-associated skin lesions have been reported as neutrophilic dermatoses and vasculitis. The appearance of a plasma cell infiltrate changes what has been described in the medical literature so far. PCOM is a benign condition of unknown cause characterized by a proliferative polyclonal plasma cell infiltrate. A comprehensive differential diagnosis workup is required to reach this exclusionary diagnosis. Several irritants have been documented in cases of PCOM, and a hypersensitivity mechanism has been proposed. Since the initial report of cocaine-associated PCOM in Spain, its incidence has experienced a surge in the country. The cause of this phenomenon may be attributed to newly unidentified adulterants. The administration of corticosteroids and discontinuation of cocaine use are the sole treatments that have demonstrated efficacy. Clinicians should be vigilant regarding this emerging condition and conduct inquiries into cocaine use. Additional research is required to clarify the pathophysiology of this emerging condition.

Prognostic value of circulating plasma cells detected by flow cytometry in newly diagnosed multiple myeloma patients: a systematic review and meta-analysis.

OBJECTIVES: Multiple myeloma (MM) is a malignant plasma cell disorder. The most widely accepted staging system for MM is the revised International Staging System based on cytogenetic and clinical biomarkers. The circulating clonal plasma cells (CPCs) were reported to have potential prognostic impact on MM. Among various diagnostic approaches, multiparametric flow cytometry (FCM) offers heightened sensitivity, minimal invasiveness and reproducibility. We conducted a meta-analysis to evaluate the prognostic value of quantifying CPCs via FCM in newly diagnosed symptomatic MM (NDMM) patients. DESIGN: Systematic review and meta-analysis. DATA SOURCE: PubMed, Web of Science, Embase and references of included studies. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included observational studies that evaluated the prognostic value of CPCs detected by FCM in NDMM. DATA EXTRACTION AND SYNTHESIS: Data were screened and extracted independently by two investigators. The pooled results originated from random effects models. The primary endpoint was overall survival (OS). The secondary endpoint was progression-free survival (PFS). To evaluate the prognostic value of CPCs in NDMM, HRs and their 95% CI for both OS and PFS were derived using COX multivariable models. These values were then used to compute the pooled estimated effect. RESULTS: Our meta-analysis encompassed a total of 2704 NDMM patients from 11 studies up to 27 August 2022. The pooled HR for OS and PFS in CPC-positive (CPCs+) group and CPC-negative group were 1.95 (95% CI 1.24 to 3.07) and 2.07 (95% CI 1.79 to 2.39), respectively. The autologous stem cell transplantation (ASCT) failed to eliminate the adverse impact on OS and PFS. The heterogeneity may stem from the use of novel agents or traditional chemotherapy as initial treatment. CONCLUSION: This meta-analysis indicates CPCs+ had an adverse impact on the prognosis of NDMM patients in the total population, and the adverse impact could not be eliminated by ASCT. PROSPERO REGISTRATION NUMBER: CRD42021272381.

An interesting case of AL amyloidosis and MM: a complex scenario with cardiac involvement.

Our patient presented with complaints of progressive shortness of breath for 1 month. She was diagnosed with a case of infiltrative type of restrictive cardiomyopathy (RCM) based on echocardiography and cardiac MRI findings. Her fat pad biopsy was suggestive of AL type of amyloidosis (AL). She was diagnosed with a case of multiple myeloma (MM) based on bone marrow biopsy findings with 48% plasma cells and a skeletal survey with lytic bone lesions on the skull, thus meeting the Crab criteria. We want to highlight the complex nature of this case and the difficulties associated with making a diagnosis. This case report presents an excellent opportunity to touch on the interesting topics of RCM, amyloidosis and MM.