Pattern Of Marrow Infiltration Research Articles

Age- and BMI-related variations of fat distribution in sacral and lumbar bone marrow and their association with local muscle fat content

This analysis investigated the age- and BMI-related variations of fat distribution in sacral and lumbar bone marrow and their association with local muscle fat content in order to detect fat distribution patterns and variations in healthy adults using proton density fat fraction (PDFF) measurements. A six-echo 3D spoiled gradient-echo sequence was used for chemical shift encoding-based water-fat separation at the sacral and lower lumbar region in 103 healthy volunteers. PDFF values of the sacrum, 5th lumbar vertebral body, the gluteal and paraspinal muscles were determined. Correlation with age was significant (p < 0.05) for PDFF of the sacrum (men (m): r = 0.58; women (w): r = 0.54), L5 (m: r = 0.58; w: r = 0.54), the gluteal (m: r = 0.51; w: r = 0.44) and paraspinal (m: r = 0.36; w: r = 0.49) muscles in both genders. BMI correlated significantly with the paraspinal musculature in men (r = 0.46) and women (r = 0.33). Correlation testing revealed significant correlations (p < 0.05) between the two osseous (m: r = 0.63, w: r = 0.75) and the muscle compartments (m: r = 0.63, w: r = 0.33) in both genders. Bone marrow and muscle fat infiltration patterns were not significantly associated with each other at the sacral and lower lumbar spine region. The presented data suggest that the two compartments may have distinct pathophysiological fat infiltration patterns. However, further clinical studies are needed to support the results.

Aspectos óseos de la enfermedad de Gaucher

The exposition aims, is to review the pathophysiological mechanisms of bone marrow involvement and the patterns of marrow infiltration by Gaucher cells. We have reviewed the different methods of assessment of bone marrow infiltration and its temporal development. Qualitative methods include simple radiography, magnetic resonance imaging (MRI), computed tomography (CT) and radioisotope. The simple radiography is the basic element, but its sensitivity is limited and only allows for assessing changes and trabecular bone remodeling MRI allows us to appreciate the bone marrow infiltration, detection of complications and response to therapy. Radioisotopes can contribute to the differential diagnosis of osteomyelitis and bone crises. Among the quantitative methods are the QCSI (quantitative chemical shift imaging) and the dual-energy X-ray absorptiometry (DEXA), as well as new quantitative techniques of CT, MRI and ultrasound densitometry. The QCSI performed an assessment of fat content of bone marrow in the spine. DEXA quantifies bone density by measuring the attenuation coefficient. The semiquantitative methods have various “scores” to establish criteria for generalized bone disease endpoints of disease progression and response to therapy.

Assessment of Bone Marrow Microvessel Density in Chronic Lymphocytic Leukemia

Angiogenesis is a physiologic process of new blood vessels formation mediated by various cytokines called proangiogenic and antiangiogenic factors. Enhancement of angiogenesis in chronic lymphocytic leukemia (CLL) has been recognized more recently. Our study assesses CD34 and von Willebrand factor (vWf) expression and microvessel density (MVD) in the bone marrow of patients with CLL. (1) To assess bone marrow MVD in CLL using 2 different monoclonal antibodies, CD34 and vWf; and (2) To examine the possible association of marrow MVD and clinical course, pattern of marrow infiltration, Rai stage, CD38 positivity, and cytogenetic abnormalities detected by fluorescence in situ hybridization. Bone marrow specimens from 33 patients with CLL and 10 controls were studied. A single microvessel was defined as any vessel with a clear lumen. The screening of the slides was carried out by hotspot method. The slides were initially screened at low power to identify the areas with highest number of microvessel or vascularity hotspot. The count of microvessel in a sufficiently extended field (40x objective lens, 10x ocular lens) was then performed. The mean value of 10 most vascularized areas at 400x field was considered as MVD for a sample. There was a significant difference between MVD counts according to the antibody used. MVD was higher using CD34 versus vWF (CD34: mean +/- SD, 35.91+/-15.7; 95% confidence interval of mean, 30.34-41.48 vessels/field versus vWF: 8.15+/-4.65; 95% confidence interval of mean, 4.11-12.44 vessels/field; P<0.0001]. Bone marrow MVD detected by CD34 was significantly higher in patients with CD38 expression more than 30% (P=0.006) and in patients with unfavorable cytogenetic abnormalities. However, no significant MVD differences were detected between CLL subgroups with regard to clinical course, pattern of marrow infiltration, and Rai stage. Bone marrow MVD in patients with CLL was significantly higher than that in controls (P<0.0001). MVD assessment using anti-CD34 resulted in higher MVD counts than when using anti-vWF antibody. However, no MVD differences were detected between CLL subgroups subdivided according to the above-mentioned prognostic factors except CD38 expression and genetic abnormalities.

