Foxwell Emmons

Hematogones: a review and update

Our knowledge regarding the nature and function of ‘hematogones’ has evolved considerably, since the initial description more than 70 years ago. Once considered the ‘mystery cells’ of the bone marrow, major advances in immunology and flow cytometry have enabled us to better characterize these cells and recognize them as physiologic precursors of B-cells. In this review, we describe the morphologic and phenotypic characteristics and clinical relevance of hematogones, and report recent advances in our understanding and knowledge of these cells as they relate to physiologic and different pathologic conditions.

FISH analysis in addition to G-band karyotyping: Utility in evaluation of myelodysplastic syndromes?

Cytogenetic analysis provides important diagnostic and prognostic information for patients with myelodysplastic syndromes (MDS). Prior studies, mostly comprised of small sample sizes, have reported conflicting results while evaluating the usefulness of FISH in addition to G-band karyotyping in MDS. In the current study, the utility of performing a tailored FISH panel, in addition to G-band karyotyping was evaluated in a series of 110 MDS patients diagnosed at our institute. Using our FISH panel, clonal cytogenetic abnormalities were detected in 3/8 (38%) of MDS cases with karyotype failure and in 5/54 (9%) cases with normal G-band karyotypes, all the latter had intermediate or high grade MDS. Of the cases with abnormal G-band karyotypes, 6/48 (13%) showed discrepancies between FISH and G-band results, however, FISH analysis only lead to reassignment of karyotypic abnormalities to different chromosomes, MDS cytogenetic risk stratification was not altered. Our findings suggest that FISH testing is informative only in MDS cases with karyotype failure and intermediate-high grade MDS cases with normal G-band karyotype and has limited utility in cases that have normal G-band karyotypes and morphologic features of low grade MDS or in cases with abnormal G-band karyotypes.

Aberrant T-cell antigen expression in B lymphoblastic leukaemia

B lymphoblastic leukaemia (B‐ALL) cells are characterized by the expression of various B‐cell antigens. Expression of T/Natural Killer‐cell antigens, however, has rarely been reported in B‐ALL (TAg+ B‐ALL), and the significance of this aberrant antigen expression is unclear. We thus analysed the frequency of TAg+ B‐ALL at our institution and investigated its significance in the context of immunophenotypes, cytogenetic/molecular findings, and prognosis. We reviewed 134 consecutive cases of B‐ALL and found 18 cases (13·4%) of TAg+ B‐ALL. The most common aberrant T‐cell antigens expressed were CD2, CD5, and CD7 at equivalent rates (each in six cases), CD4 (two cases), and CD56 (three cases). Adverse cytogenetic abnormalities were seen in a significantly larger proportion of the TAg+ cases (72·2%) than the TAg− cases (32·2%; P = 0·003). Multivariate Cox‐regression analysis showed that the risk of relapse over time was higher in the TAg+ cases, independent of high risk status (based on age and white blood cell count) and the presence of adverse cytogenetic abnormalities (hazard ratio = 2·256, P = 0·065). These findings suggest that T‐cell antigen expression in B‐ALL may be an independent predictor of poor prognosis, and a useful marker to identify patients at increased risk for relapse and for harbouring adverse cytogenetic abnormalities.

Cytochemical diagnosis of Gaucher's disease by iron stain

Gaucher’s disease, the most common lysosomal storage disorder, arises from mutations in the gene encoding glucocerebrosidase. The glucocerebrosidase enzyme, which cleaves glucose from ceramide, is markedly reduced or absent. This results in accumulation of glucocerebroside, primarily in phagocytic cells. Of the various subtypes, the most common form, accounting for up to 99% of cases, is that of type I, or the chronic non-neuronopathic form. The disease is inherited in an autosomal recessive fashion, manifests in adulthood with splenic and skeletal involvement, and occurs predominantly in the Ashkenazi Jewish population. Clinical features include pathological fractures as well as cytopenia(s) caused by hypersplenism. The diagnosis is generally made by cytomorphologic examination of the bone marrow, and confirmed by measurement of glucocerebrosidase activity in peripheral blood leucocytes or cultured skin fibroblasts. Gaucher’s cells show diffuse and avid iron staining using a Prussian blue iron stain (left, Prussian blue stain with Wright–Giemsa inset), in contrast to normal bone marrow histiocytes or pseudo-Gaucher histiocytes associated with chronic myeloproliferative disorders such as chronic myeloid leukaemia (right, Prussian blue stain with Wright–Giemsa inset). This was determined over a generation ago to be probably due to phagocytosed erythrocytes. The current generation of haematologists and pathologists need to be aware of this phenomenon. Any histiocyte with diffuse iron uptake should be considered as highly suspicious for Gaucher’s disease, and an appropriate clinical work-up should be instituted.

