Pancytopenia due to bone marrow necrosis in acute myelogenous leukemia: Role of reactive CD8 cells

Bone marrow necrosis is a rare clinical condition often associated with hematological malignancy. The mechanism by which malignant disease causes marrow necrosis is unknown. We present a case of a patient with newly diagnosed pancytopenia with bone marrow biopsy evidence of extensive marrow necrosis. Upon further work-up utilizing Tc bone scan directed bone marrow biopsy, a massive CD8+ T cell marrow infiltrate was discovered engulfing AML-M2 blasts. The role of Tc bone scans in the work-up of bone marrow necrosis as well as the potential mechanism of AML-M2 induced marrow necrosis in the setting of reactive CD8+ T cell infiltration is discussed. Am. J. Hematol. 59:74– 78, 1998. © 1998 Wiley-Liss, Inc.     

Bone marrow necrosis and degeneration.

Bone marrow necrosis, regarded as a rare finding in specimens from living patients, has been associated with a poor prognosis in patients with serious hematologic diseases and metastatic carcinoma. Two patients with extensive idiopathic bone marrow necrosis and a relatively benign course of illness were found. Therefore, we examined 500 consecutive bone marrow biopsy specimens that were obtained in a university hospital complex. Review of this material showed evidence of necrosis and degenerative changes of variable severity in one third of the biopsy specimens. It was found with approximately the same incidence in patients who underwent bone marrow biopsy for either neoplastic or nonneoplastic disorders; an increased prevalence was not observed in the group of patients who had received chemotherapy. Based on these observations, we believe necrosis and degeneration of the bone marrow is a commonplace finding that is frequently overlooked in a wide variety of acute and chronic disorders, and that requires further investigation to determine its clinical importance.     

Kaposi's sarcoma with bone marrow involvement: occurrence in a patient with the acquired immunodeficiency syndrome

A patient with the acquired immune deficiency syndrome (AIDS) and the lymphadenopathic variant of Kaposi's sarcoma developed skin, gastrointestinal and pulmonary lesions. A cellular specimen was obtained on bone marrow aspiration, but the bone marrow biopsy revealed dense reticulin fibrosis with slit-like spaces and endothelial-lined channels consistent with Kaposi's sarcoma. At postmortem examination, Kaposi's sarcoma was found in the pleura and lungs, throughout the gastrointestinal tract, in the liver and spleen, and in the thoracic and abdominal lymph nodes. Bone marrow architecture appeared grossly normal, but microscopic examination revealed numerous foci of Kaposi's sarcoma. This is the first reported example of bone marrow involvement with Kaposi's sarcoma in AIDS recognized antemortem.     

Nécrose médullaire avec sepsis compliquant une thrombocytémie essentielle : à propos d’une observation et revue de la littérature

Introduction

Bone marrow necrosis is a very rare condition which is characterized by a necrosis of hematopoietic progenitors, adipocytes and reticulin network.

Case report

We report a 62-year-old woman admitted to an intensive care unit for an essential thrombocytemia associated with bone marrow necrosis complicated by septic shock and progressive multi-organ failure. To our knowledge, this is the second case reported in the literature. The clinical presentation of bone marrow necrosis includes non-specific symptoms such as fever, bone pain and sometimes a clinically significant medullar insufficiency syndrome. Biology can reveal cytopenias, elevated LDH and alkaline phosphatase serum levels. The diagnosis is confirmed by bone marrow trephine biopsy. Bone marrow necrosis is classified as extensive if more than 50% of the bone marrow biopsy show necrosis. Haematological malignancies (particularly leukaemia), and solid malignant tumours (particularly gastro-intestinal or lung cancers) represent up to 90% of aetiologies and must be actively researched. Also, sickle cell disease and catastrophic anti-phospholipid syndrome must also be investigated. Essential thrombocytemia remains an exceptional cause of bone marrow necrosis.

Conclusion

Overall the prognosis of bone marrow necrosis is poor unless appropriate and intensive treatment, especially for sickle cell disease in which complete medullar regeneration has been observed.     

