Hematology

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Anemia in malignancies: Pathogenetic and

diagnostic considerations

Balan Louis Gaspar, Prashant Sharma & Reena Das

To cite this article: Balan Louis Gaspar, Prashant Sharma & Reena Das (2015) Anemia in
malignancies: Pathogenetic and diagnostic considerations, Hematology, 20:1, 18-25, DOI:
10.1179/1607845414Y.0000000161

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 Narrative review
Anemia in malignancies: Pathogenetic and
diagnostic considerations
Balan Louis Gaspar, Prashant Sharma, Reena Das
Department of Hematology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Objectives: The aim of this paper is to review the pathogenesis and diagnostic approaches to anemia in
cancer patients.
Methods: PubMed was queried for various combinations of anemia and cancer-related terms using
appropriate filters for articles and practice guidelines published in the last 5 years. Specific searches were
conducted for individual pathogenetic mechanisms and malignancies of specific anatomic sites.
Results: Anemia is the commonest hematological manifestation of cancer, afflicting 40–64% of patients
treated for malignancies. Pathophysiologically, cancer-related anemia can be classified into four broad
but overlapping categories: hypoproliferative anemia including the common anemia of inflammation/
chronic disease, hemolytic anemia, miscellaneous etiologies, and uncertain etiologies. Anemia incidence
increases with the administration of chemotherapy/radiotherapy. It reduces the quality of life and shortens
survival in cancer patients. A positive correlation is observed between anemia and tumor hypoxia.
Experimentally, hypoxemia enhances tumor growth and resistance to therapy by stimulating angiogenesis,
acquisition of genomic mutations, and increasing resistance to apoptosis as well as to the killing effects of
chemo/radiotherapy-generated free radicals.
Discussion: Diagnostic approaches to the anemic cancer patient begin with a detailed clinical history and
physical examination. Peripheral blood morphology and reticulocyte count are also helpful. Patients with
unexplained anemia are evaluated by standard approaches also used in patients of similar age without
malignancy. Serum iron profile and bone marrow examination are often required in difficult cases. This
review focuses on major aspects of the pathogenesis of the individual entities. Diagnostic approaches
and uncommon causes including hemophagocytic lymphohistiocytosis, acquired hemoglobinopathies,
and myelodysplasia are also discussed.
Keywords: Anemia, Cancer, Chemotherapy, Chronic disease, Etiopathogenesis, Hypoxia, Malignancy, Radiotherapy

Introduction gastrointestinal tract adenocarcinoma (refractory iron

Cancer is the commonest cause of mortality in devel-
oped countries and the second leading cause of mor-
tality in the developing world. Global estimates for
2008 pointed to 12.7 million cancer cases and 7.6
million cancer deaths.1,2 Anemia is a major public
health problem affecting 1.62 billion people world-
wide. A World Health Organization (WHO) Global
Database on Anemia for 1993–2005 pegged the preva-
lence of anemia worldwide at 25%.3
Anemia is the commonest hematological manifes-
tation of cancer and a majority of cancer patients are
anemic.4 Anemia may at times be the sole manifes-
tation of cancer and a diagnostic work-up of anemia
may unmask a hidden malignancy like a
Correspondence to: Prashant Sharma, Department of Hematology,
Postgraduate Institute of Medical Education and Research, Level 5,
Research Block A, Sector 12, Chandigarh 160012, India.
Email: sharma.prashant@pgimer.edu.in
deficiency anemia (IDA) may be sole manifestation),
hairy cell leukemia (HCL), or a myelodysplastic syn-
drome (MDS). The commonest anemia in patients
with malignancies is anemia of inflammation/
chronic disease,4 although other causes depending on
the site may be also common (e.g. blood loss in
stomach, bladder, uterine, and cervical malignancies).
Multiple etiologies are encountered in many cases. In
the current era of multimodality cancer therapy, the
prevalence of treatment-related anemia is likely to be
increasing even though definite estimates are difficult.
We review here the pathogenetic and etiological
approaches to anemia in cancer patients. For this, we
queried PubMed for various combinations of the
terms anemia, cancer, malignancy, diagnosis, and
pathogenesis using the following filters: reviews, sys-
tematic reviews, articles published in the last 5 years,
and practice guidelines. Subsequently, specific

