Enhanced Histopathology of the Bone Marrow

Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences/NIH, 111 Alexander Drive, Research Triangle Park, NC 27709, USA.
Toxicologic Pathology (Impact Factor: 2.14). 02/2006; 34(5):666-86. DOI: 10.1080/01926230600939971
Source: PubMed


Changes in bone marrow cellularity can be an indicator of systemic toxicity and, therefore, bone marrow should be included in the battery of tissues examined for enhanced histopathology. However, the majority of changes in the bone marrow that are observed in toxicology studies are a response to hematological changes or lesions elsewhere in the body. For this reason, a consideration of all tissue changes in the body is required in order to differentiate toxic effects versus physiological responses in the bone marrow. While enhanced histopathology involves evaluation of the separate compartments in each lymphoid organ using descriptive rather than interpretive terminology, bone marrow is unique in that it lacks specific compartments. Furthermore, identification of erythroid, myeloid, megakaryocytic, and stromal cells, plus adipose tissue and hemosiderin-laden macrophages, can be accomplished from conventional H&E-stained sections, but conclusive identification of lymphoid lineage cells is not likely. This limits the extent of initial enhanced histopathology on bone marrow and argues for the use of cytological preparations for more comprehensive assessment of potential immunomodulatory effects.

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    • "The genesis of hematological alterations in both red and white blood cell series is often related to bone marrow disorders such as dysplasia and aplasia [13]–[14]. A detailed examination of bone marrow provides the hematopoietic status of an individual [15], thus indicating that bone marrow disorders are related to peripheral blood alterations. Moreover, when used in combination with a complete blood count, examination of bone marrow smears provides information about the hematopoietic system that might otherwise be missed by analysis of the peripheral blood alone [16]. "
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    ABSTRACT: Hematological analysis has limited applications for disease diagnosis in Leishmania infantum-infected dogs, but it can be very important in evaluating the clinical forms of the disease and in understanding the evolution of canine visceral leishmaniasis (CVL) pathogenesis. Recently, we demonstrated that alterations in leucopoiesis and erythropoiesis are related to clinical status and bone marrow parasite density in dogs naturally infected by L. infantum. To further characterize these alterations, we evaluated the association between the hematological parameters in bone marrow and peripheral blood alterations in groups of L. infantum-infected dogs: asymptomatic I (AD-I: serum negative/PCR+), asymptomatic II (AD-II: serum positive), oligosymptomatic (OD), and symptomatic (SD). Results were compared with those from noninfected dogs (NID). The SD group was found to present a decrease in erythropoietic lineage with concomitant reductions in erythrocytes, hemoglobin, and hematocrit parameters, resulting in anemia. The SD group also had increased neutrophils and precursors and decreased band eosinophils and eosinophils, leading to peripheral blood leucopenia. In the AD-II group, lymphocytosis occurred in both the peripheral blood and the bone marrow compartments. The SD group exhibited lymphocytosis in the bone marrow, with lymphopenia in the peripheral blood. In contrast, the AD-I group, showed no significant changes suggestive of CVL, presenting normal counts in bone marrow and peripheral blood. Our results showed for the first time that important changes in hematopoiesis and hematological parameters occur during ongoing CVL in naturally infected dogs, mainly in symptomatic disease. Taken together, our results based on myelogram and hemogram parameters enable better understanding of the pathogenesis of the anemia, lymphocytosis, and lymphopenia, as well as the leucopenia (eosinopenia and monocytopenia), that contribute to CVL prognosis.
    Full-text · Article · Dec 2013 · PLoS ONE
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    • "The compartments to be evaluated include the cortex and medulla of the thymus (Elmore 2006a); the periarteriolar lymphoid sheaths (PALS), follicles, marginal zone, and red pulp of the spleen (Elmore 2006b); and the cortex (follicles, subcapsular sinus), paracortex , and medulla (cords, sinuses) of the lymph nodes (Elmore 2006c). Although anatomic pathologists do not recognize different compartments within the bone marrow, the individual cell populations should be evaluated and the myeloid:erythroid ratio determined (Elmore 2006d). Any potential treatmentrelated effects observed in the bone marrow should be followed up with clinical pathology. "
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    ABSTRACT: Enhanced histopathology (EH) of the immune system is a tool that the pathologist can use to assist in the detection of lymphoid organ lesions when evaluating a suspected immunomodulatory test article within a subchronic study or as a component of a more comprehensive, tiered approach to immunotoxicity testing. There are three primary points to consider when performing EH: (1) each lymphoid organ has separate compartments that support specific immune functions; (2) these compartments should be evaluated individually; and (3) semiquantitative descriptive rather than interpretive terminology should be used to characterize any changes. Enhanced histopathology is a screening tool that should be used in conjunction with study data including clinical signs, gross changes, body weight, spleen and thymus weights, other organ or tissue changes, and clinical pathology. Points to consider include appropriate tissue collection, sectioning, and staining; lesion grading; and diligent comparison with concurrent controls. The value of EH of lymphoid organs is to aid in the identification of target cell type, changes in cell production and cell death, changes in cellular trafficking and recirculation, and determination of mechanism of action.
    Full-text · Article · Nov 2011 · Toxicologic Pathology
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    • "The tissues were then stained with hematoxylin and eosin, and they were examined for normal histologic appearance as well as any lesions through standard light microscopy by two independent veterinary pathologists who were blinded to treatment groups. Bone marrow analysis was done according to established guidelines [19]. The bone marrow was evaluated for necrosis, fibrosis, hemorrhage , overall cellularity, M/E ratios, and megakaryocytic counts. "
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    ABSTRACT: We recently developed a Janus kinase 2 (Jak2) small-molecule inhibitor called G6 and found that it inhibits Jak2-V617F-mediated pathologic cell growth in vitro, ex vivo, and in vivo. However, its ability to inhibit Jak2-V617F-mediated myeloproliferative neoplasia, with particular emphasis in the bone marrow, has not previously been examined. Here, we investigated the efficacy of G6 in a transgenic mouse model of Jak2-V617F-mediated myeloproliferative neoplasia. We found that G6 provided therapeutic benefit to the peripheral blood as determined by elimination of leukocytosis, thrombocytosis, and erythrocytosis. G6 normalized the pathologically high plasma concentrations of interleukin 6 (IL-6). In the liver, G6 eliminated Jak2-V617F-driven extramedullary hematopoiesis. With respect to the spleen, G6 significantly reduced both the splenomegaly and megakaryocytic hyperplasia. In the critically important bone marrow, G6 normalized the pathologically high levels of phospho-Jak2 and phospho-signal transducer and activator of transcription 5 (STAT5). It significantly reduced the megakaryocytic hyperplasia in the marrow and completely normalized the M/E ratio. Most importantly, G6 selectively reduced the mutant Jak2 burden by 67%on average, with virtual elimination of mutant Jak2 cells in one third of all treated mice. Lastly, clonogenic assays using marrow stem cells from the myeloproliferative neoplasm mice revealed a time-dependent elimination of the clonogenic growth potential of these cells by G6. Collectively, these data indicate that G6 exhibits exceptional efficacy in the peripheral blood, liver, spleen, and, most importantly, in the bone marrow, thereby raising the possibility that this compound may alter the natural history of Jak2-V617F-mediated myeloproliferative neoplasia.
    Full-text · Article · Nov 2011 · Neoplasia (New York, N.Y.)
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