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1.
IEEE J Biomed Health Inform ; 26(9): 4773-4784, 2022 09.
Article in English | MEDLINE | ID: mdl-35588419

ABSTRACT

Differentiating types of hematologic malignancies is vital to determine therapeutic strategies for the newly diagnosed patients. Flow cytometry (FC) can be used as diagnostic indicator by measuring the multi-parameter fluorescent markers on thousands of antibody-bound cells, but the manual interpretation of large scale flow cytometry data has long been a time-consuming and complicated task for hematologists and laboratory professionals. Past studies have led to the development of representation learning algorithms to perform sample-level automatic classification. In this work, we propose a chunking-for-pooling strategy to include large-scale FC data into a supervised deep representation learning procedure for automatic hematologic malignancy classification. The use of discriminatively-trained representation learning strategy and the fixed-size chunking and pooling design are key components of this framework. It improves the discriminative power of the FC sample-level embedding and simultaneously addresses the robustness issue due to an inevitable use of down-sampling in conventional distribution based approaches for deriving FC representation. We evaluated our framework on two datasets. Our framework outperformed other baseline methods and achieved 92.3% unweighted average recall (UAR) for four-class recognition on the UPMC dataset and 85.0% UAR for five-class recognition on the hema.to dataset. We further compared the robustness of our proposed framework with that of the traditional downsampling approach. Analysis of the effects of the chunk size and the error cases revealed further insights about different hematologic malignancy characteristics in the FC data.


Subject(s)
Algorithms , Hematologic Neoplasms , Hematologic Neoplasms/diagnosis , Humans
2.
Hum Pathol ; 123: 11-19, 2022 05.
Article in English | MEDLINE | ID: mdl-35167894

ABSTRACT

Chromosome rearrangements involving NUP98 at 11p15 are rare but recurring abnormalities in acute myeloid leukemia (AML). Here we described 12 cases of myeloid neoplasms with t(v; 11p15); NUP98 rearrangement and characterized their pathologic features. Our patient cohort included 10 adults and 2 children with a median age of 51 years. They were predominantly AML (n = 10) including de novo AML, therapy-related AML, chronic myeloid leukemia with myeloid blast crisis, and mixed phenotype acute leukemia, as well as therapy-related myelodysplastic syndrome (MDS) and MDS/myeloproliferative neoplasm with increased blasts. The blasts shared some common features including pink/red cytoplasmic granules, presence of a perinuclear hof, Auer rods, and occasional bilobed nuclei, mimicking acute promyelocytic leukemia (APML). Flow cytometric studies showed blasts positive for MPO, CD117, CD13 and CD33, with a subset of cases negative for CD34 and/or HLA-DR and a subset of cases expressing monocytic markers. The translocations of 11p15 included t(7; 11) (p15; p15), t(2; 11) (q31; p15), t(9; 11) (p22; p15), t(5; 11) (q32; p15), and t(11; 12) (p15; q13). Three cases showed cryptic NUP98 rearrangement. These patients showed incomplete response to therapy with median overall survival of 17.5 months, a complete remission rate of 25% following chemotherapy induction and primary refractory disease of 58%. It is clinically important to recognize this group of diseases because the blasts can be misclassified as promyelocytes, and NUP98 rearrangement may be cryptic requiring fluorescence in situ hybridization (FISH) study. This case series highlights that NUP98-rearranged myeloid neoplasms are clinically, morphologically, and cytogenetically distinct and could be considered as a separate entity in the WHO classification defined by cytogenetic abnormality.