© W. S. Maney & Son Ltd 2015

18 DOI 10.1179/1607845414Y.0000000161 Hematology 2015 VOL. 20 NO. 1

searches were conducted for the individual pathoge-
netic mechanisms (e.g. chemotherapy-related anemia)
and malignancies of specific anatomic sites.
Pathophysiological classification of anemia in
malignancies
Anemia in cancer can be broadly classified into four
major categories: hypoproliferative anemia, hemolytic
anemia, anemia of miscellaneous etiology, and anemia
of uncertain etiology (Table 1). The rubric hypoproli-
ferative anemia includes anemia of inflammation or
chronic disease/iron sequestration anemia, anemia of
iron deficiency and other malnutritive/malabsorptive
states, pure red cell aplasia (PRCA), megaloblastic
anemia, myelophthisic or leukoerythroblastic
anemia, myelodysplasia, and anemia due to marrow
aplasia or hypoplasia. Hemolytic anemias include
autoimmune hemolytic syndromes and microangio-
pathic hemolytic anemia (MAHA). Anemias of
Table 1 A pathogenesis-based classification of etiologies of
anemia in patients with malignancies
Anemia of inflammation/chronic disease
Anemia secondary to chemotherapy and radiation therapy
Hypoplastic/aplastic bone marrow
Anorexia, vomiting
Drug-induced hemolysis
Anemia of blood loss
Exogenous blood loss (acute or chronic): gastrointestinal
malignancies, head and neck cancer, genitourinary
cancers, cervical and vaginal cancers, post-tumor
resection surgery
Intra-tumor bleeding: sarcomas, bulky melanomas,
hepatoma, ovarian cancer, adrenocortical tumors
Nutritional anemia
Anorexia and decreased dietary intake
Iron deficiency due to blood loss
Secondary folate deficiency in neoplasms with high-cell
turnover
Post-gastrointestinal resection
Gastrointestinal obstruction by tumor (intraluminal, intramural,
or extramural due to pressure effects)
Intractable hyperemesis
Use of folate antagonist agents
Autoimmune gastritis resulting from neuroendocrine
neoplasms
Anemia of bone marrow replacement (myelophthisic anemia)
Acute and chronic leukemias, Hodgkin and non-Hodgkin
lymphomas, plasma cell myeloma, metastatic tumors
(breast, prostate, lung, neuroblastoma, etc.)
Secondary myelofibrosis
Myelonecrosis
Hemolytic anemia
MAHA
TTP
Immune hemolytic anemias
AIHA: warm antibody type, cold antibody type, and mixed
type
Miscellaneous causes
Secondary hemophagocytic syndrome/HLH: histiocytic
medullary reticulosis, histiocytic lymphomas, other
histiocytic neoplasms
Anemia due to infections in immunocompromised patients
Anemia of renal failure: including abnormalities of
erythropoietin production and utilization
Hypersplenism
Anemia of unknown etiology
Gaspar et al. Anemia in malignancies
miscellaneous etiologies include a wide variety of
causes including those due to hypersplenism, second-
ary hemophagocytic syndrome, acquired (especially
alpha) thalassemia, and blood loss. At times, the
cause of anemia cannot be established where the
term anemia of uncertain etiology is more appropriate.
These entities are discussed further below.
Hypoproliferative anemia
Anemia of inflammation or chronic disease/iron
sequestration anemia
It is the commonest cause of anemia in cancer
patients.4,5 Among the malignancies, solid tumors
account for majority of cases. Mechanisms of
anemia of inflammation/chronic disease in cancer
are both functional as well as iron deficiency-
related.5 Though these two processes are not mutually
exclusive, the pathogenesis of anemia of inflam-
mation/chronic disease needs separate discussion.
The master regulator of iron homeostasis is hepci-
