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| Anemia in Cancer Patients: |
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Introduction and Overview
Hussain I. Saba, MD, PhD
Anemia is a common complication of malignancies. Because its causes and
mechanisms are complex, the term “multifactorial” has been applied.
Cancer-related anemia may occur as a direct effect of the neoplasm, it may
be due to products of the cancer, or it may develop as a result of the
cancer treatment itself. In the past, anemia occurring in cancer patients
was often referred to as “chronic anemia” or “anemia of chronic disease.”
These effects may be reflective of a paraneoplastic syndrome.
Anemia Occurring as a Direct Effect of the Neoplasm
Direct-acting factors due to the effects of the cancer are summarized in
Table 1. Notable among these are solid tumor malignancies, such as breast
and prostate cancer, that invade the marrow. Often overlooked as factors
in inducing anemia, these malignancies produce a desmoid or fibrotic
reaction, with increased marrow fibrosis that results in alteration of
marrow space and sinusoidal matrix. This can affect the orderly release of
mature blood cells from bone marrow and can produce a leukoerythroblastic
picture with immature red cells and early myeloid white cells seen in
peripheral blood.
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Table 1. -- Anemia of Cancer: Direct Effects of the Neoplasm |
| Exogenous blood loss (acute or chronic): |
Gastrointestnal malignancies
Head and neck cancer
Genitourinary cancers
Cervical and vaginal cancers |
| Intratumor bleeding: |
Sarcomas
Bulky melanomas
Hepatoma
Ovarian cancer
Adrenocortical tumors |
| Anemia due to erthrophagocytosis: |
Histiocytic medullary reticulosis
Histiocytic lymphomas
Other histiocyctic neoplasms |
| Bone marrow replacement: |
Leukemias
Lymphomas
Myelomas
Carcinomas (breast, prostate) |
Direct causes of anemia in malignancy
include known substances or proteins produced by the cancer (Table 2). The
deposits of amyloid in myelomas and amyloidosis can be extensive enough to
replace the bone marrow. The development of antibodies in chronic
lymphocytic leukemia, lymphoma, and sometimes solid tumor malignancies can
lead to immune hemolytic anemias. Furthermore, development of
microangiopathic hemolytic anemia, which is seen in some solid tumor
malignancies, may result from procoagulants released from cancers.
| Table 2. -- Anemia Due to Known
Products of Cancer |
| Substance |
Mechanism |
Neoplasm |
| Amyloid |
Marrow replacement |
Plasma cell dyscrasia |
| Antibodies |
Immune hemolytic anemia |
Chronic lymphocytic leukemia,
lymphoma, adenocarcinoma |
| Procoagulant proteins |
Microangiopathic hemolytic anemia |
Gastrointestinal malignancies (mucin),
prostate cancer |
| Anemia of Cancer: Anemia of Chronic
Disease or a Cytokine-Associated Syndrome? |
In many cancer patients, the causative mechanism of anemia is incompletely
defined; thus, the term “anemia of chronic disease” is used. Defective
iron utilization, the hallmark of anemia of chronic disease, is common
among patients suffering from anemia of malignancy.
The concept of anemia of chronic disease was reported 150 years ago by
German investigators Andral and Cavarret. Despite extensive studies by
William Cartwright after World War II, its pathophysiologic mechanism
remains unclear. However, in 1966, Dr Cartwright suggested a conceptual
mechanism for the anemia of chronic disease that could easily be applied
to the anemia of malignancy. Cartwright’s three mechanisms include
shortened red cell survival, failure of the bone marrow to increase
erythropoiesis to meet the demand and to repair the deficiency (ie, a
hypoproliferative state), and failure of bone marrow to release iron from
the senescent red cells phagocytosed by the bone marrow macrophages (ie,
defective iron reutilization). Each of these mechanisms pertains to the
development of the anemia of malignancy.
New lines of evidence suggest that abnormalities in the production of
erythropoietin (EPO) are involved. The hypoproliferative state in anemia
of cancer appears to be related to either decreased EPO production or
impaired bone marrow response to EPO.
Recent evidence has indicated that recombinant EPO can correct the anemia
of malignancy in many patients. This finding has rekindled interest in
decreased EPO production as an important factor in the anemia of cancer.
One concept states that inappropriate secretion of EPO is related to
increased cytokine production by the tumor. In vitro studies have shown
that tumor necrosis factor (TNF) and interleukin-1 (IL-1) inhibit EPO mRNA
synthesis. This indicates that hypoproliferative response of the marrow in
cancer patients could be a cytokine-mediated phenomenon. Cytokines
liberated in cancer patients could cause inhibition of EPO secretion and
possibly EPO responsiveness of the marrow erythroid progenitors.
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