Aplastic crisis in sickle cell disorders: bone marrow necrosis and human parvovirus infection

Aplastic crisis in patients with sickle cell disease who develop a parvovirus infection may be associated with extensive bone marrow necrosis as well as acute selective erythroblastopenia. This illness may be manifested by pyrexia, lymphadenopathy, bone tenderness and significant hypoxemia with minimal roentgenographic findings in the lungs. It is uncertain whether the hypoxemia is caused by the effects of the viral infection on the lungs or is secondary to sickling of red blood cells in the pulmonary vasculature or both. The hypoxia may be sufficiently severe to require treatment with both oxygen and transfusion. The physical damage to the bone marrow associated with bone marrow necrosis may be more important than selective acute erythroblastopenia in inducing aplastic crisis in patients with sickle cell disorders. Studies of bone marrow biopsy specimens collected during parvovirus-associated aplastic crisis in patients with nonsickle cell hemolytic disorders would be helpful in determining the pathophysiology of parvovirus-associated disorders.     

Bone marrow biopsy in patients with hepatitis C virus infection: Spectrum of findings and diagnostic utility

Patients with hepatitis C virus (HCV) infection develop a number of hematologic disorders, with benign and malignant B‐cell proliferations being the most common. HCV‐infected patients are also prone to developing peripheral cytopenias, the etiologies of which are multifactorial and include hypersplenism and/or antiviral medications. Some of these patients may undergo bone marrow biopsy but no study has systematically recorded the bone marrow findings in this patient group. Here, we report on the range of bone marrow findings in 47 adult HCV‐infected patients. These patients, who lacked concurrent human immunodefiency virus (HIV) infection, most commonly presented for a bone marrow biopsy due to abnormal peripheral cell counts. The bone marrow biopsies displayed a range of findings. Dyserythropoiesis, present in 19% of the cases, was the most common finding. Patients with pancytopenia(n = 6), as defined by current World Health Organization standards, were the most likely to have bone marrow abnormalities; two pancytopenic patients had acute myeloid leukemia, and one patient had a primary myelodysplastic syndrome. There was no correlation in bone marrow findings and antiviral medications, MELD score, cirrhosis or splenomegaly, suggesting that the degree of bone marrow dysfunction is independent of stage of HCV. The results of this study suggest that bone marrow biopsy in HCV‐infected patients, even those with features of hypersplenism and/or documented antiviral therapy, can be a valid test for hematologic evaluation, especially for patients with severe pancytopenia and/or sudden alterations in peripheral cell counts. Am. J. Hematol. 85:106–110, 2010. © 2009 Wiley‐Liss, Inc.     

Bone marrow necrosis

Bone marrow necrosis has been regarded as a rare entity in specimens obtained from living patients and has been associated with poor prognosis. In contrast, we believe that it is a commonplace finding in bone marrow specimens which is frequently overlooked and which occurs in patients with multiple acute and chronic disorders. It is postulated that bone marrow necrosis eventuates from vascular occlusion of small blood vessels as a result of a number of causes. When bone marrow necrosis is prolonged, it may be associated with the development of bone marrow fibrosis and serve as a predisposing lesion for idiopathic myelofibrosis. Additional investigation of this phenomenon is required to determine its usefulness in the diagnosis of disease states and its role in the pathophysiology of a number of disorders.     

Successful treatment of hemophagocytic syndrome in a patient with T cell lymphoma,EBV infection,and bone marrow necrosis: A case report

