Posttransplant MNs have a latency period between that seen in AML/MDS related to alkylators and that associated with topoisomerase II inhibitors. The cytogenetic profile suggests a mutagenic effect on leukemogenesis. The clinical outcome for AML/MDS is dismal, with death occurring at an early phase of treatment.
Objectives To improve diagnostic accuracy in differentiating hematogones from leukemic blasts in cases of precursor B-lymphoblastic leukemia/lymphoma (B-ALL), particularly those that are posttreatment or after bone marrow transplant, and to provide an algorithmic approach to this diagnostic challenge. Methods A seven-color antibody panel including CD10, CD19, CD45, CD38, CD34, CD58, and CD81 was generated to assess the feasibility of a single tube panel and provide an algorithmic approach to distinguish hematogones from B-ALL. Fifty-three cases were analyzed, and results were correlated with histology and ancillary studies. Results There was a significant difference in mean fluorescent intensity (MFI) for CD81 and CD58 when comparing hematogones and B-ALL populations (P < .001). B-ALL cases had a mean (SD) MFI of 24.6 (27.5; range, 2-125) for CD81 and 135.6 (72.6; range, 48-328) for CD58. Hematogones cases had a mean (SD) MFI of 70.2 (19.2; range, 42-123) for CD81 and 38.8 (9.4; range, 23-58) for CD58. Conclusions The flow cytometry panel with the above markers and utilization of the proposed algorithmic approach provide differentiation of hematogones from B-ALL. This includes rare cases of hematogones and B-ALL overlap where additional ancillary studies are necessary.
Introduction: Idiopathic multicentric Castleman disease (iMCD) is a heterogenous group of lymphoproliferative disorders believed to be driven by IL-6 with the cell(s) of origin not yet identified (Fajgenbaum et al. 2019). One clinical subtype with thrombocytopenia, anasarca, fever, renal dysfunction, and organomegaly (TAFRO) is especially aggressive. We encountered a case of TAFRO syndrome that prompted a systematic literature review focusing on the role of VEGF in the pathogenesis of TAFRO syndrome. Interim findings support a role of VEGF in the etiopathogenesis of TAFRO syndrome, with fibroblastic reticular cells (FRCs) as the pathological cell. Methodology: We started with a focused review (step 1, Table 1), followed by empirical review (step 2, Table 1) of published articles on TAFRO syndrome, using methods of qualitative review (Campbell et al. 2011, Levitt 2018) and discussed interim results from phase 1 review (Table 2). The process of reciprocally translating the findings from each study into those from all the other studies in the synthesis, if applied rigorously, provides a method for combining qualitative data in a structured manner. Interim Results: During phase 1 step 1, we reviewed 97 articles published between 2012 and 2020. Majority were case reports. The interim data comprised a total of 34 male and 32 female patients with age ranging from 3 to 85 (median age of 50.5). 26 patients were identified as severe disease and 25 were non-severe per iMCD diagnostic criteria. At the time of presentation, VEGF levels ranged from 44-7520 pg/ml (median 360), IL-6 ranged from 5-4800 pg/ml (median 39.3), and sIL-2Rα ranged from 448-8944 (median 1250). Histologically, hyaline vascular subtype was most common as seen in 24 lymph nodes compared to 4 plasmacytic and 14 mixed. Most common bone marrow cellularity was hypercellular in 19 cases, compared to 16 normocellular, and 4 hypocellular (Table 2). During phase 1 step 2, we explored the fundamental relationship between IL-6 and VEGF. In the lymph node, IL-6 is secreted from endothelial cells and FRCs. IL-6 is further augmented due to stimulation of bone marrow stromal cells by VEGF secreted from FRCs (Tanaka, Narazaki, and Kishimoto 2014). FRCs are the principal cells facilitating entry of dendritic cells and present a cognate antigen by mediating interaction between dendritic cells and T-cells (Fletcher, Acton, and Knoblich 2015, Brown and Turley 2015). Persistent antigenic stimulation leads to the release of VEGF by FRCs in the lymph node and its potentiation through release of IL-6 through VEGF-mediated stimulation of bone marrow stromal cells (Novotny et al. 2008). This reciprocal stimulation between lymph nodes and bone marrow mediate growth effects driven by VEGF, while autocrine-paracrine stimulation of VEGF and IL-6 within lymph nodes and bone marrow drives IL-6 induced flares. Discussion: IL-6 is considered a main driver of pathogenesis underlying TAFRO syndrome, but in the only randomized controlled trial of IL-6 blockade in iMCD, 66% patients did not respond to therapy. IL-6 blockade targets PI3K/Akt/mTOR signaling, an underlying pathway for the pathogenesis of TAFRO syndrome. Our empirical review of literature into TAFRO syndrome reveals elevated VEGF and CD8+ T cells as the hallmarks of TAFRO flares. FRCs are the principal VEGF mRNA-expressing cells in lymph nodes and also contribute to IL-6 production. Bone marrow stromal cells are the principal cells that drive IL-6 release due to potent stimulation from VEGF. This intertwined loop of IL-6 and VEGF becomes a vicious cycle due to chronic antigenic persistence from infections to inflammations. The data from Phase 1 review provide evidence to explain the clinical and pathologic findings in TAFRO syndrome. Atretic germinal centers, characteristic of MCD, result from the mass recruitment of centroblasts and their differentiation into plasmablasts due to chronic VEGF stimulation. IL-6 promotes differentiation of plasmablasts into plasma cells as well as maintaining their survival. We hypothesize that hyperplastic germinal centers and plasmacytosis of plasmacytic lymph node reflect predominant pathologic features during early stages of pathogenesis, while regressed germinal centers and prominent FDCs due to hyalinization of the hypervascular lymph node represent advanced pathologic features. Our findings could potentially be translated into distinguishing clinical stages of MCD. Disclosures No relevant conflicts of interest to declare.