din.6 This polypeptide hormone with antimicrobial
activity acts by binding to ferroportin and causing its
degradation. This prevents iron from being exported
out of the cell and results in functional iron deficiency.
Bone morphogenetic protein-6 (BMP6) and its down-
stream signaling pathway mediated by second messen-
gers act as key physiological regulators of hepcidin.
Hypoxia regulates hepcidin production directly
through hypoxia-inducible factor or indirectly by
increased erythropoietin production.7 Cytokines,
especially interleukin-6 (IL-6) increase hepcidin pro-
duction via signal transducer and activator of tran-
scription-3 (STAT3), as well as by other pathways.6–9
Recently, the role of activin receptor-mediated
pathways has been unraveled and dysregulation of
these pathways too appears to contribute to the
development of iron sequestration anemia in
malignancies.9
Iron deficiency anemia
Absolute iron deficiency commonly observed in cancer
may be nutritional, related to blood loss, insufficient
iron uptake from food, or increased utilization. Solid
tumors comprised of 22%, and hematological malig-
nancies 8% of the total causes of intravenous iron
requirement for IDA.10 Other causes of IDA are
bleeding associated with malignancies of gastrointesti-
nal, urogenital, and respiratory tracts. Bleeding may
also occur due to acquired platelet dysfunction in
malignancies like the myeloproliferative neoplasms
and in paraproteinemias.11 In patients with tumors
requiring gastric resection, iron deficiency develops
because of decreased iron absorption. An underlying
malignancy should be strongly considered in any
patient presenting with IDA which is unexplained by
common approaches.
Hematology 2015 VOL. 20 NO. 1 19
Gaspar et al. Anemia in malignancies
Red cell hypoplasia and PRCA
PRCA is a syndrome characterized by a severe normo-
cytic anemia, reticulocytopenia, and the absence of
erythroblasts from an otherwise normal bone
marrow. Cancer is an important cause of secondary
PRCA. Both hematological neoplasms as well as
various solid malignancies have been implicated
although the exact pathogenesis remains unclear.
PRCA has rarely been reported in association with
lymphoproliferative disorders and among the hemato-
logical malignancies chronic lymphocytic leukemia
(CLL), T-cell large granular leukemia (LGL)/natural
killer (NK) cell leukemia, plasma cell myeloma, non-
Hodgkin lymphoma, MDS, and acute lymphoblastic
leukemia (ALL) have been reported.12–14 PRCA
might precede, may present simultaneously, or might
follow the lymphoproliferative disorder, either in
relapse or even in remission.
Various pathogenetic roles of autoreactive B-cells,
T-cells, and NK-cells in erythroid hypoproliferation
have been described. B-cells mainly act via production
of IgG antibodies.12,14,15 IgG binds complement, may
be directly cytotoxic via type II hypersensitivity reac-
tion, targets erythroblasts in vitro, or inhibits hemo-
globin synthesis. IgG produced following a viral or
bacterial infection cross-reacts with erythroid precur-
sor cells or erythropoietin. Anti-erythropoietin anti-
bodies form immune complexes with erythropoietin,
causing functional inactivation. Obstruction of the
erythropoietin receptor by anti-erythroblast antibody
has also been described.15 The role of T-cells is
mainly by major histocompatibility complex-I
(MHC-I)-restricted CD8+ cytotoxic T-lymphocytes
and NK-cells is via MHC-unrestricted CD3+ T-
LGLs with T-cell receptor (TCR)-expressing killer-
cell immunoglobulin-like receptors.16 There is also
an interplay between all the cell types wherein anti-
