Acute myeloid leukemia in SRP54-mutated congenital neutropenia.

SRP54 mutations have recently been implicated in congenital neutropenia (CN) and the in-frame deletion, p.Thr117del, is the most common pathogenic mutation reported. The largest study of SRP54-mutated CN to-date followed 23 patients for a median of 15 years. No patients developed a hematologic malignancy in that study. Given the known risk of leukemia in other CNs it is crucial to know whether patients with SRP54-mutated CN have an increased risk of leukemia. We report the first case of leukemia in a patient with SRP54-mutated CN. A 15-year-old male with SRP54-mutated CN (p.Thr117del) was diagnosed with acute myeloid leukemia with myelodysplasia-related changes on a screening bone marrow evaluation. Next generation sequencing of the leukemia cells identified CSF3R and RUNX1 mutations. These mutations commonly co-exist in CN-associated malignancies and suggest leukemogenesis in SRP54-mutated CN may occur in a similar manner to other CNs. He was successfully treated with CPX-351 followed by hematopoietic cell transplant (HCT) and remains in remission at a follow-up time of 9 months. Although conclusions from this single report must be limited, this has potentially significant implications for both screening and treatment practices for these patients, including the role and timing of HCT.

Donor-derived myeloid sarcoma in two kidney transplant recipients from a single donor.

We report the rare occurrence of donor-derived myeloid sarcoma in two kidney transplant patients who received organs from a single deceased donor. There was no evidence of preexisting hematologic malignancy in the donor at the time of organ recovery. Both recipients developed leukemic involvement that appeared to be limited to the transplanted organ. Fluorescence in situ hybridization (FISH) and molecular genotyping analyses confirmed that the malignant cells were of donor origin in each patient. Allograft nephrectomy and immediate withdrawal of immunosuppression were performed in both cases; systemic chemotherapy was subsequently administered to one patient. Both recipients were in remission at least one year following the diagnosis of donor-derived myeloid sarcoma. These cases suggest that restoration of the immune system after withdrawal of immunosuppressive therapy and allograft nephrectomy may be sufficient to control HLA-mismatched donor-derived myeloid sarcoma without systemic involvement.

Ferritin H is a novel marker of early erythroid precursors and macrophages.

AIMS: Macrophages play a critical role in iron homeostasis by recycling iron from red cells and storing it in ferritin, an iron storage protein. The recycled iron is delivered to erythroid precursors for erythropoiesis. In this study, we aimed to determine whether ferritin is highly expressed in macrophages and erythroid precursors, and whether it can be used as a marker for these two cell types. METHODS AND RESULTS: A ferritin monoclonal antibody was developed, and immunohistochemistry was performed. In normal bone marrows, ferritin antibody stained early erythroid precursors and macrophages. In contrast, myeloid cells, lymphoid cells and megakaryocytes lacked ferritin expression. In leukaemic bone marrows, ferritin was selectively expressed in erythroid blasts (M6), whereas all other blasts were negative. In lymph nodes, ferritin was highly and specifically expressed in macrophages, whereas lymphocytes completely lacked ferritin expression. In non-haematopoietic tissues, ferritin antibody highlighted alveolar macrophages in the lung, as well as sinus macrophages in the liver and spleen. CONCLUSIONS: We conclude that ferritin is a novel and reliable marker for macrophages and early erythroid precursors, and may be of clinical utility in the diagnosis of diseases associated with these two cell types.

Burkitt's Lymphoma Presenting as Late-Onset Posttransplant Lymphoproliferative Disorder following Kidney and Pancreas Transplantation: Case Report and Review of the Literature.

Posttransplant lymphoproliferative disorders (PTLD) are a rare, but serious complication following transplantation. Late-onset PTLD are often associated with more monoclonal lesions and consequently have a worse prognosis. There are only isolated case reports of Burkitt's lymphoma presenting as PTLD. We present an extremely rare, aggressive Burkitt's lymphoma years after kidney and pancreas transplantation which was successfully treated with combination chemotherapy along with withdrawal of immunosuppression. The patient remains in complete remission more than 2 years after his diagnosis. We also provide a succinct review of treatment of various PTLD and discuss the role of Epstein-Barr virus infection in the pathogenesis of PTLD.

Flow cytometric analysis of immunoglobulin heavy chain expression in B-cell lymphoma and reactive lymphoid hyperplasia.