Prognostic Value of Angiogenesis Assessment in Chronic Lymphocytic Leukemia: More Data Needed.

Abstract 4396 IntroductionThe association between angiogenesis and cancer progression in solid tumors has been documented, but its significance in chronic lymphocytic leukemia (CLL) has not been completely evaluated. Vascular endothelial growth factor /VEGF/ is the major pro-angiogenic factor in humans and his transduction pathway may be very active in CLL cells contributes to their enhanced survival. In this context VEGF can be additional tool for predicting the clinical course in early CLL. Patients and MethodsTo predict the risk of disease progression, we analyzed serum levels VEGF (sVEGF) using ELISA tehnique in 33 Binet stage A de novo CLL patients. In addition, We analyzed microvessel density (MVD) of the same patients using immunohistochemical staining with CD34 and vWf. Finally, we explored wheather changes of circulating VEGF concentrations and MVD reflected clinico-biological features of CLL (peripheral blood lymphocytosis (PBL), bone marrow (BM) histology, beta-2 microglobulin (β2m) level, lactat dehidrogenase (LDH) level) and kariotype abnormalities. ResultsThe VEGF serum levels (sVEGF) was not significantly elevated (p=0.31) in CLL patients (mean: 70.9 pg/mL; range: 16–483) compared with and age- and sex-matched healthy controls (mean: 44.7 pg/mL; range: 22–69.2). sVEGF level positively correlated with elevated LDH level (p=0.008), but no correlation with other clinico-biological features was found.Bone marrow MVD was significantly higher (p<0.0001) in CLL patients (mean: 35.91 vessels/field ± 15.71) compared to controls (mean:8.27 vessels/field ±6.19). Also, there was a significant difference between MVD counts according to the antibody used. MVD was higher using CD34 vs vWF (CD34, 35.91 vessels/field ±15.7, vs vWF, 8.15 vessels/field ±4.65, p<0.0001). Bone marrow MVD detected by CD34 was significantlyhigher in patinents with CD38 expression more than 30% (p=0.006). However, no significant MVD differences were detected between CLL subgroups with regard to clinical course, pattern of marrow infiltration, Rai stage and FISH abnormalities.In univariate analysis sVEGF (p=0.018), Rai substages (p=0.027), PBL (p=0,030), β2m level (p=0.008) and diffuse bone marrow infiltration (p=0.006) were significantly associated with increased risk of disease progression. But, in multivariate analysis only sVEGF (p=0.002) and β2m level (p=0.008) retained their prognostic significance. ConclusionsSerum VEGF level although not increased in comparasion with healthy controls, may improve the assessment of individual prognosis of patients with early CLL. Assessment of real clinical significance of bone marrow angiogenesis in CLL is required. Disclosures:No relevant conflicts of interest to declare.

Choice of endothelial marker is crucial for assessment of bone marrow microvessel density in chronic lymphocytic leukemia

Angiogenesis is a potential prognostic factor in chronic lymphocytic leukemia (CLL). Elevated circulating levels of angiogenic factors in CLL have been repeatedly reported. Nevertheless, the issue of bone marrow neovascularization in CLL remains controversial, partly due to limited number of published studies, different methods of assessing microvessel density (MVD) and small patient cohorts. Moreover, there are very scarce data regarding the relationship of marrow angiogenesis to prognostic markers in CLL. Our objectives were: 1. To assess bone marrow MVD in CLL using two different monoclonal antibodies and a reproducible method of MVD quantification; 2. To examine the possible association of marrow MVD and clinical course, pattern of marrow infiltration, Rai stage, cytogenetic abnormalities detected by fluorescence in situ hybridization (FISH), and mutation status of immunoglobulin heavy chain variable region (IgVH). MVD was higher using CD34 vs vWF antibody (p<0.0001). However, no MVD differences were detected between CLL subgroups subdivided according to the above-mentioned prognostic factors. In conclusion, MVD assessment using anti-CD34 resulted in higher MVD counts than when using anti-vWF antibody. No association of MVD with any prognostic factors was observed, possibly due to the limited patient cohort. As the need for bone marrow trephine biopsies in CLL is significantly decreasing, a standardized method of neovascularization assessment is required to enable possible multicentre studies in order to conduct larger investigations and thereby shed more light on the real clinical significance of bone marrow angiogenesis in CLL.

Bone Marrow Angiogenesis in Chronic Lymphocytic Leukemia: Relationship to Classical and Modern Prognostic Factors.