bodies cross-link the TCR of the T-LGLs with the
Fc receptor on target cells or cross-links the Fc recep-
tor on the T-LGLs or NK-LGLs (CD16) with any
specific ligand for the antibody on the target
cells.15,17,18
Megaloblastic anemia in malignancies
Megaloblastic anemia is a less common form of hypo-
proliferative anemia encountered in cancer patients.
Folic acid or vitamin B12 deficiency may be nutri-
tional or may result from anorexia and decreased
dietary intake. Increased requirements for folic acid
or vitamin B12 that cannot be replenished by the
regular dietary intake may occur due to increased cel-
lular proliferation and high-cell turnover as in leuke-
mias with hyperleukocytosis. Gastric tumor patients
who have been treated by total or subtotal gastrectomy
are at increased risk for the development of megalo-
blastic anemia because of vitamin B12 malabsorption.
20 Hematology 2015 VOL. 20 NO. 1
Folate antagonists, nucleoside analogs, and other
drugs interfering with DNA synthesis including hydro-
xycarbamide, cytarabine, methotrexate, 5-fluoroura-
cil, thioguanine, azathioprine, and 6-mercaptopurine
frequently produce megaloblastosis.19,20
Myelophthisic or leukoerythroblastic anemia
Myelophthisic or leukoerythroblastic anemia refers to
anemia due to replacement of the normal marrow
elements by (in this context) a neoplastic process
thereby resulting in hypoproliferation of the normal
marrow elements including the erythroid precursors.
Bone marrow examination is always indicated in
persons with anemia of obscure etiology, even
occasionally yielding the first clue to the presence of
an occult malignancy.21 The neoplastic process can
be in the form of frankly malignant cellular elements
as well as tumor diatheses in the form of fibrosis,
osteomyelosclerosis, and rarely necrosis or granuloma-
tous responses. Both metastatic (e.g. breast, prostate,
renal carcinomas, etc.) as well as hematological malig-
nancies (e.g. HCL, Hodgkin lymphoma, primary mye-
lofibrosis, and other myeloproliferative neoplasms)
commonly produce secondary myelofibrosis.
Myelodysplastic syndromes
MDS are a heterogeneous group of clonal hemato-
poietic stem cell disorders that are characterized by
ineffective hematopoiesis/bone marrow failure, per-
ipheral blood cytopenias, and a propensity for leuke-
mic transformation (usually into acute myeloid
leukemia, AML). The WHO classification system cur-
rently recognizes distinct pathological subtypes of
MDS based on morphological features, percentage
of nucleated bone marrow cells that are blasts, and
the number of hematopoietic lineages affected.
The diagnosis of MDS in a patient with a known
malignancy should however be made with extreme
caution as myriad tumor and therapy-related influ-
ences can mimic the morphological appearances of
MDS. Cytogenetic studies and, to a lesser extent,
flow cytometry can be useful in this distinction
although clinical and hematological follow-up includ-
ing repeat bone marrow examinations is always
judicious.22
Hypoplastic/aplastic anemia in patients with cancer
More appropriately termed ‘secondary’ hypoplastic/
aplastic anemia; this is nearly always therapy-related.
Even so, hematological malignancies (and concomi-
tant diminished hematopoietic reserves) as well as
their treatments are more common causes than non-
hematological malignancies. The pathophysiology of
marrow cell destruction (direct cytotoxicity) has been
inferred from the results of treatment in humans,
with substantial support from in vitro and animal
models.23

