Myelophthisic Anemia 

Updated: Jan 16, 2019
Author: Emmanuel C Besa, MD; Chief Editor: Koyamangalath Krishnan, MD, FRCP, FACP 

Overview

Practice Essentials

Myelophthisis is a form of bone marrow failure that results from the destruction of bone marrow precursor cells and their stroma, which nurture these cells to maturation and differentiation. (See Etiology.)

Infiltrating lesions caused by nonhematopoietic cells invading bone marrow can result in varying degrees of cytopenia, including anemia, thrombocytopenia, neutropenia, and pancytopenia.[1]  Bone marrow failure resulting from secondary infiltration is a possible cause of lack of blood cell production (as differentiated from a primary cause of failure). Manifestations range from a leukoerythroblastic picture[2]  to the presence of a few teardrop-shaped red blood cells and early myeloid precursor cells in the peripheral blood smear.[3] (See the image below.) (See Etiology, Differentials, and Workup.)

This blood film at 1000X magnification demonstrate This blood film at 1000X magnification demonstrates a leukoerythroblastic blood picture with the presence of precursor cells of the myeloid and erythroid lineage. In addition, anisocytosis, poikilocytosis, and polychromasia can be seen. Courtesy of Ulrich Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

The most common causes of infiltrative myelopathy are metastatic carcinomas (eg, lung, breast, and prostate cancer),[4, 5]  lymphoproliferative malignancies (eg, lymphomas), disseminated granulomatous diseases (eg, miliary tuberculosis),[6] and rare diseases (eg, Gaucher disease). (See the image below.) (See Etiology.)

This bone marrow film at 400X magnification demons This bone marrow film at 400X magnification demonstrates carcinoma metastasis. Bone marrow cells are completely replaced by large carcinoma cells with clear nucleoli. Courtesy of Ulrich Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

Go to Anemia, Chronic Anemia, Megaloblastic Anemia, Hemolytic Anemia, and Sideroblastic Anemias for complete information on these topics.

Etiology

Generally, in myelophthisic anemia, a form of fibrosis, occurs secondary to injury by nonhematopoietic cells or pathogens. This fibrosis destroys the normal hematopoietic cells and their supportive stromal cells. The bone marrow becomes infiltrated by collagen, reticulin, and other forms of fibrosis, which replace the normal, hematopoietic cells. The most common causes of extensive bone marrow infiltrative damage or invasion without much structural damage are discussed below. The expanding number and volume of pathologic cells and the release of suppressive cytokines can eventually lead to bone marrow failure without the characteristic morphologic features of myelophthisis.

Leukemic cells, such as those occurring in chronic leukemias in which the expanding cells are mature and coexist peacefully with the normal bone marrow cells, show no evidence of myelophthisis, and marrow damage does not occur.

In agnogenic and secondary myelofibrotic disorders, megakaryocytes release platelet-derived growth factors, which are fibroblastic stimulants for growth and proliferation. This leads to the consequences of bone marrow space reduction and to disruption of normal bone marrow architecture.

Agnogenic myeloid metaplasia is a stem cell abnormality associated with myeloproliferative diseases. It is related to an abnormal stem cell clone that stimulates increased myelofibrosis and damage. It progresses to acute leukemia and is associated with extramedullary hematopoiesis in the liver and spleen, causing hypertrophy of these organs.

Secondary myelofibrosis is due to implantation or invasion by malignant cancer cells that have metastasized because of implantation of blood-borne tumor cells from a distant cancer. The most common sources are cancers of the lung, breast, and prostate[7] and sarcomas.

Nonmalignant causes of myelophthisis include the following:

  • Inflammatory cells, miliary tuberculosis, and fungal infections

  • Sarcoidosis

  • Macrophage proliferation in storage diseases, such as Gaucher disease

  • Necrosis in sickle cell disease and septicemia

  • Bone disease in congenital osteopetrosis

With regard to Gaucher disease, infiltration by cells with "onion-peel" cytoplasm, called Gaucher cells, is caused by a lipid storage disorder (ie, glucosylceramide lipidosis). Gaucher cells clog or infiltrate the bone marrow, spleen, and liver. This disorder is inherited.

Epidemiology and Prognosis

Myelophthisis is observed more frequently in countries where access to medical care is difficult and diseases are allowed to progress to advanced stages. In the United States, infiltrative myelopathy occurs in less than 10% of cancer patients with metastatic disease.

Mortality is dependent on the underlying condition.[5] The leukoerythroblastic blood picture is often associated with imminent death in some extreme cases. Patients with varying degrees of cytopenia are at risk for infection or bleeding.

 

Presentation

History and Physical Examination

Focus the history and physical examination on establishing the underlying disease, such as an advanced carcinoma, lymphoma, or granulomatous disease. Family history is important for eliciting information in congenital and inherited forms of the disease.

Physical findings usually reflect the underlying medical condition, such as metastatic carcinoma, lymphoma, or tuberculosis. Anemia may cause skin pallor. Severe thrombocytopenia may produce petechiae or ecchymoses. Patients with severe neutropenia may become infected and present with fever.

 

DDx

Diagnostic Considerations

The leukoerythroblastic picture, the characteristic laboratory changes associated with myelophthisic anemia, is characterized by the following findings in the peripheral blood smear:

  1. Nucleated red blood cells and teardrop forms
  2. Giant platelets
  3. Immature white blood cells (eg, myelocytes, metamyelocytes, occasionally promyelocytes and myeloblasts) 

See the image below.

