Eosinophilic granuloma of lymph node: case report with cytohistologic, immunohistochemical, and flow cytometric observations

A case study of eosinophilic granuloma (Langerhans cell histiocytosis) of lymph node in a 32-year-old white man is presented. Clinical, cytologic, histologic, immunohistochemical, and flow cytometric findings are reported. Intraoperative cytologic findings can serve as valuable adjuncts to the frozen section, in this case serving as the sole method for diagnosis. This case is presented in light of the rarity of node-based eosinophilic granuloma and the absence of flow cytometric immunophenotypic findings in the literature.     

Oligo-monocytic CMML and other pre-CMML states: Clinical impact,prognostication and management

Chronic myelomonocytic leukemia (CMML) is defined by myelodysplasia, pathologic accumulation of monocytes and a substantial risk to transform to secondary acute myeloid leukemia (sAML). In recent years, minimal diagnostic criteria for classical CMML and CMML-variants were proposed. Moreover, potential pre-stages of CMML and interface conditions have been postulated. Oligomonocytic CMML is a condition where the absolute peripheral blood monocyte count does not reach a diagnostic level but all other criteria for CMML are fulfilled. Among potential pre-stages of CMML, clonal and non-clonal conditions have been described, including idiopathic monocytosis (IMUS) and clonal monocytosis of unknown significance (CMUS). Patients with myelodysplastic syndromes (MDS), clonal cytopenia of unknown significance (CCUS), clonal hematopoiesis of indeterminate potential (CHIP) and idiopathic cytopenia of undetermined significance (ICUS) may also progress to CMML. The current article provides an overview of pre-CMML conditions and oligomonocytic CMML, with special reference to diagnostic criteria, differential diagnoses, clinical outcomes and management.     

Depletion of CD11c+ cells in the CD11c.DTR model drives expansion of unique CD64+ Ly6C+ monocytes that are poised to release TNF‐α

Dendritic cells (DCs) play a vital role in innate and adaptive immunities. Inducible depletion of CD11c⁺ DCs engineered to express a high‐affinity diphtheria toxin receptor has been a powerful tool to dissect DC function in vivo. However, despite reports showing that loss of DCs induces transient monocytosis, the monocyte population that emerges and the potential impact of monocytes on studies of DC function have not been investigated. We found that depletion of CD11c⁺ cells from CD11c.DTR mice induced the expansion of a variant CD64⁺ Ly6C⁺ monocyte population in the spleen and blood that was distinct from conventional monocytes. Expansion of CD64⁺ Ly6C⁺ monocytes was independent of mobilization from the BM via CCR2 but required the cytokine, G‐CSF. Indeed, this population was also expanded upon exposure to exogenous G‐CSF in the absence of DC depletion. CD64⁺ Ly6C⁺ monocytes were characterized by upregulation of innate signaling apparatus despite the absence of inflammation, and an increased capacity to produce TNF‐α following LPS stimulation. Thus, depletion of CD11c⁺ cells induces expansion of a unique CD64⁺ Ly6C⁺ monocyte population poised to synthesize TNF‐α. This finding will require consideration in experiments using depletion strategies to test the role of CD11c⁺ DCs in immunity.     

Evolving Understanding of Chronic Myelomonocytic Leukemia: Implications for Future Treatment Paradigms

Chronic myelomonocytic leukemia (CMML) is a relatively uncommon hematologic malignancy that manifests as peripheral monocytosis, has varying degrees of bone marrow dysplasia, and is associated with poor outcomes. Despite a growing appreciation of the pathobiologic mechanisms driving CMML, current therapies have not clearly demonstrated any survival benefit. The complex pathobiology of CMML highlights the intricate aberrantly activated cellular pathways that influence disease phenotype and limit current treatment options. Understanding of these oncogenic pathways may provide novel mechanism-based treatment strategies that may ultimately offer better outcomes for patients. We reviewed the current diagnostic, prognostic, and molecular understandings, and we assessed the current and future treatment options for CMML.     