Hemolytic anemia in cancer patients
Autoimmune hemolytic anemia
Cancer-associated autoimmune hemolytic anemia
(AIHA) can be broadly divided into warm and cold
AIHA. Warm AIHA occurs in both lymphoid a well
as non-lymphoid malignancies. CLL and lymphomas
account for nearly 80% of secondary warm-antibody
AIHA cases.24 In addition, some non-lymphoid malig-
nancies like ovarian tumors have also been shown to
produce warm AIHA.
IgG1, the most commonly encountered subclass,
and IgG3 autoantibodies appear to be the most
effective in shortening red blood cell (RBC) life
spans.25,26 Destruction of autoantibody-coated RBCs
is mediated primarily by sequestration and phagocyto-
sis in macrophages of the splenic Billroth cords and to
a lesser extent in hepatic Kupffer cells. These macro-
phages express cell surface receptors for the Fc
region of IgG, especially IgG1 and IgG3 and also
for fragments of the complement proteins C3 and
C4. When present together on the RBC surface, IgG
and complement fragments act synergistically to
enhance RBC trapping and phagocytosis.
Most RBC sequestration in warm-antibody AIHA
occurs in the spleen, but trapping in the liver occurs
in the presence of large quantities of RBC-bound
IgG or the concomitant presence of complement
proteins on the RBC surface. Trapped RBCs may be
partially or completely ingested by a macrophage.
Partial phagocytosis is most common and leads to
the formation of spherocytes. Since membrane loss
exceeds volume, the escaped RBC assumes a spherical
shape, a sphere being the geometric shape with the
lowest ratio of surface area-to-volume. Certain
cancer chemotherapeutic drugs are well-known
causes of hemolytic anemia. Carmustine (bis-chlor-
oethylnitrosourea) reduces glutathione reductase and
results in hemolysis in patients who are glucose 6-
phosphate dehydrogenase (G6PD) deficient.
Doxorubicin generates reactive oxygen species and
results in oxidative hemolysis, also marked in patients
with G6PD deficiency.27 Pentostatin, used in HCL,
CLL, and graft-versus-host disease, may also cause
hemolysis.28
MAHA including disseminated intravascular
coagulation
Cancer-related MAHA is a paraneoplastic syndrome
characterized by Coombs-negative hemolytic anemia
with schistocytes, thrombocytopenia, elevated
plasma hemoglobin, and lactate dehydrogenase and
frequently, renal failure or dysfunction.29 Cancer-
related microangiopathy is a rare cause but frequent
terminal cause of secondary MAHA.30 A recent
review of cancer-related MAHA found that 154
cases were associated with solid cancers and 14 with
Gaspar et al. Anemia in malignancies
lymphoma.31 Over 90% of the cancers were metastatic,
and in 19.4% of solid cancers, the MAHA occurred at
recurrence/relapse. In general, adenocarcinoma was
the commonest histological type of cancer in
MAHA, in part due to the erythrocytopathic effects
of mucins produced. Gastric carcinoma was the com-
monest cancer site in that review, followed by breast,
prostate, lung, lymphomas, unknown primary,
abdominal, genitourinary, and endocrine cancers.
Lymphomas associated with MAHA included
Hodgkin disease, angiotropic lymphoma (especially
T-cell types), diffuse large B-cell lymphomas, and
plasma cell myelomas.31
A special feature of MAHA in malignancies is that,
unlike in other paraneoplastic syndromes, a relatively
high proportion of MAHA cases occur at the time of
cancer recurrence. In the review cited above, clinical
and laboratory findings revealed that only a minority
of cases presented with the features of thrombotic
thrombocytopenic purpura (TTP) or atypical hemoly-
tic uremic syndrome (aHUS), with the exception of
prostate cancer, whereas aHUS was a common presen-
tation and compared to hereditary or immune TTP or
aHUS.31 Bone marrow was the commonest site of
metastasis in cancer-related MAHA. About one-
third of patients with MAHA had laboratory signs
suggesting disseminated intravascular coagulation
(DIC). Pulmonary symptoms were more common in
cancer-related MAHA as compared to non-malignant
TTP/HUS. In the vast majority of cancer patients (a
disintegrin and metalloproteinase with thrombospon-
din-like motif-13), ADAMTS13 levels were >20% in
contrast to hereditary and acquired TTP where
ADAMTS13 activity is more or less reduced.
The pathogenesis of MAHA in cancer is largely
speculative. In solid cancers, the most likely cause
may be red cell fragmentation and platelet destruction
in small vessels of cancerous tissue, in particular, in
bone marrow, lung, or other organs. Cytokine
production by tumor cells may also play a role, for
instance, in tumor necrosis factor (TNF)-mediated
red cell damage. Massive tumor necrosis could
release tissue factor and initiate the coagulation
cascade leading to thrombotic microangiopathies.31,32
Endothelial cells too are likely to play a role.
Clinically, MAHA is a serious complication of malig-
nancy with a very poor prognosis. Nearly half of all
patients (46.5%) in the aforementioned study died
within a month with or without treatment.31
Miscellaneous hemolytic processes in patients with
malignancies
These include hemolytic reactions (acute or delayed)
as well as alloimmunization leading to reduced life
span of transfused RBCs in patients requiring blood
transfusions, co-incident infections like malaria,