This blood film at 1000X magnification demonstrate This blood film at 1000X magnification demonstrates a leukoerythroblastic blood picture with the presence of precursor cells of the myeloid and erythroid lineage. In addition, anisocytosis, poikilocytosis, and polychromasia can be seen. Courtesy of Ulrich Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

The differential diagnosis to separate myelophthisic process secondary from a primary myeloproliferative syndrome that is a clonal stem cell disorder resulting in myelofibrosis due to excessive proliferation of one or more cell lineages is performing a cytogenetic evaluation of the bone marrow cells. However, this test can only be successfully performed if dividing cells can be obtained from the bone marrow aspiration for classic cytogenetic testing. Fluorescent in situ hybridization (FISH) can be performed in nondividing cells but is limited to a panel of set abnormalities. Secondary myelofibrosis due to a myelophthisic process should have normal cytogenetics. The frequency of a "dry" bone marrow aspiration owing to fibrosis of the marrow limits the performance of this test.

Using immunomorphometric methods by immunostaining for CD34 to differentiate primary from secondary myelofibrosis has not been successful.[8]  The 2016 World Health Organization (WHO) classification of myeloid neoplasms defines strict criteria for the primary diseases.[9]  

Go to Anemia, Chronic Anemia, Megaloblastic Anemia, Hemolytic Anemia, and Sideroblastic Anemias for complete information on these topics.

Differential Diagnoses

 

Workup

Approach Considerations

The presence of lytic and blastic lesions on skeletal radiographic films is common in patients with prostate, lung, or breast cancer metastases.

Bone scans are sensitive for detecting abnormalities found in myelophthisic anemia and for detecting bone metastases, while magnetic resonance imaging (MRI) scans of the involved area can detect marrow infiltration.

The bone marrow aspirate is usually a dry tap, because myelofibrosis makes aspirating blood from the marrow cavity difficult. Biopsy results usually reveal the underlying infiltrative process. Clusters or islands of large, anaplastic cancer cells that bear characteristics of their primary tumor are often observed. Malignant lymphomas invade bone marrow and can cause a myelophthisic myelopathy.

In miliary tuberculosis, caseating granulomas demonstrate positive acid-fast organisms. Tuberculosis granulomas also reveal typical Langhans-type giant cells with multiple nuclei.

Leukoerythroblastic Picture

The characteristic laboratory changes associated with myelophthisic anemia are referred to as a leukoerythroblastic picture, and they include the following (see the image below):

  • Nucleated red blood cells and teardrop forms

  • Giant platelets

  • Immature white blood cells (eg, myelocytes, metamyelocytes, occasionally promyelocytes and myeloblasts) in the peripheral blood smear

    This blood film at 1000X magnification demonstrate This blood film at 1000X magnification demonstrates a leukoerythroblastic blood picture with the presence of precursor cells of the myeloid and erythroid lineage. In addition, anisocytosis, poikilocytosis, and polychromasia can be seen. Courtesy of Ulrich Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

Histologic Findings

Immature cells are present in the peripheral blood because the blood-marrow barrier is disrupted. This causes the early release of immature cells into the circulation, resulting in leukoerythroblastic anemia. Changes in the bone marrow are caused by the replacement of normal marrow cells with abnormal, nonhematopoietic cells, such as cells tainted by cancer, lymphoma, or infectious agents. (See the image below.) This results in fibrosis or scarring of the marrow cavity.

This bone marrow film at 400X magnification demons This bone marrow film at 400X magnification demonstrates carcinoma metastasis. Bone marrow cells are completely replaced by large carcinoma cells with clear nucleoli. Courtesy of Ulrich Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
 

Treatment

Approach Considerations

Treat the underlying disease and provide supportive measures for symptomatic patients. Treat anemia with packed red blood cell transfusions. Rarely, patients have low erythropoietin levels and may respond to supplemental erythropoietin therapy. Patients with other cytopenias generally do not need treatment unless bleeding or infection is present.

In a case report, melanoma metastases causing myelophthisis and pancytopenia responded to immune checkpoint inhibition with the anti-programmed cell death-1 (PD-1) inhibitor pembrolizumab.

Consultation with a hematologist and an oncologist is warranted.

Go to Anemia, Chronic Anemia, Megaloblastic Anemia, Myelophthisic Anemia, Hemolytic Anemia, and Sideroblastic Anemias for complete information on these topics.

 

Medication

Medication Summary

Correction of anemia often requires blood and/or blood products. The therapy is used to restore the hemodynamics of the vascular system and replace lost red blood cells. Major morbidities of anemia can be prevented by providing timely transfusion to restore hemoglobin to safe levels.

Blood Product Derivatives

Class Summary

Some agents in this category are used as needed to treat anemia.

Packed red blood cells

Packed red blood cells (PRBCs) are used preferentially to whole blood because they limit volume, immune, and storage complications. PRBCs have 80% less plasma, are less immunogenic, and can be stored for about 40 days (vs 35 d for whole blood). PRBCs are obtained after centrifugation of whole blood. Leukocyte-poor PRBCs are used in patients who are transplantation candidates/recipients or in those with prior febrile transfusion reactions. Washed or frozen PRBCs are used in individuals with hypersensitivity transfusion reactions.