Rationale:Hemophagocytic syndrome (HPS) is associated with a high mortality rate, and Epstein–Barr virus infection and hematological malignancies, especially T/natural killer cell lymphomas, are the most common causes; however, due to the complexity of clinical manifestations, the diagnosis is usually delayed. There are few reports of lymphoma-associated HPS (LAPS) in combination with bone marrow necrosis, and there is still no standard treatment for LAPS.Patient concerns:A 64-year-old man developed a fever, mild jaundice, fatigue, and bone pain. Positron emission tomography and bone marrow biopsy with immunohistochemistry were performed.Diagnosis:Imaging analysis and bone marrow examinations were compatible with HPS, T-cell lymphoma, and bone marrow necrosis.Interventions:The patient received combination therapy of rituximab and Cyclophosphamide, epirubicin, vincristine, glucocorticoid, etoposide.Outcomes:The patient achieved complete remission and a disease-free survival of 52 months.Lessons:HPS and its potential diseases should be diagnosed and treated as soon as possible. Clinicians should be aware of the presence of lymphoma in patients with HPS. Rituximab plays an important role in the prognosis of HPS, particularly Epstein–Barr virus positivity. Cyclophosphamide, epirubicin, vincristine, glucocorticoid remains an effective regimen for the treatment of T-cell LAPS. This study provides a better understanding of the diagnosis and treatment of LAPS.     

A novel G6PC3 gene mutation in severe congenital neutropenia: pancytopenia and variable bone marrow phenotype can also be part of this syndrome

Glucose‐6‐phosphatase catalytic subunit 3 (G6PC3) deficiency is a newly described syndrome characterized by severe congenital neutropenia associated with multiple organ abnormalities including cardiac and urogenital malformations. The underlying pathophysiology of increased apoptosis of myeloid cells and of neutrophil dysfunction in G6PC3 deficiency involves disturbed glucose metabolism, increased endoplasmic reticulum stress and deficient protein folding. Here, we report a new case of G6PC3 deficiency caused by a novel homozygous G6PC3 gene mutation p.Trp59Arg. The patient showed pancytopenia and a variable bone marrow phenotype with maturation arrest and vacuolization in myeloid lineage cells and a normocellular marrow, respectively. She also showed persistent lymphopenia with low CD4 T‐ and CD19 B‐cell counts. Lymphopenia and even pancytopenia as well as a variable bone marrow phenotype can be part of this syndrome. These clinical findings in a patient with chronic neutropenia should alert the clinician to consider a diagnosis of G6PC3 deficiency.     

Nasal NK cell lymphoma with hemophagocytic syndrome developed tumor lysis syndrome after CHOP therapy

A 24-year-old man was admitted with fever and rhinostenosis. A bulky mass was observed in his left nasal cavity. A biopsy showed diffuse proliferation of large atypical lymphocytes, which were positive for CD45RO, CD56, MIB-1, and EBER. Bone marrow aspiration showed many histiocytes with active hemophagocytosis. A diagnosis of nasal NK cell lymphoma with hemophagocytic syndrome (clinical stage IVB) was made. Following CHOP regimen chemotherapy, the tumor transiently reduced in size, but the patient developed multiple organ failure possibly due to tumor lysis syndrome. His general condition was improved by intensive supporting therapy. Two weeks later, the tumor again got worse. Despite salvage chemotherapy with a P-IMVP16/CBDCA regimen, the patient died of multiple organ failure due to tumor lysis syndrome. Autopsy revealed diffuse necrosis and fibrosis without proliferation of lymphoma cells in the liver, spleen, bone marrow, and lymph nodes. During the clinical course, hypercytokinemia including soluble IL-2 receptor, interferon-gamma and IL-18 was observed. The poor prognosis of NK/T cell lymphoma might be associated with massive tissue damage with hypercytokinemia.     

Eosinophilic hepatic necrosis in hypereosinophilic syndrome

Hypereosinophilic syndrome has been reported to be associated with liver disease, predominantly in men, in the form of acute and chronic active hepatitis with an inflammatory infiltrate that is mainly composed of eosinophils. We describe a female patient with peripheral blood and bone marrow eosinophilia, in whom liver biopsy displayed areas of necrosis with eosinophilic inflammation, with other regions showing features of chronic hepatitis. The patient also had antimitochondrial antibodies in serum. She responded favorably to immunosuppressive therapy.     

Bone marrow necrosis.