Background: Angiogenesis is considered a potential prognostic factor in chronic lymphocytic leukemia (CLL). Elevated levels of various angiogenic factors have been identified in plasma or serum of CLL patients. However, results of studies assessing bone marrow neovascularization in CLL are controversial, in part due to different antibodies used for immunohistochemical identification of endothelial cells and different methods of assessing microvessel density (MVD). Moreover, there are insufficient data regarding relationship of bone marrow angiogenesis to other prognostic markers in CLL such as clinical stage, pattern of marrow infiltration, genetic abnormalities detected by fluorescent in situ hybridization (FISH), or mutation status of immunoglobulin heavy-chain variable-region genes (IgVH).Aims: To quantify MVD in bone marrow biopsies from CLL patients and control group and to assess its relationship to other prognostic factors.Methods: We analyzed bone marrow biopsy specimens from 22 untreated patients with CLL (16 males, 6 females, median age 62 years, range, 31–74). Control group consisted of 17 biopsies from individuals without evidence of malignant disease in bone marrow. Neovascularization was assessed using immunohistochemical staining of endothelial cells in bone marrow trephine biopsies with anti-CD34 monoclonal antibody. Microvessel density was assessed under light microscope equipped with image analysis software and calculated using hot spot method, i.e. identification of three loci with highest accumulation of microvessels under low (100x) magnification and counting microvessels in three high-power fields (400x magnification) per hot spot. MVD was expressed as mean number of microvessels per mm2. CLL cohort was further divided into subgroups according to clinical course (stable, n=11 vs. progressive, n=11), Rai stage (0, n=9 vs. I-IV, n=13), pattern of marrow infiltration (non-diffuse, n=11 vs. diffuse, n=11), genetic abnormalities (favourable, i.e. no abnormality or del13q14 as a sole aberration, n=10 vs. unfavourable, i.e. all other abnormalities, n=11), and IgVH mutation status (mutated, n=7 vs. unmutated, n=14).Results: MVD was significantly elevated in CLL group in comparison to controls (mean ± standard deviation [SD], 75.6 ± 50.6, 95% confidence interval [CI], 53.2–98.1/mm2 vs. 47.4 ± 21.8, 95% CI, 36.2–58.6/mm2, p=0.039). However, there were no significant MVD differences between CLL subgroups with regard to clinical course, pattern of marrow infiltration, Rai stage, FISH abnormalities or IgVH mutation status. Interestingly, when each subgroup was compared to controls, only patients with diffuse bone marrow infiltration (p=0.011), Rai stage I-IV (p=0.014) and mutated IgVH genes (p=0.019) had significantly increased MVD.Conclusions: This study shows that microvessel density is significantly elevated in CLL. However, this difference is maintained in three subgroups only: diffuse pattern of infiltration, mutated IgVH genes and Rai stage I-IV. We did not observe significant MVD differences between CLL subgroups with regard to classical or modern prognostic factors. Large prospective studies are necessary to confirm our results and elucidate the real clinical relevance of bone marrow angiogenesis in CLL.

Weighted Prognostic Models for Survival in Untreated and Previously Treated Patients with CLL.

The clinical course for patients with chronic lymphocytic leukemia (CLL) is remarkably variable. Patient characteristics have been correlated with meaningful clinical endpoints such as time to treatment, response to treatment, progression-free survival, and overall survival (OS) for patients with CLL. Identification of such characteristics enables informed discussion about timing of treatment, treatment options, and can provide insight into the basic biology of the disease. The Rai staging system identifies risk groups for survival based on characteristics in untreated patients. However, within each stage there is still heterogeneity in survival. In addition to factors used in clinical staging, several other characteristics have been correlated with survival including: age, gender, pattern of marrow infiltration, lymphocyte doubling time, presence of prolymphocytes, presence of chromosome abnormalities, elevated serum levels of beta-2 microglobulin (ß-2M), thymidine kinase, and soluble CD23, IgVH mutation status, and expression of ZAP70 and CD38 by leukemia cells. Alone, each of these independent prognostic factors, including stage, has limited utility in predicting overall survival. A nomogram is a graphic representation of a statistical model with scales for calculating the cumulative affect of weighted variables on the probability of a particular outcome. The strength of using nomograms is that they combine multiple independent variables to predict an outcome and enable appreciation of the prognostic weight of each variable. They are useful in counseling patients and in developing expectations for clinical trials as well as identifying patients "at risk" who should be targeted for aggressive therapy or investigational approaches. We retrospectively evaluated 1607 chemotherapy-naive and 1602 previously treated patients with CLL that presented to MD Anderson Cancer Center to identify independent characteristics that could be used to predict OS. Based on significant characteristics identified in univariate analyses, a multivariate model was developed for OS for each patient group. Characteristics evaluated included age, gender, Rai stage, performance status (PS), # of affected node sites, WBC count, absolute lymphocyte count (ALC), HGB, PLT, ALB, serum alkaline phosphatase (AP) and LDH, % BM lymphocytes, spleen and liver size, ß-2M, # of prior therapies and refractoriness to fludarabine for previously treated patients. Univariate and multivariate analyses identified several patient characteristics at presentation that predicted for overall survival for each patient group. The final multivariate Cox proportional hazards model included the following characteristics for chemotherapy-naive patients: age, ALC. LDH, β2M, Rai stage, and # of involved lymph node groups. For previously treated patients, the final multivariate Cox hazards model included the following significant characteristics: β2M, # prior Rx, age, IgM, PLT, and HGB. Nomograms were constructed for each group using the respective significant characteristics to estimate 2-, 5-, and 10-year survival probability and median survival time. These prognostic model may help patients and clinicians in decision-making as well as in clinical research and design of clinical trials. Nomograms are powerful tools for predicting important clinical endpoints including survival, for counseling patients, and developing and analyzing clinical trials.