Subject(s)
Leukemia, Myeloid, Acute , Myeloproliferative Disorders , Chromosome Aberrations , Humans , In Situ Hybridization, Fluorescence , Leukemia, Myeloid, Acute/genetics , Middle Aged , Myeloproliferative Disorders/genetics , Nuclear Pore Complex Proteins/genetics , Translocation, Genetic
3.
Am J Clin Pathol ; 157(4): 546-553, 2022 04 01.
Article in English | MEDLINE | ID: mdl-34643210

ABSTRACT

OBJECTIVES: Flow cytometry (FC) is critical for the diagnosis and monitoring of hematologic malignancies. Machine learning (ML) methods rapidly classify multidimensional data and should dramatically improve the efficiency of FC data analysis. We aimed to build a model to classify acute leukemias, including acute promyelocytic leukemia (APL), and distinguish them from nonneoplastic cytopenias. We also sought to illustrate a method to identify key FC parameters that contribute to the model's performance. METHODS: Using data from 531 patients who underwent evaluation for cytopenias and/or acute leukemia, we developed an ML model to rapidly distinguish among APL, acute myeloid leukemia/not APL, acute lymphoblastic leukemia, and nonneoplastic cytopenias. Unsupervised learning using gaussian mixture model and Fisher kernel methods were applied to FC listmode data, followed by supervised support vector machine classification. RESULTS: High accuracy (ACC, 94.2%; area under the curve [AUC], 99.5%) was achieved based on the 37-parameter FC panel. Using only 3 parameters, however, yielded similar performance (ACC, 91.7%; AUC, 98.3%) and highlighted the significant contribution of light scatter properties. CONCLUSIONS: Our findings underscore the potential for ML to automatically identify and prioritize FC specimens that have critical results, including APL and other acute leukemias.


Subject(s)
Leukemia, Myeloid, Acute , Leukemia, Promyelocytic, Acute , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Flow Cytometry/methods , Humans , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/pathology , Leukemia, Promyelocytic, Acute/diagnosis , Machine Learning , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology
4.
Am J Clin Pathol ; 152(5): 625-637, 2019 10 07.
Article in English | MEDLINE | ID: mdl-31338515

ABSTRACT

OBJECTIVES: Hematopathology (HP) is a rapidly changing field with insufficient data to provide guidance to program directors (PDs), the Accreditation Council for Graduate Medical Education, or the American Board of Pathology. METHODS: Two surveys were performed-one for HP PDs and one, given twice, for HP diplomates doing Maintenance of Certification/Continuing Certification reporting in 2017 to 2018. RESULTS: Bone marrow (BM), lymph node (LN), and flow cytometry interpretations and peripheral blood/fluid reviews are performed by more than 80% of hematopathologists and are the areas with the greatest amount of training. A smaller proportion of hematopathologists is involved in other HP-related activities. Most PDs believed fellows should perform BM procedures. Interpretation of 400 or more LNs and 500 BMs was PDs' median expectations for fellows. PDs and HP diplomates considered coagulation and benign RBC disorders overemphasized on the certification examination. CONCLUSIONS: These results highlight how varied the practice of HP is and can provide guidance to HP PDs, those responsible for assessing HP programs, and the American Board of Pathology.


Subject(s)
Education, Medical, Graduate/standards , Hematology/education , Pathology, Clinical/education , Accreditation , Bone Marrow Examination , Certification , Clinical Competence , Curriculum , Flow Cytometry/standards , Hematologic Diseases/diagnosis , Hematologic Diseases/pathology , Hematologic Tests/standards , Hematology/standards , Humans , Lymph Nodes/pathology , Pathology, Clinical/standards , Program Evaluation , Surveys and Questionnaires , United States
8.
Haematologica ; 103(10): 1688-1697, 2018 10.
Article in English | MEDLINE | ID: mdl-29954930

ABSTRACT

The immunomodulatory drugs, lenalidomide and pomalidomide yield high response rates in multiple myeloma patients, but are associated with a high rate of thrombocytopenia and increased risk of secondary hematologic malignancies. Here, we demonstrate that the immunomodulatory drugs induce self-renewal of hematopoietic progenitors and upregulate megakaryocytic colonies by inhibiting apoptosis and increasing proliferation of early megakaryocytic progenitors via down-regulation of IKZF1. In this process, the immunomodulatory drugs degrade IKZF1 and subsequently down-regulate its binding partner, GATA1. This results in the decrease of GATA1 targets such as ZFPM1 and NFE2, leading to expansion of megakaryocytic progenitors with concomitant inhibition of maturation of megakaryocytes. The down-regulation of GATA1 further decreases CCND1 and increases CDKN2A expression. Overexpression of GATA1 abrogated the effects of the immunomodulatory drugs and restored maturation of megakaryocytic progenitors. Our data not only provide the mechanism for the immunomodulatory drugs induced thrombocytopenia but also help to explain the higher risk of secondary malignancies and long-term cytopenia induced by enhanced cell cycling and subsequent exhaustion of the stem cell pool.