The clinical findings of bone marrow necrosis in 13 patients undergoing bone marrow examination to investigate a peripheral blood cytopenia or leukoerythroblastic blood smear were reviewed and compared to those in the literature. Excluding sickle cell disease, all cases of bone marrow necrosis diagnosed during life were associated with a neoplastic process involving the marrow. A myeloproliferative disorder was found in five patients, metastatic carcinoma in five patients, a lymphoma in two patients, and both a myeloproliferative disorder and metastatic carcinoma in one patient. Marrow necrosis was found to involve the marrow at multiple sites in a piecemeal fashion with areas of necrotic marrow and structurally intact marrow adjacent to each other. Severe bone pain without roentgenographic abnormality was the major symptom in 85% of the patients. Marrow and fat emboli, hypercalcemia and peripheral blood cytopenias were identified as direct complications of marrow necrosis. The prognosis of patients with marrow necrosis secondary to neoplastic disease was found to be extremely poor with a median survival of less than one month. However, one patient responded to antineoplastic chemotherapy and showed healing of the bone marrow.     

ICSH guidelines for the standardization of bone marrow specimens and reports

The bone marrow examination is an essential investigation for the diagnosis and management of many disorders of the blood and bone marrow. The aspirate and trephine biopsy specimens are complementary and when both are obtained, they provide a comprehensive evaluation of the bone marrow. The final interpretation requires the integration of peripheral blood, bone marrow aspirate and trephine biopsy findings, together with the results of supplementary tests such as immunophenotyping, cytogenetic analysis and molecular genetic studies as appropriate, in the context of clinical and other diagnostic findings. Methods for the preparation, processing and reporting of bone marrow aspirates and trephine biopsy specimens can vary considerably. These differences may result in inconsistencies in disease diagnosis or classification that may affect treatment and clinical outcomes. In recognition of the need for standardization in this area, an international Working Party for the Standardization of Bone Marrow Specimens and Reports was formed by the International Council for Standardization in Hematology (ICSH) to prepare a set of guidelines based on preferred best practices. The guidelines were discussed at the ICSH General Assemblies and reviewed by an international panel of experts to achieve further consensus.     

Bone marrow necrosis in two patients with acute promyelocytic leukemia during treatment with all-trans retinoic acid

All-trans retinoic acid has been used for the treatment of acute promyelocytic leukemia (APL) with encouraging results. However, it has recently been associated with a number of potentially serious complications including the retinoic acid syndrome. We describe two patients with APL who were begun on all-trans retinoic acid therapy (45 mg/m²), but who developed leukocytosis which was treated with hydroxyurea. Both patients demonstrated clinical and laboratory findings of disseminated intravascular coagulation, massive cell lysis manifested by marked increases in serum lactic dehydrogenase, and rapid clinical deterioration. Both patients developed bone marrow necrosis within viable, non-infarcted bone trabeculae. We postulate that the development of bone marrow necrosis in these two patients was not a chance occurrence. Rather, the specific combination of cytotoxic and differentiating agents used in these patients (hydroxyurea with all-trans retinoic acid) caused massive cell lysis and death. The absence of bone marrow necrosis in the setting of induction therapy for APL both with and without all-trans retinoic acid therapy suggests that the addition of hydroxyurea was critical to the development of marrow necrosis. We, therefore, recommend caution in the use of hydroxyurea and all-trans retinoic acid in the treatment of APL. © 1994 Wiley-Liss, Inc.     

BMT: Bone Marrow Transplant Associated Thrombotic Microangiopathy

Thrombotic microangiopathy is a severe microvascular disorder which may occur in up to 70% of patients undergoing bone marrow transplant. Clinically the term thrombotic microangiopathy encompasses a wide spectrum of syndromes, most importantly the thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). Thrombotic microangiopathy is characterized by the presence of thrombocytopenia, microangiopathic hemolytic anemia, renal impairment, neurological disturbances and multiorgan failure. Several causative agents have been advocated as triggering factors for bone marrow transplant associated thrombotic microangiopathy, including cyclosporine, FK506, the use of total body irradiation, infections and the presence of severe graft-versus-host disease. Plasma exchange represents the standard treatment for patients who develop TTP/HUS after bone marrow transplant, however, the mortality rate still remains high despite aggressive therapy.     