Contemporary Risk Stratification and Treatment of Chronic Myelomonocytic Leukemia

Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy characterized by absolute monocytosis, one or more lineage dysplasia, and proliferative features including myeloid hyperplasia, splenomegaly, and constitutional symptoms. Because of vast clinical heterogeneity in presentation and course, risk stratification is used for a risk‐adapted treatment strategy. Numerous prognostic scoring systems exist, some of which incorporate mutational information. Treatment ranges from observation to allogeneic hematopoietic stem cell transplantation. Therapies include hydroxyurea for cytoreduction, hypomethylating agents, and the JAK1/2 inhibitor ruxolitinib to address splenomegaly and constitutional symptoms. Recently, oral decitabine with cedazuridine was approved and represents a convenient treatment option for CMML patients. Although novel therapeutics are in development for CMML, further work is needed to elucidate possible targets unique to the CMML clone. In this review, we will detail the pathophysiology, risk stratification, available treatment modalities, and novel therapies for CMML, and propose a modern treatment algorithm.Implications for PracticeChronic myelomonocytic leukemia (CMML) is a clinically heterogenous disease, which poses significant management challenges. The diagnosis of CMML requires bone marrow biopsy and aspirate with thorough evaluation. Risk stratification and symptom assessment are essential to designing an effective treatment plan, which may include hypomethylating agents (HMAs) in intermediate or high‐risk patients. The recently approved oral decitabine/cedazuridine provides a convenient alternative to parenteral HMAs. Ruxolitinib may be effective in ameliorating proliferative symptoms and splenomegaly. Allogeneic stem cell transplantation remains the only treatment with curative potential; however, novel therapies are in clinical development which may significantly alter the therapeutic landscape of CMML.     

Advantages and limitations of mouse models to deplete dendritic cells

Dendritic cells (DCs) play a key role in regulating innate and adaptive immunity. Our understanding of DC biology has benefited from studies in CD11c.DTR and CD11c.DOG mouse models that use the CD11c promoter to express a diphtheria toxin (DT) receptor transgene to inducibly deplete CD11c⁺ cells. Other models to inducibly deplete specific DC subsets upon administration of DT have also been generated. However, most models suffer from limitations such as depletion of additional cell types or the requirement to be used as radiation chimeras. Moreover, CD11c.DTR and CD11c.DOG mice have recently been reported to display neutrophilia and monocytosis upon DT injection. We discuss here some of the limitations that should be taken into consideration when interpreting results obtained with mouse models of DC ablation.     

Peripheral blood monocyte counts are elevated in the pre-diagnostic phase of pancreatic cancer: A population based study

BackgroundEarly diagnosis of pancreatic ductal adenocarcinoma (PDAC) is associated with improved outcomes. A biomarker with incremental change in the pre-diagnostic phase of the disease would be valuable for early detection. In our clinical experience, we have observed elevated peripheral blood monocyte (PBM) counts in PDAC patients at diagnosis. In this study, we aimed to compare PBM counts in PDAC cases and healthy controls at diagnosis and in the 2-year pre-diagnostic period.MethodsUsing the Rochester Epidemiology Project database, we identified all patients diagnosed with PDAC between 2000 and 2015 (n = 219) and age-and gender-matched disease-free controls (n = 438). PBM counts and temporal trends were analyzed over a 24 month period before PDAC diagnosis. The groups were compared using Fisher’s exact test and t-test.ResultsAt diagnosis, compared to controls PDAC cases more often had monocytosis (23% vs 8%; p < 0.001) and higher mean PBM count (x10⁹/L) (0.73 vs 0.59; p < 0.001). In the 2-year pre-diagnostic period, mean PBM counts were significantly higher in PDAC cases in the interval from 6 months to diagnosis (0.69 vs 0.61; p = 0.03). PDAC cases with monocytosis at diagnosis had a significantly lower median survival (1.9 months vs. 7.6 months; p = 0.001).ConclusionMonocytosis is more prevalent in PDAC patients at diagnosis compared to controls and is associated with lower median survival. In a subset of patients, PBM count elevation precedes PDAC diagnosis by 6 months. This novel observation can possibly augment strategies for early diagnosis of PDAC but needs further study.