Subject(s)
Apoptosis/drug effects , Down-Regulation/drug effects , Hematopoietic Stem Cells/metabolism , Ikaros Transcription Factor/biosynthesis , Immunologic Factors/pharmacology , Megakaryocytes/metabolism , Female , Hematopoietic Stem Cells/cytology , Humans , Male , Megakaryocytes/cytology
9.
J Pediatr Hematol Oncol ; 39(4): e227-e232, 2017 05.
Article in English | MEDLINE | ID: mdl-28085746

ABSTRACT

Concurrent perturbations in different driver genes have been reported primarily in lymphoma. In acute myeloid leukemia (AML), cases with concurrent alterations in 2 driver genes are infrequently reported. In contrast to pathogenetic pathways in lymphoma with concurrently perturbed genes, the initial gene alteration in AML arrests maturation and the alteration in the second gene promote self-renewal of the blasts. Here, we report a unique case of infantile leukemia in which chromothripsis in chromosome 8 completely altered the G-band structure and resulted in concurrent changes in MOZ/NCOA2, FGFR1, RUNX1T1, and RUNX1. These multiple-hit abnormalities in AML have not been reported previously.


Subject(s)
Chromosomes, Human, Pair 8/genetics , Chromothripsis , Leukemia, Myeloid, Acute/genetics , Core Binding Factor Alpha 2 Subunit/genetics , Histone Acetyltransferases/genetics , Humans , Infant , Nuclear Receptor Coactivator 2/genetics , Oligonucleotide Array Sequence Analysis , Proto-Oncogene Proteins/genetics , RUNX1 Translocation Partner 1 Protein , Receptor, Fibroblast Growth Factor, Type 1/genetics , Transcription Factors/genetics
10.
Am J Clin Pathol ; 146(1): 107-12, 2016 Jul.
Article in English | MEDLINE | ID: mdl-27357289

ABSTRACT

OBJECTIVES: The biannual Fellow In-Service Hematopathology Examination (FISHE) assesses knowledge in five content areas. We examined the relationship between taking the FISHE and performance on it with outcomes on the first attempted American Board of Pathology Hematology subspecialty certifying examination (ABP-HE). METHODS: The pass rate between the ABP-HE candidates who took the spring FISHE and those who did not were compared. The likelihood of fellows passing the ABP-HE based on their percentiles on the FISHE was also assessed. RESULTS: ABP-HE candidates who took the spring FISHE had a higher pass rate (96.4%) than those who did not (76.1%, P < .001). Spring FISHE performance, including total percentile and percentiles in four of five FISHE content areas, was only a weak predictor of passing the ABP-HE. CONCLUSIONS: Candidates who take the spring FISHE do better on the ABP-HE than those who do not. Most fellows passed the first attempted ABP-HE regardless of FISHE performance. Whether this is due to fellows making use of the FISHE as a self-evaluation tool to help identify and then correct their knowledge deficiencies remains to be determined.