The diagnosis of B-cell lymphoma (BCL) is often dependent on the detection of clonal immunoglobulin (Ig) light chain expression. In some BCLs, the determination of clonality based on Ig light chain restriction may be difficult. The aim of our study was to assess the utility of flow cytometric analysis of surface Ig heavy chain (HC) expression in lymphoid tissues in distinguishing lymphoid hyperplasias from BCLs, and also differentiating various BCL subtypes. HC expression on B-cells varied among different types of hyperplasias. In follicular hyperplasia, IgM and IgD expression was high in mantle cells while germinal center cells showed poor HC expression. In other hyperplasias, B cell compartments were blurred but generally showed high IgD and IgM expression. Compared to hyperplasias, BCLs varied in IgM expression. Small lymphocytic lymphomas had lower IgM expression than mantle cell lymphomas. Of importance, IgD expression was significantly lower in BCLs than in hyperplasias, a finding that can be useful in differentiating lymphoma from reactive processes.

Concomitant occurrence of sinus histiocytosis with massive lymphadenopathy and nodal marginal zone lymphoma.

Sinus histiocytosis with massive lymphadenopathy (SHML), also known as Rosai-Dorfman disease, is a rare self-limiting disorder of histiocytes with unknown etiology. Sinus histiocytosis with massive lymphadenopathy is most common in children and young adults and is characterized by painless lymphadenopathy. Histologically there is a proliferation of sinus histiocytes with lymphophagocytosis or emperipolesis. On rare occasions, SHML has been associated with lymphoma, usually involving different anatomic sites and developing at different times. We report a case of concomitant SHML and nodal marginal zone lymphoma involving the same lymph node without involvement of other nodal or extranodal sites. The presence of concomitant SHML within the lymph node involved by nodal marginal zone lymphoma may represent the responsiveness of SHML histiocytes to B-cell-derived cytokines in lymphoproliferative disorders. To our knowledge, this is the first description of concomitant occurrence of SHML and nodal marginal zone lymphoma.

An unusual case of acute myeloid leukemia: late isolated testicular relapse followed by isolated central nervous system relapse.

Testicular relapse of acute myeloid leukemia without bone marrow involvement is a rare event. We describe a case of an 18-year-old male who had an isolated testicular relapse 86 months (7.2 years) from original diagnosis. He was treated with surgery only, without adjuvant therapy. The patient then developed central nervous system involvement 9 months later. Fluorescence in situ hybridization and immunohistochemistry were used to establish the diagnosis of a relapse rather than a new leukemic process. He was treated with intrathecal chemotherapy and systemic reinduction, followed by a stem cell transplant. This patient had a 7.2-year period between original diagnosis and the testicular relapse of acute myeloid leukemia.

Spatial distribution of blood vessels and CD34+ hematopoietic stem and progenitor cells within the marrow cavities of human cancellous bone.

UNLABELLED: Current bone marrow dosimetry methods inherently assume that the target cells of interest for the assessment of leukemia risk (stochastic effects) or marrow toxicity (deterministic effects) are uniformly localized throughout the marrow cavities of cancellous bone. Previous studies on mouse femur, however, have demonstrated a spatial gradient for the hematopoietic stem and progenitor cells, with higher concentrations near the bone surfaces. The objective of the present study was to directly measure the spatial concentration of these cells, as well as marrow vasculature structures, within images of human disease-free bone marrow. METHODS: Core-biopsy samples of normal bone marrow from the iliac crest were obtained from clinical cases at Shands Hospital at the University of Florida Department of Pathology. The specimens were sectioned and immunohistochemically stained for CD34 (red) and CD31 (brown) antigens. These 2 stains were used simultaneously to differentiate between hematopoietic stem and progenitor cells (CD34(+)/CD31(-)) and vascular endothelium (CD34(+)/CD31(+)). Distances from hematopoietic CD34(+) cells and blood vessels to the nearest bone trabecula surface were measured digitally and then binned in 50-mum increments, with the results then normalized per unit area of marrow tissue. The distances separating hematopoietic CD34(+) cells from vessels were also tallied. RESULTS: Hematopoietic CD34(+) cells were found to exist along a linear spatial gradient with a maximal areal concentration localized within the first 50 mum of the bone surfaces. An exponential spatial concentration gradient was found in the concentration of blood vessel fragments within the images. Distances between hematopoietic CD34(+) cells and blood vessels exhibited a lognormal distribution indicating a shared spatial niche. CONCLUSION: Study results confirm that the spatial gradient of hematopoietic stem and progenitor cells previously measured in mouse femur is also present within human cancellous bone. The dosimetric implication of these results may be significant for those scenarios in which the absorbed dose itself is nonuniformly delivered across the marrow tissues, as would be the case for a low-energy beta- or alpha-particle emitter localized on the bone surfaces.