AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Infiltrating lesions caused by nonhematopoietic cells invading bone marrow can result in varying degrees of cytopenia, including anemia, thrombocytopenia, neutropenia, and pancytopenia. 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^{1, 2} to the presence of a few teardrop-shaped red blood cells and early myeloid precursor cells in the peripheral blood smear.

Pathophysiology

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.

Generally, 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 that replace the normal hematopoietic cells.

Frequency

United States

Infiltrative myelopathy occurs in less than 10% of cancer patients with metastatic disease. It most commonly occurs during the advanced stages of cancer, and the outcome depends on the patient's access to medical care.

International

Myelophthisis is observed more frequently in countries where access to medical care is difficult and diseases are allowed to progress to advanced stages.

Mortality/Morbidity

Mortality is dependent on the underlying condition. 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.
• If patients are symptomatic, treat their anemia with red blood cell transfusions.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• 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

• 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.

Causes

• The most common causes of extensive bone marrow infiltrative damage or invasion without much structural damage are listed below. The expanding number and volume of pathologic cells and release of suppressive cytokines can eventually lead to bone marrow failure without the characteristic morphologic features of myelophthisis.
• Leukemic cells, such as 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 both 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 prostate⁶ and sarcomas.
• Nonmalignant causes of myelophthisis include (1) inflammatory cells, miliary tuberculosis, and fungal infections; (2) sarcoidosis; (3) macrophage proliferation in storage diseases such as Gaucher disease; (4) necrosis in sickle cell disease and septicemia; and (5) bone disease in congenital osteopetrosis.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• The characteristic laboratory changes associated with myelophthisic anemia are referred to as a leukoerythroblastic picture, and they include the following:
• • 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
• In miliary tuberculosis, caseating granulomas demonstrate positive acid-fast organisms. Tuberculosis granulomas also reveal typical Langhans-type giant cells with multiple nuclei.
• Infiltration by cells with "onion-peel" cytoplasm, called Gaucher cells, is caused by a lipid storage disorder (ie, glucosyl ceramide lipidosis).
• • Gaucher cells clog or infiltrate the bone marrow, spleen, and liver.
  • This disorder is inherited. Obtaining family history is very important.

Imaging Studies

• The presence of lytic and blastic lesions on skeletal x-ray films is common in patients with prostate, lung, or breast cancer metastases.
• Bone scans are sensitive for detecting these abnormalities and for the presence of bone metastases.
• MRIs of the involved area can detect marrow infiltration.

Procedures

• 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.

Histologic Findings

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

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

• 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.

Consultations

• Hematologist
• Oncologist

FOLLOW-UP

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Complications

Patients with varying degrees of cytopenia are at risk for infection or bleeding.

Prognosis

• Mortality is dependent on the underlying condition.⁴
• Infiltrative myelopathy most commonly occurs during the advanced stages of cancer, and the outcome depends on the patient's access to medical care.

MISCELLANEOUS

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

In cases of inherited or congenital causes, obtaining a complete family history is crucial.

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  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 U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
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Media type:  Photo

Media file 2:  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 U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

1. Delsol G, Guiu-Godfrin B, Guiu M, Pris J, Corberand J, Fabre J. Leukoerythroblastosis and cancer frequency, prognosis, and physiopathologic significance. Cancer. Sep 1979;44(3):1009-13. [Medline].
2. Weick JK, Hagedorn AB, Linman JW. Leukoerythroblastosis. Diagnostic and prognostic significance. Mayo Clin Proc. Feb 1974;49(2):110-3. [Medline].
3. Brochamer WL Jr, Keeling MM. The bone marrow biopsy, osteoscan, and peripheral blood in non-hematopoietic cancer. Cancer. Aug 1977;40(2):836-40. [Medline].
4. Makoni SN, Laber DA. Clinical spectrum of myelophthisis in cancer patients. Am J Hematol. May 2004;76(1):92-3. [Medline].
5. Bodem CR, Hamory BH, Taylor HM, Kleopfer L. Granulomatous bone marrow disease. A review of the literature and clinicopathologic analysis of 58 cases. Medicine (Baltimore). Nov 1983;62(6):372-83. [Medline].
6. Shamdas GJ, Ahmann FR, Matzner MB, Ritchie JM. Leukoerythroblastic anemia in metastatic prostate cancer. Clinical and prognostic significance in patients with hormone-refractory disease. Cancer. Jun 1 1993;71(11):3594-600. [Medline].
7. Jandl JH. Blood. In: Pathophysiology. Oxford, England: Blackwell Scientific; 1991:104-5.

Article Last Updated: Jan 4, 2008