Hematogones are markedly reduced in pediatric acquired aplastic anemia: multiparametric flow cytometric analysis

Acquired aplastic anemia (AA) and myelodysplastic syndromes (MDS) are bone marrow (BM) failure syndromes with overlapping clinical features, and at least a subset appears to share common pathophysiologic mechanisms. Recent studies of MDS have shown down-regulation of genes involved in B-cell development and decreased B-cell precursors (hematogones). We explored the possibility that AA, similar to MDS, might also be associated with defects in development of lymphoid cells, especially B-cells, by using flow cytometry to assess the presence of hematogones and mature lymphocytes in BM samples from 25 children with AA and 41 age-matched controls. We observed that the percentage of total and early (stage I) hematogones were significantly decreased in AA compared to controls, and they returned to normal numbers after hematopoietic stem-cell transplant. This demonstrates early B-cell lineage involvement in AA, similar to recent findings in MDS. Our findings suggest dysfunction of an early multilineage progenitor in the pathogenesis of AA.

The pattern of cytoplasmic IgM expression in the context of the three currently recognised maturational stages of hematogones.

Hematogones are physiologic B-cell precursors found in the bone marrow (BM). They vary in number and are more commonly seen in pediatric patients and in reactive or regenerative conditions [1]. They exhibit characteristic and well-documented phenotypic patterns of maturation and do not demonstrate asynchronous or aberrant antigen expression by flow cytometric analysis (FC) [1–4]. Three stages of hematogone maturation have been described [4]. Early hematogones (Stage I) are the most immature forms, usually comprising a small minority of the total hematogone population. They express the immaturity markers CD34 and TdT, and express dim CD19, and relatively bright CD10 and CD43. No expression of CD20 is seen at this early stage. A larger proportion of hematogones belong to the intermediate stage of maturation (Stage II), during which both immaturity markers, CD34 and TdT, are lost, and CD19 expression becomes relatively brighter. The intensity of CD10 and CD43 expression decreases gradually. In the later stage of maturation (Stage III), the cells acquire CD20 expression, whereas both CD10 and CD43 expression eventually disappear. There are morphological and phenotypic similarities between hematogones and lymphoblasts of B-ALL. Various groups have reported that virtually all B-ALL show phenotypic abnormalities that can be detected using variably extensive FC panels [1,5]. Thus, in cases where the phenotype of the diagnostic leukemic marrow sample is available and the current marrow contains a significant proportion of phenotypically abnormal cells, differentiating residual or recurrent leukemia may be straight-forward. However, differentiating minimal marrow involvement by B-ALL from a small population of hematogones is still challenging. This distinction is further complicated if the predominant hematogone population is left-shifted (i.e. increased Stage 1 CD34þ/TdTþ hematogones) as has been previously observed in rapidly regenerating marrows during the early stages after BM transplantation [1,6]. Thus, despite the well-characterised phenotype and maturation patterns of hematogones, they may still pose problems in differentiation from residual or recurrent leukemic lymphoblasts. Although it has been known for decades that proB-cells do not express cyt IgM and pre-B-cells do [7,8], the pattern of cyt IgM expression in the context of the three currently recognised maturational stages of hematogones has not been characterised. This expression is particularly relevant as a small, but significant proportion (25%) of B-ALL express cyt IgM [9]. We investigated cyt IgM expression in the context of the three recognised maturational stages of hematogones, in both regenerating marrow samples post-chemotherapy for B-ALL and for diseases other than B-ALL, in an attempt to provide an additional resource in differentiating the hematogones from leukemic lymphoblasts. We analysed 25 BM aspirate samples by FC (20 aspirates from patients receiving treatment for a disease other than B-ALL [seven acute myeloid

Spectrum of Childhood Epstein-Barr Virus–Associated T-Cell Proliferations and Bone Marrow Findings

Systemic Epstein-Barr virus-positive (EBV+) T-cell lymphoproliferative disorder of childhood is a recently described entity. The majority of such cases have been reported from Asia, which suggests an underlying genetic predisposition. We analyzed the clinicopathologic characteristics of 5 children with EBV+ T-cell lymphoid proliferations evaluated and treated at our institute over a 2-year period. There were 3 males and 2 females of Latino (n = 4) or Caucasian (n = 1) heritage with a median age of 5 years (age range 2–18 years). All patients presented with EBV infection (acute, n = 4) with elevated serum EBV viral loads at the time of diagnosis and had systemic manifestations, including fever, hepatosplenomegaly, and pancytopenia. The bone marrow biopsies showed EBV+/CD8+ T-cell lymphocytosis in all patients, with variable degrees of histiocytosis, plasmacytosis, and hemophagocytosis. Interestingly, there was marked and consistent depletion of mature and precursor B cells in the marrow (<1% of total marrow cellularity) in all patients. Three of the patients died of disease-associated complications 2 to 12 weeks after initial diagnosis. Our study describes the detailed bone marrow findings, contributes to the growing number of cases of systemic EBV+ T-cell lymphoproliferative disorder of childhood occurring in the Western hemisphere, and documents this disorder in patients from the Caribbean countries.

Atlas of Differential Diagnosis in Neoplastic Hematopathology, Second Edition

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