Hematology 2015 VOL. 20 NO. 1 21
Gaspar et al. Anemia in malignancies
shigellosis, clostridial sepsis, leishmaniasis,33 etc., and
hemolysis associated with extra-corporeal circulatory
devices and dialysis membranes.
Anemias of miscellaneous etiology in cancer
patients
Hypersplenism
Hypersplenism secondary to lymphoproliferative
disorders and less commonly, myeloproliferative
neoplasms, is a rare cause of anemia. In myeloproli-
ferative neoplasms, the primary pathology is in bone
marrow whereas in lymphoproliferative neoplasms,
hypersplenism might play a significant role. Anemia
is caused by RBC pooling in the enlarged spleen,
decreased survival of RBCs, and hemodilution result-
ing from an increased plasma volume.34,35
Secondary hemophagocytic syndrome/
hemophagocytic lymphohistiocytosis
Malignancies presenting with prominent hemophago-
cytosis are rare and anemia resulting from
malignancy-associated hemophagocytic lymphohistio-
cytosis (HLH) is exceedingly rare. Only a few case
series are available in the literature and in virtually
all the anemia is associated with other cytopenias. In
the series by Shabbir et al. 36 in 18 adult patients, hem-
atological malignancies and stem cell transplantation
constituted 33% of all HLH cases and no solid
tumors were noted. Celkan et al. 37 analyzed 29 pedi-
atric malignancy-associated HLH and observed that
60% were due to hematological malignancies while
40% were due to solid tumors. ALL constituted
83.3% of the hematological malignancies.
Rhabdomyosarcoma and neuroblastoma constituted
50% each of the solid malignancies. Both genders
were equally represented. They postulated that pre-
sumably, malignant cells secrete the proinflammatory
cytokines TNF-α and IL-6 that contribute to
immune dysregulation.
Regardless of the underlying condition, the hallmark
in many studies of HLH in malignancies appears to be
acquired NK-cell dysfunction. Lymphoma-associated
HLH, harbor either a bi-allelic or mono-allelic
mutation in the perforin gene.38 Soluble CD163 is a sca-
venger receptor exclusively expressed in the monocyte–
macrophage system and increased shedding of its
extracellular domain has been demonstrated with
various inflammatory stimuli. Very high levels of
soluble interleukin-2 receptor alpha (sIL-2R-alpha)
are rarely seen in conditions other than HLH.
Measurement of both sIL2R-alpha and sCD163 can
aid in making a timely diagnosis of HLH, especially
when the presentation is not classical. Hence, HLH
should be borne in mind as a diagnostic possibility in
sick, febrile patients with cytopenias, and organome-
galy where commoner causes of anemia are unlikely.
22 Hematology 2015 VOL. 20 NO. 1
Acquired thalassemias
Acquired hemoglobinopathies including acquired
hemoglobin H disease and other α-thalassemias are
characteristically seen in patients with hematological
malignancies. They are usually associated with
MDS or less commonly, with myeloproliferative
neoplasms and erythroleukemia.39–41 These
relatively rare disorders may cause diagnostic dilem-
mas with the commoner inherited hemoglobin
abnormalities.
Molecular pathogenesis for acquired α-thalassemia
includes inactivating somatic mutations of trans-acting
chromatin-associated factor on the X-chromosome
(ATRX) that down-regulate α-globin gene expression
and, less commonly, acquired deletion of the
α-globin gene cluster on chromosome 16.39–41
Effects of anemia and tissue hypoxia on tumor
growth and sensitivity to therapy
Tumor hypoxia in anemic patients is well-known clini-
cally to reduce the effectiveness of radiation therapy. It
has also emerged, through experimental studies, as a
major factor influencing malignant cell proliferation
and tumor progression.42 Although hypoxia can also
negatively impact tumor cell growth, in vivo it more
often leads to hypoxia-driven responses that enhance
malignant progression and aggressiveness, ultimately
resulting in increased resistance to therapy and
poorer long-term prognosis. Malignant progression
associated with tumor hypoxia appears to be mediated
by several mechanisms, including changes in gene
expression, inactivation of tumor suppressor genes,
activation of proto-oncogenes, genomic instability,
and clonal selection.43,44
These genetic changes further result in increased
angiogenesis, cellular resistance to apoptosis, and to
oxidative free radicals generated by chemotherapy
and radiotherapy finally leading to enhanced tumor
growth and escape from therapy. A meta-analysis of
19 clinical studies of cancer-related anemia and 8
studies on tumor hypoxemia in 2005 attempted to
determine the effect of these variables on loco-regional
control and survival in patients with cancer.43 Despite
varying definitions of anemia and hypoxemia, all
studies indicated positive correlations between
reduced hemoglobin and higher levels of tumor
hypoxia with inferior prognosis. Attempted radiosensi-
tization by improved tumor oxygenation or hypoxic
cell sensitization through hyperbaric oxygen, electro-
philic radiosensitizer pharmacological agents, and
mitomycin had limited success.
Diagnostic approach to anemia in malignancy
Although heavily dependent on the clinical back-
ground and historical and examination findings,
certain generic approaches can be defined for the
 Gaspar et al. Anemia in malignancies