Diffuse large B-cell lymphoma with distinctive patterns of splenic and bone marrow involvement: clinicopathologic features of two cases

Two unusual cases of large B-cell lymphoma with predominant splenic and bone marrow (BM) involvement and similar clinical and histopathologic features are described. Both patients presented with nonspecific constitutional symptoms, unexplained cytopenias, and splenomegaly. Splenectomy revealed diffuse red pulp involvement by large B-cell lymphoma. The perisplenic lymph nodes were also involved diffusely with effacement of normal nodal architecture, excluding a diagnosis of intravascular large B-cell lymphoma. BM biopsies revealed striking erythroid hyperplasia without overt morphologic evidence of involvement by lymphoma. Immunoperoxidase staining of the marrow biopsies with antibodies to CD20 and erythroid-associated antigens revealed involvement by large B-cell lymphoma morphologically resembling the early pronormoblasts. In both cases there was prominent, but not exclusive, intravascular/intrasinusoidal lymphomatous marrow infiltration. These cases represent an unusual variant of large B-cell lymphoma with distinctive patterns of splenic and BM involvement. Furthermore, they underscore the difficulties in identifying intrasinusoidal marrow infiltration by lymphoma in H&E-stained biopsy slides and demonstrate that this pattern of marrow infiltration may be seen in cases of large B-cell lymphoma distinct from the intravascular variant.

Bone marrow findings in systemic mastocytosis

The neoplastic proliferation of tissue mast cells constitutes a group of rare diseases that have localized and systemic variants. The cytologic (n = 7) and histologic (n = 38) findings in bone marrow from a total of 45 patients with systemic mastocytosis were evaluated. Three distinct histologic patterns of marrow involvement were distinguished. In 21 cases a patchy or focal infiltration pattern was encountered. Mast cell aggregates were located predominantly in peritrabecular and perivascular areas. The adjacent trabeculae were thickened. A dense network of reticulin fibers and foci of lymphocytes accompanied the mast cell infiltrates. Increased numbers of eosinophils frequently demarcated the mast cell infiltrates from the surrounding tissue. In the noninfiltrated marrow areas hematopoiesis and the distribution of fat cells appeared to be normal. This histologic pattern, designated type 1, was observed exclusively in patients showing primary involvement of the skin, indistinguishable from urticaria pigmentosa. In 14 additional cases peritrabecular and perivascular sheets of mast cells, with concomitant fibrosis and osteosclerosis, were also present. Unlike the findings in type 1, however, the noninfiltrated marrow areas showed marked reductions in fat cell content and markedly increased granulocytopoiesis or increased numbers of blast cells (infiltration pattern type 2). On the basis of the hematologic and clinical findings, chronic myeloid leukemia was diagnosed in six of these cases, myelomonocytic leukemia in three cases, and acute myeloid leukemia in two cases. The bone marrow of three patients was diffusely infiltrated by atypical mast cells, leading to marked hypoplasia of fat cells and blood cell precursors. These histologic features were identified as infiltration pattern type 3. The diagnosis of mast cell leukemia was confirmed in all three cases by the presence of numerous mast cells in the blood. The prognosis for patients with the type 1 marrow infiltration pattern and primary skin involvement was favorable (actuarial survival rate five years after diagnosis, 0.75). This variant was called benign systemic mastocytosis. Primary skin involvement did not occur in the patients with type 2 or 3 infiltration patterns. The prognosis for these patients was poor (actuarial survival five years after diagnosis, 0.17 for type 2 and 0.00 for type 3). These two forms were accordingly designated malignant systemic mastocytosis.