Subject(s)
Clinical Competence , Education, Medical, Graduate , Educational Measurement , Fellowships and Scholarships , Certification , Humans , United States
11.
Leuk Lymphoma ; 54(9): 1965-74, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23216269

ABSTRACT

Lenalidomide (LEN) treatment in multiple myeloma (MM) results in a superior outcome. However, there is concern for increased myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) associated with LEN. Thus, bone marrow morphology and cytogenetics studies from 40 patients were evaluated for early signs of MDS prior to therapy, during therapy and at follow-up. Newly diagnosed patients with MM treated with LEN and dexamethasone (LD) alone or followed by autologous stem cell transplant (LD/ASCT), or patients with relapsed/refractory MM treated with LEN, bendamustine and dexamethasone (BLD) were included. One patient developed MDS. Baseline prevalence of mild morphologic myelodysplasia was highest in pretreated patients with MM (BLD, 71%), but was also seen in newly diagnosed patients (LD and LD/ASCT, 17%). The prevalence of myelodysplasia did not increase over time. Thus, this study did not reveal rapidly emerging MDS in 39 of 40 patients with MM treated with LEN. The development of MDS in one patient suggests that longer follow-up is needed for all.


Subject(s)
Bone Marrow/pathology , Immunologic Factors/adverse effects , Multiple Myeloma/complications , Multiple Myeloma/pathology , Myelodysplastic Syndromes/etiology , Thalidomide/analogs & derivatives , Aged , Biopsy , Cytogenetic Analysis , Female , Humans , Immunologic Factors/therapeutic use , In Situ Hybridization, Fluorescence , Lenalidomide , Longitudinal Studies , Male , Middle Aged , Multiple Myeloma/diagnosis , Multiple Myeloma/drug therapy , Retrospective Studies , Thalidomide/adverse effects , Thalidomide/therapeutic use
12.
Cytometry B Clin Cytom ; 82(4): 217-28, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22431481

ABSTRACT

BACKGROUND: Altered neutrophil maturation patterns have been reported useful for identification of myelodysplastic syndromes (MDS). METHODS: Neutrophil maturation patterns based on CD11b, CD13, and CD16 were visually and numerically evaluated in 19 control, 23 MDS, 37 nondiagnostic for MDS (NDM) specimens, and 19 also processed 1 and 2 days subsequently. RESULTS: In contrast to maturation patterns illustrated previously by others as "normal," 84% of controls displayed diminished acquisition of CD16, imparting a contracted appearance. Such divergence from published "normal" patterns was usually mild-moderate, considered nonspecific, and associated with delayed processing: longer intervals between collection and processing (median 20.5 vs. 5.2 h), and following 1 and 2 days delay. Findings restricted to nonspecific contraction were found in 56% MDS and 78% NDM specimens. Evaluation for aberrant patterns was still performed with mild-moderate contraction present, but concern for over interpretation led to use of an equivocal-aberrant category. Nine cases had aberrant or equivocal-aberrant patterns (seven MDS, two NDM) with distinct visual alterations that differed from nonspecific contraction and had numerical evidence for a left shift: myeloblasts increased (67%) and least mature neutrophils (CD11b-/low, CD16-/low) increased (78%). Although evidence for a left shift was associated with MDS, it was also seen in NDM specimens with a synchronous left shift. CONCLUSIONS: Neutrophil maturation patterns that diverge from previously illustrated "normal" patterns, not specific for MDS, may be common in some settings. Laboratories seeking to implement FC evaluation for MDS must determine which findings have sufficient specificity for MDS within their own practice and patient population.


Subject(s)
Granulocyte Precursor Cells/physiology , Myelodysplastic Syndromes/pathology , Neutrophils/metabolism , CD11b Antigen/metabolism , CD13 Antigens/metabolism , Case-Control Studies , Flow Cytometry , GPI-Linked Proteins/metabolism , Humans , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/metabolism , Neutrophils/pathology , Neutrophils/physiology , Receptors, IgG/metabolism , Specimen Handling , Time Factors
13.
Diagn Cytopathol ; 40(7): 629-34, 2012 Jul.
Article in English | MEDLINE | ID: mdl-21591274