Figure 1 An algorithmic approach to anemia in a cancer patient. [Note: The black boxes highlight key investigations often vital
to the differential diagnosis.]

anemic cancer patient. These are outlined in Fig. 1. Conclusions

Specific malignancies have differing incidences and 1. Anemia is a common manifestation of malignancies
features of anemia. Data on a few of the common and is estimated to occur in up to 60% of cancer
ones are presented in Table 2. patients.

Hematology 2015 VOL. 20 NO. 1 23

Gaspar et al. Anemia in malignancies

Table 2 Salient findings in anemia in common malignancies

Anatomic site
[reference] Incidence and features of anemia

Breast44,45 • Commonest etiology in western data is therapy-related anemia

• Most of the commonly used chemotherapy regimens in the adjuvant setting, FAC (5-fluorouracil,
doxorubicin, cyclophosphamide) and CMF (cyclophosphamide, methotrexate, 5-fluorouracil) induce
anemia (Hb < 120 g/l) in 43–47% patients. Severe anemia (Hb level ≤79 g/l) occurs in 11% of patients
treated with FAC
• Hb level 11–80 g/l occurs in 67–97% previously untreated patients receiving taxanes as single agents
Lung46,47 • Frequency varies from 48 to 80%
• Pre-operative leukocytosis, anemia, and thrombocytosis are associated with poor survival in non-small
cell lung cancer
Prostate48 • Incidence varies from 33 to 70% in various studies
• Additional causes include androgen deprivation, hematuria, nutritional decline due to age, bone marrow
infiltration, treatment-related toxicity, and chronic inflammatory states
Lymphomas49 • Prevalences of anemia at diagnosis of CLL, NHL, and Hodgkin lymphoma have been reported as ∼25,
∼50, and 37.4%
• In one recent Indian study, anemia of inflammation/chronic disease was present in 72%, iron deficiency
in 39%, vitamin B12 and/or folate deficiency in 22% patients, and AIHA in 11% patients
• In only three patients, anemia was attributable to bone marrow involvement alone. Anemia was
multifactorial in 18 of 46 (39.1%) patients
• Nutritional deficiencies alone or in combination were present in 48% patients
Colorectal50,51 • Causes include insidious or acute blood loss, malabsorption, surgical resections, chemotherapy, DIC
• Anemia is present in ∼30–50% of the patients. Right-sided and non-rectal cancers are significantly
more likely to be anemic
• Anemia during neoadjuvant chemo–radiotherapy is associated with significant reductions in tumor
downstaging and regression

2. Anemia in cancer is usually multifactorial, with
anemia of inflammation/chronic disease being the
commonest component. Other common causes
include nutritional deficiencies, blood loss, and
anemia as a consequence of anti-neoplastic therapy.
3. Diagnostic approaches are similar to those in anemic
non-cancer patients, albeit with special consideration
to exclude causes peculiar to malignancy. A detailed
history and examination along with the complete
blood count including a reticulocyte count are of
paramount importance.
4. A pathogenetic approach to investigating the cause of
anemia in acancer patient is often clinically more reward-
ing than a pure blood film morphology-based scheme.
5. Anemia in cancer patients affects the quality of life,
survival, and possibly also the tumor response to
chemo- and radiotherapy.
Disclaimer statements
Contributors PS conceived of the idea. BLG and PS per-
formed the literature search. BLG wrote the first draft of
the manuscript. PS and RD edited the manuscript forcriti-
cal intellectual content. All authors read and approved the
final submission. PS is guarantor for the manuscript.
Funding None.
Conflicts of interest None.
Ethics approval Ethical approval was not required for
this review article which contains no identifying infor-
mation from any specific patient.
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