Akanthozyten und Proteinurie bei einem 47-jährigen Mann

We report the case of a 47-year old male patient who presented in our nephrological outpatient unit with acute prostatitis with increased serum creatinine levels and macrohematuria following repeated successful antibiotic treatments for prostatitis. The patient was able-bodied and capable of reporting that he had taken no medication other than the antibiotic medication prescribed. Initial findings of classic nephritic sediment, significant proteinuria and the onset of acute kidney failure lead to the suspicion of nephritic syndrome, which was not confirmed by an otherwise inconclusive biopsy. A diagnosis was reached only after bone marrow biopsy and later findings from the renal biopsy: isolated vascular light chain nephropathy and marginal zone B-cell lymphoma with plasma cell differentiation, the causes of which remain unclear. Following initial steroid and antibiotic treatment the patient received further oncological treatment according to the R-CHOP protocol.     

Bone marrow necrosis in a patient with acute myeloblastic leukemia during administration of G-CSF and rapid hematologic recovery after allotransplantation of peripheral blood stem cells

Allogeneic peripheral blood stem cell transplantation from an HLA-identical sibling was performed for a 38-year-old male with refractory acute myeloblastic leukemia. The patient was conditioned with total body irradiation (TBI) and high-dose cytosine arabinoside (Ara-C). G-CSF (300 μg/body) was started for priming of residual leukemic cells 24 hrbefore the beginning of TBI (day −9). However, intolerable generalized bone pain appeared shortly after the start of first dose of G-CSF, and persisted for 3 days in spite of the cessation of G-CSF. Posttransplant hematopoietic engraftment was very rapid. Bone marrow biopsy specimens on day 14 and 30 showed typical bone marrow necrosis histologically. This is the first case of bone marrow necrosis during administration of G-CSF, and our experience suggests that PBSC could repopulate hematopoiesis in spite of severe bone marrow necrosis. Am. J. Hematol. 57:238–240, 1998. © 1998 Wiley-Liss, Inc.     

Primary splenic lymphoma with hypoplastic bone marrow

A 44-year-old man was admitted because of persistent fever and pancytopenia. Because his bone marrow was hypoplastic and the karyotype of his marrow cells was normal, he was given a diagnosis of aplastic anemia, and treated with glucocorticoids and granulocyte colony-stimulating factor. Splenomegaly was later found and a splenectomy performed: pathological findings on resected tissue specimens disclosed non-Hodgkin's lymphoma, B-cell diffuse large. The patient was transferred to our hospital, where a bone marrow biopsy revealed lymphoma cells infiltrating his hypoplastic marrow. Complex chromosomal abnormalities were detected in marrow cells, but no lymphadenopathy was observed. A diagnosis of primary splenic lymphoma with infiltration of lymphoma cells into bone marrow was made, and chemotherapy was accordingly started. After multiple cycles of chemotherapy, the patient's marrow recovered to a normal state and his karyotype abnormalities disappeared. Six months later, pancytopenia reappeared and lymphoma cells were again detected in the patient's bone marrow. We reasoned that the hypoplastic state of his bone marrow was associated with the lymphoma, and that cytokines, including interferon-gamma, may have been responsible for this association.     

The hematologic manifestations of the antiphospholipid syndrome

Various hematological pathologies have been described in association with antiphospholipid syndrome (APS). Thrombocytopenia is frequently found in APS patients, its incidence has ranged from 22-42% in different series, it is usually moderate (>50x10(9)/L) without clinical manifestation and requires no intervention. A high percentage of patients with isolated idiopathic thrombocytopenic purpura have antiphospholipid antibodies, however the pathogenetic role and the clinical importance of these antibodies in this condition is still not clear. Other hematological manifestations reported in association with APS include: bone marrow necrosis, and various thrombotic microangiopathic syndromes such as: thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, HELLP (hemolysis, elevated liver enzymes, low platelet) syndrome, and catastrophic APS. A high index of suspicion is needed for the early recognition and treatment of these conditions.