ABSTRACT

Toxoplasma gondii usually causes an asymptomatic and then latent infection in human adults; however, a potentially fatal disseminated form can occur in immunocompromised patients. Given that the diagnosis of acute Toxoplasma infection, as opposed to latent disease, relies on finding direct evidence of T. gondii infection in tissue, pathologic examination is critical. There have only been a few reports describing the cytomorphology of Toxoplasma in exfoliative cytology, and no reports of the findings in Thin Prep. In this report, we describe a fatal case of toxoplasmosis in a cardiac transplant patient that was diagnosed by respiratory cytopathology. Although the extracellular organisms were well visualized on the Wright-Giemsa stained cytospin, they were only faintly seen on the Pap-stained cytospin trapped within mucin and were not easily appreciated on the ThinPrep slides nor the H&E stained cell block sections. An immunohistochemical stain for Toxoplasma performed on the cell block was strongly positive, and an autopsy performed on the patient confirmed disseminated infection. Our case illustrates that the diagnosis of Toxoplasma in exfoliative cytology specimens can be challenging since organisms are not well visualized on ThinPrep or Pap-stained material; therefore, Wright-Giemsa stained material can be particularly helpful.


Subject(s)
Bronchoalveolar Lavage Fluid/parasitology , DNA, Protozoan/isolation & purification , Toxoplasma/isolation & purification , Toxoplasmosis/diagnosis , Bronchoalveolar Lavage/methods , DNA, Protozoan/genetics , Fatal Outcome , Heart Transplantation/pathology , Heart Transplantation/rehabilitation , Humans , Immunohistochemistry/methods , Lung Diseases/diagnosis , Lung Diseases/parasitology , Lung Diseases/pathology , Male , Middle Aged , Multiple Organ Failure/parasitology , Toxoplasma/genetics , Toxoplasma/pathogenicity , Toxoplasmosis/parasitology , Toxoplasmosis/pathology
14.
Cytometry B Clin Cytom ; 82(2): 85-92, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22031455

ABSTRACT

BACKGROUND: Flow cytometric immunophenotyping has an established role in the diagnosis and monitoring of B-lymphoblastic leukemia (B-LL). However, the search continues for an optimal reagent set that can identify leukemic blasts with specificity, reproducibility, and sensitivity, at any point during the course of the disease and in every specimen type. METHODS: This study evaluated the diagnostic utility of detecting the intracytoplasmic antigens zeta-associated protein (ZAP-70) and Bcl-2 in the distinction between the leukemic blasts of B-LL and hematogones. RESULTS: In comparison with hematogones in reference specimens, significantly higher levels of Bcl-2 were identified in 21 of 23 (91%) B-LL. In particular, Bcl-2 expression was consistently higher in leukemic blasts with bright intensity CD10 expression than the equivalent most immature (CD10 bright intensity) hematogones. As previously reported, Bcl-2 expression was lower in B-LL with BCR-ABL1 gene rearrangement, but the fluorescence intensity of this group of specimens was still significantly higher than that seen for hematogones. In contrast, ZAP-70 was expressed at significantly higher levels in only 7 of 23 (30%) B-LL and demonstrated other findings that might limit clinical utility, including differences in the level of ZAP-70 expression during therapy and between blasts in the peripheral blood and bone marrow. CONCLUSIONS: Bcl-2 over-expression provides a useful tool for the distinction between B-LL and hematogones. In contrast, although further optimization of the ZAP-70 assay might increase the sensitivity of detection, over-expression of ZAP-70 was identified in only a minority of B-LL.


Subject(s)
Flow Cytometry/methods , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Proto-Oncogene Proteins c-bcl-2/biosynthesis , ZAP-70 Protein-Tyrosine Kinase/biosynthesis , ZAP-70 Protein-Tyrosine Kinase/blood , Adolescent , Adult , Aged , B-Lymphocytes/pathology , Bone Marrow Cells/immunology , Bone Marrow Cells/metabolism , Child , Child, Preschool , Female , Humans , Immunophenotyping/methods , Infant , Male , Middle Aged , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Young Adult
15.
Blood ; 117(19): 5157-65, 2011 May 12.
Article in English | MEDLINE | ID: mdl-21389327