Objective Granulomatous mastitis (GM) is a benign breast disease that can have an extended clinical course impacting quality of life and causing breast disfigurement. Granulomatous mastitis has been studied throughout the world; however, less is known about GM patients in the United States. We aim to identify demographic and socioeconomic factors associated with GM in the United States. Methods An IRB-approved retrospective case-control study was performed of 92 patients with biopsy-proven GM at two institutions in Los Angeles, California: a safety-net hospital and an academic institution. Age-matched controls were selected from patients presenting for diagnostic breast imaging. Demographic and socioeconomic characteristics were collected. Data were analyzed using univariable test for odds ratios (ORs) with 95% confidence intervals (CIs) and multivariable conditional logistic regression. Results Patients with GM were more likely to prefer Spanish language (OR 6.20, 95% CI: 2.71%–14.18%), identify as Hispanic/Latina (OR 5.18, 95% CI: 2.38%–11.30%), and be born in Mexico (OR 3.85, 95% CI: 1.23%–12.02%). Cases were more likely to have no primary care provider (OR 3.76, 95% CI: 1.97%–7.14%) and use California Medicaid for undocumented adults (OR 3.65, 95% CI: 1.89%–7.08%). In the multivariable analysis, participants who preferred Spanish language had four times higher odds of GM versus those who preferred English language (OR 4.32, 95% CI: 1.38%–13.54%). Conclusion Patients with GM may have barriers to health care access, such as preferring Spanish language, being an undocumented immigrant, and not having a primary care provider. Given these health care disparities, further research is needed to identify risk factors, etiologies, and treatments for this subset of GM patients.
Background: Hematogones (HG) are benign precursor B-cells that are seen in increased numbers in the bone marrow during childhood, following chemotherapy or bone marrow transplant, in certain immune deficiencies, and in autoimmune disorders. Flow cytometry typically shows expression of TdT, CD10, CD19, variable CD20, dim CD22, CD34 (early HG), and dim CD45. As this phenotype is also seen in patients with B lymphoblastic leukemia (B-ALL), it causes a significant problem in distinguishing leukemic blasts from HG, particularly in a regenerating marrow. Furthermore, hematogones are usually more numerous at baseline in younger patient populations, the same age group with a relatively higher incidence of B-ALL. Despite guidance by earlier studies using the above markers for differentiating HG from B-ALL, these markers are not always sufficient and may hinder correct interpretation. Previous studies demonstrate CD58 is commonly expressed in B-ALL but not in hematogones; however, CD58 as a single marker is somewhat limited when expressed at lower levels. In order to improve diagnostic accuracy, we generated a five color antibody panel including CD10, CD19, CD45, CD38, and CD58 to assess the utility of a single tube panel in distinguishing B-ALL from HG. Design: A total of 35 cases with immature B-cell populations, 16 B-ALL (diagnostic and residual/relapsed cases) and 19 HG, were analyzed by 5-color flow cytometry. 32/35 cases were bone marrow aspirates and 3/35 cases were peripheral blood. A single tube containing CD10 FITC/CD58 PE/CD19 ECD/CD38 PC5/CD45 PC7 was analyzed together with the standard acute leukemia panels. To eliminate technical and fluorochrome variability in expression level analysis, relative antigenic expression was determined through comparison with appropriate internal controls. Antigen expression, as measured by the geometric mean fluorescent intensity (MFI), was then compared between B-ALL and HG using the Mann-Whitney U-test to assess for significant difference. Results were correlated with the morphologic, immunohistochemical, cytogenetic, and molecular findings for precise diagnostic classification as HG or leukemia. Results: HG demonstrated significantly brighter expression of CD38 (p<0.01) than that seen in B-ALL. In contrast, B-ALL expressed significantly brighter CD58 (p <0.01) than HG, which showed dim to no expression of the antigen. HG also showed significantly bright expression of CD10 relative to internal control granulocytes; however, this level of expression was similar to that seen in B-ALL. Median antigen expression. Hematogones show bright CD38, but dim to no CD58. Conversely, B-ALL expresses very dim CD38 and variable CD58. CD10 expression, though, demonstrates overlap between the two populations. B-ALL = B lymphoblastic leukemia, MFI = mean fluorescent intensity Comparative antigenic expression levels in hematogones and B-ALL. Select representative histograms showing HG and B-ALL blasts for the antigens CD38, CD58, and CD10 were selected from various patients studied based on those with the closest relative MFI to the overall median detected for that population in the study. The far right column shows the distribution in MFI of relative antigen expression exhibited the populations studied. HG show significantly brighter CD38 expression than B-ALL does (p<0.01). While B-ALL generally expresses brighter CD58 relative to internal controls, expression levels are variable. HG, though, show significantly dimmer CD58 to essentially no CD58 expression, compared to B-ALL (p<0.01). Similar to CD38, HG demonstrate significantly bright CD10, while B-ALL shows overall bright CD10 but variable expression levels amongst studied cases. These expression levels for CD10 overlap between HG and B-ALL and show no real statistical difference. Conclusions: The combination of CD38 and CD58 in a single tube increases the diagnostic accuracy in differentiation of HG from B-ALL. Without utilizing both antigens together, certain cases would have been difficult to interpret. Based on this analysis, we recommend that these markers be utilized in the routine evaluation for acute lymphoblastic leukemia. This is especially critical in post treatment cases in order to avoid misdiagnosis. Furthermore, the use this single tube panel would cut costs while at the same time improve patient care. Table Table. Figure Figure. Disclosures No relevant conflicts of interest to declare.
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