ABSTRACT

Immunomodulatory derivatives of thalidomide (IMiD compounds), such as pomalidomide and lenalidomide, are highly active in multiple myeloma (MM) treatment. However, the precise mechanisms of action and resistance in MM are unresolved. Here we show that IMiD compounds down-regulate CCAAT/enhancer-binding protein-ß (C/EBPß) resulting in abrogation of cell proliferation. Overexpression of C/EBPß rescued MM cells from IMiD-induced inhibition of proliferation, indicating that C/EBPß is critical in mediating antiproliferative effects. IMiD-induced decrease of C/EBPß protein led to impaired transcription of interferon regulatory factor 4 (IRF4). Down-regulation of IRF4 by lenalidomide was confirmed by longitudinal studies of bone marrow samples from 23 patients obtained before and during lenalidomide treatment using CD138⁺/IRF4⁺ double labeling. In contrast to down-regulation of C/EBPß protein, IMiD compounds did not alter C/EBPß mRNA levels or protein stability, suggesting translational regulation of C/EBPß. We could demonstrate that C/EBPß protein expression is under eIF4E-translational control in MM. Furthermore, inhibition of the eIF4E-C/EBPß axis by IMiD compounds was not observed in IMiD-resistant MM cells. However, targeting translation at a different level by inhibiting eukaryotic translation initiation factor 4E-binding protein 1 phosphorylation overcame resistance, suggesting that this pathway is critical and might be a target to overcome drug resistance.


Subject(s)
CCAAT-Enhancer-Binding Protein-beta/biosynthesis , Eukaryotic Initiation Factor-4E/metabolism , Gene Expression Regulation/drug effects , Immunologic Factors/pharmacology , Multiple Myeloma/metabolism , Apoptosis/immunology , Blotting, Western , Cell Separation , Down-Regulation , Flow Cytometry , Gene Knockdown Techniques , Humans , Immunohistochemistry , Interferon Regulatory Factors/biosynthesis , Lenalidomide , Protein Biosynthesis/drug effects , Reverse Transcriptase Polymerase Chain Reaction , Thalidomide/analogs & derivatives , Thalidomide/pharmacology , Transfection
16.
Blood ; 115(3): 605-14, 2010 Jan 21.
Article in English | MEDLINE | ID: mdl-19965623

ABSTRACT

The immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide yield high response rates in patients with multiple myeloma, but the use of IMiDs in multiple myeloma is associated with neutropenia and increased risk for venous thromboembolism (VTE) by mechanisms that are unknown. We show that IMiDs down-regulate PU.1, a key transcription factor involved in granulocyte differentiation in vitro and in patients treated with lenalidomide. Loss of PU.1 results in transient maturation arrest with medullary accumulation of immature myeloid precursors and subsequent neutropenia. Accumulation of promyelocytes leads to high levels of the platelet aggregation agonist, cathepsin G stored in the azurophilic granules of promyelocytes. High levels of cathepsin G subsequently may increase the risk of VTE. To our knowledge, this is the first report investigating the underlying mechanism of IMiD-induced neutropenia and increased risk of VTE in multiple myeloma.


Subject(s)
Cell Differentiation/drug effects , Immunologic Factors/pharmacology , Myeloid Progenitor Cells/drug effects , Neutropenia/chemically induced , Proto-Oncogene Proteins/genetics , Trans-Activators/genetics , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Differentiation/immunology , Cells, Cultured , Down-Regulation , Granulocyte Colony-Stimulating Factor/pharmacology , Granulocyte Precursor Cells/drug effects , Granulocyte Precursor Cells/metabolism , Granulocyte Precursor Cells/physiology , Granulocytes/drug effects , Granulocytes/physiology , Humans , Immunologic Factors/adverse effects , Immunologic Factors/therapeutic use , Lenalidomide , Models, Biological , Multiple Myeloma/blood , Multiple Myeloma/drug therapy , Multiple Myeloma/pathology , Myeloid Progenitor Cells/metabolism , Myeloid Progenitor Cells/physiology , Neutropenia/immunology , Neutrophils/drug effects , Neutrophils/metabolism , Neutrophils/physiology , Platelet Aggregation/drug effects , Proto-Oncogene Proteins/metabolism , Risk Factors , Thalidomide/analogs & derivatives , Thalidomide/pharmacology , Trans-Activators/metabolism , Venous Thromboembolism/etiology
17.
Am J Clin Pathol ; 123(1): 125-31, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15762288

ABSTRACT

Copper deficiency is a rare cause of sideroblastic anemia and neutropenia that often is not suspected clinically. The morphologic findings in bone marrow, while not pathognomonic, are sufficiently characteristic to suggest the diagnosis, leading to further testing to establish the correct diagnosis. Excess zinc ingestion is among the causes of copper deficiency. We present 3 cases of zinc-induced copper deficiency in which the diagnosis first was suggested on the basis of bone marrow examination. The first patient was a 47-year-old man with a debilitating peripheral neuropathy that had progressed during the previous 18 months, mild anemia, and severe neutropenia. The second was a 21-year-old man receiving zinc supplementation for acrodermatitis enteropathica in whom moderate normocytic anemia and neutropenia developed. The third patient was a 42-year-old man with anemia, severe neutropenia, and a peripheral neuropathy that had progressed during 8 months. The bone marrow findings in all cases suggested copper deficiency, which was confirmed by further laboratory testing and determined to be due to zinc excess. The morphologic features, clinical manifestations, differential diagnosis, and pathogenetic mechanisms are discussed.


Subject(s)
Bone Marrow/pathology , Copper/deficiency , Zinc/adverse effects , Adult , Anemia, Sideroblastic/etiology , Biopsy , Bone Marrow Examination , Copper/metabolism , Diagnosis, Differential , Humans , Male , Metallothionein/metabolism , Middle Aged , Neutropenia/etiology , Peripheral Nervous System Diseases/etiology , Zinc/metabolism
18.
Cytometry B Clin Cytom ; 56(1): 30-42, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14582135

ABSTRACT

BACKGROUND: The classic immunophenotype for chronic lymphocytic leukemia (CLL) is CD19(+), restricted dim surface expression of kappa or lambda light chain, CD5(+), CD23(+), dim CD20(+), negative FMC7, and negative CD79b. However, the necessity of assaying for all 3 pan B-cell markers (CD20, FMC7, and CD79b) by flow cytometry has not been definitively documented for CLL. METHODS: Qualitative patterns and semi-quantitative assessment of staining intensity for CD20, FMC7 and CD79b were performed in 70 cases with a current or prior diagnosis of CLL or CLL with increased prolymphocytes leukemia (CLL/PL). The concurrent morphology in 66 of 70 specimens was classified as typical CLL in 53 cases, CLL/PL in 10 cases, and large cell lymphoma in 3 cases. RESULTS: Forty percent of the cases varied from the characteristic immunophenotype by having moderate or bright staining of CD20 (36%), FMC7 (7%), and/or CD79b (18%). Discrepant qualitative staining patterns were found between FMC7 and CD20 (21%), CD20 and CD79b (15%), and CD79b and FMC7 (10%). Semiquantitative measurement of staining intensity showed little correlation between CD79b and CD20 or FMC7. Moderate correlation was seen between CD20 and FMC7. No correlation was observed between morphology and intensity of marker expression. CONCLUSIONS: Variable patterns and intensity of staining were seen for FMC7, CD20, and CD79b in this cohort of CLL samples. Dim or negative staining was most consistently seen for FMC7 (93% of specimens). Although FMC7 staining intensity was moderately correlated with CD20, CD79b intensity was poorly correlated with either CD20 or FMC7, and thus, may provide some independent information.


Subject(s)
B-Lymphocytes/immunology , Biomarkers, Tumor/immunology , Immunophenotyping , Leukemia, Lymphocytic, Chronic, B-Cell/classification , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Antigens, CD/analysis , Antigens, CD/immunology , Antigens, CD20/analysis , Antigens, CD20/immunology , B-Lymphocytes/pathology , Biomarkers, Tumor/analysis , CD79 Antigens , Flow Cytometry , Fluorescent Antibody Technique , Glycoproteins/analysis , Glycoproteins/immunology , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Reproducibility of Results
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