University of Khartoum

Graduate college
Medical and Health Studies Board

HAEMATOLOGICAL MANIFESTATIONS ASSOCIATED WITH

MALIGNANT
SOLID NEOPLASMS IN SUDANESE PATIENTS

A thesis submitted in partial fulfillment for the requirements of the Degree of M.D
in Clinical Medicine

By
Amier Mohamed El Hassan Fadl Alla
(M.B.B.S Omdurman Islamic University)

Supervisor:
Dr. Musa Mohamed Khair

Co supervisor:
Dr. Kamal Hamad

MBBS, M Med, DTM & H, MSc CTM,

F.F.R.R.C.S.I. , D.M.R.T. ,D.S.N.

DLSHTM,

Associate professor U. of K.

Associate professor U. of K.

Department of Oncology
March 2005

) (

)(

TO MY KIND & GENEROUS PARENTS.

TO MY WIFE & OUR COMING BABY
TO ALL WHOM I LOVE

AMIER

CONTENTS
Page
Acknowledgements .

Abstract .

ii

Abstract (Arabic) ..

iii

Abbreviations ...

iv

List of Tables .

vi

List of figures ....

vii

CHAPTER ONE
Introduction ..

Literature Review

Objectives ..

34

CHAPTER TWO
Materials and Methods .......

35

CHAPTER THREE
Results ...

38

CHAPTER FOUR
Discussion .

63

Conclusions ..

67

Recommendations ...

68

References .

70

Appendix (Questionnaire) .

ACKNOWLEDGEMENT
I WOULD LIKE TO TRANSMIT MY GREAT THANKS AND
RESPECT TO MY TEACHER & SUPERVISOR DR. MUSA MOHAMED
KHAIR, I APPRECIATE VERY MUCH HIS GUIDANCE & SUPPORT IN
COMPLETING THIS STUDY.
I EXTEND MY THANKS AND APPRECIATION TO DR. KAMAL
HAMAD

FOR

HIS

VALUABLE

OPINIONS,

CORRECTIONS

&

ADDITIONS HE MADE.
LOTS OF THANKS TO DR. OSMAN HASSAN MUSA FOR HIS
ADVISES, VALUABLE SUGGESTIONS AND FOR REVIEWING MY
RESOURCES FOR THE STUDY.
I AM GRATEFUL FOR THE LAB. TECHNICIANS ( AMEL

AND

SALMA ) ,WHO RENDERED THEIR HELP PATIENTLY FOR ME.

SPECIAL THANKS AND APPRECIATION TO MY FRIEND DR.
KHALID FOR HIS ASSISTANCE.
FINALLY I AM THANKFUL AND APPRECIATIVE TO ALL THOSE
WHO HELP & SUPPORT ME ESPECIALLY MY FRIENDS & A LOT OF
THANKS EXTENDED TO MY FAMILY & MY WIFE FAMILY.

ABSTRACT
This is a prospective descriptive study which was conducted in
Khartoum teaching hospital and (The Radiation & isotopes centre Khartoum), during the period between September 2004 January
2005, to determine the prevalence of haematological changes in
patients with solid malignant tumours, focusing more on anaemia.
103 of patients already diagnosed as having malignant solid
neoplasms were reviewed for their haematological changes 75.7% of
the patients had anaemia regardless of the stage of disease compared
to 72% in study done in western countries (32).
Other haematological changes observed were high E.S.R seen in 70
patients (68)% and high T.W.B.C. (41.7%) .
11 pts. (10.7%) proved to have hypercoagulable state, 2 patients
(1.9%) had polycythaemia, 8 patients (7.8%) developed DVT and 1
patient (IVC) thrombosis shown by CT-scan.
19.2% of the patients presented with bleeding in a form of frank
rectal or vaginal bleeding, epistaxis, haemoptysis, melaena or
haematuria.



-
.
.

.
.
%
)( % %
. %
% %
.

ABBREVIATIONS
ACD = Anemia of Chronic Disease
AIDS = Acquired Immune Deficiency Syndrome
AIHA = Auto Immune Hemolytic Anemia
APTT = Activated Partial Thromboplastin Time
BT

= Bleeding Time

CP .= Cancer Procoagulant
CT.SCAN= Computerised Tomography Scan
DVT=Deep Vein Thrombosis
DIC = Disseminated Intravascular Coagulation
EPO = Erythropoietin
ESR = Erythrocyte Sedimentation Rate
GI. = Gastrointestinal
G-CSF= Granulocyte Colony Stimulating Factor
GM-CSF= Granulocyte Macrophage Colony Stimulating Factor
Hb% = Haemoglobin
HCC = Hepatocellular carcinoma
Ig

= Immunoglobulin

IL

= Interleukin

INR = International Normalized Ratio

K.T.H. = Khartoum Teaching Hospital
LDH = lactate Dehydrogenase
MAHA = Micro Angiopathic Hemolytic Anemia
MCH% = Mean Cell Hemoglobin%
MCHC = Mean Cell Hemoglobin Content
MCV = Mean Cell Volume
NSCLC = Non Small Cell Lung Cancer
PCV = Packed Cell Volume
8

PRCA= Pure Red Cell Aplasia

PT = Prothrombin Time
RBC = Red Blood Cell
RHu-EPO = Recombinant Human Erythropoietin
RIC-Khartoum = Radiation and Isotopes Centre - Khartoum
TGF beta = Tumor Growth Factor
TNF = Tumor Necrosis Factor
TTP-HUS = Thrombotic Thrmbocytopenic Purpura
TWBC = Total White Blood Cell

List of Tables
Table 1:

The frequency of diagnosis in 103 patients with solid malignant

43

neoplasms presenting to (RIC-K) & KTH between Sept. 2004Jan.2005

Table 2:

The relationship between sex and age in 103 patients with solid

44

malignant neoplasms presenting to (RIC-K) & KTH between Sept.

2004-Jan.2005

Table 3:

The common presenting symptoms in 103 patients with solid

45

malignant neoplasms presenting to (RIC-K) & KTH between Sept.

2004-Jan.2005

Table 4:

Presence of pallor according to hemoglobin level in 103 patients

46

with solid malignant neoplasms presenting to (RIC-K) & KTH

between Sept. 2004-Jan.2005

Table 5:

The clinical finding on the examination of 103 patients with solid

47

malignant neoplasms presenting to (RIC-K) & KTH between Sept.

2004-Jan.2005

Table 6:
Table 7:

Incidence of types of anaemia in 103 patients with solid malignant

neoplasms presenting to (RIC-K) & KTH between Sept. 2004Jan.2005
Distribution of platelet changes in tumours in 103 patients with

48

49

solid malignant neoplasms presenting to (RIC-K) & KTH between

Sept. 2004-Jan.2005

Table 8:

Other hematological changes seen in 103 patients with solid

50

malignant neoplasms presenting to (RIC-K) & KTH between Sept.

2004-Jan.2005

Table 9:

The incidence of ESR changes in 103 patients with solid malignant

51

neoplasms presenting to (RIC-K) & KTH between Sept. 2004Jan.2005

Table 10:

The incidence of WBCs changes in 103 patients with solid

malignant neoplasms presenting to (RIC-K) & KTH between Sept.
2004-Jan.2005

10

52

List of Figures
Figure 1:

Frequency of diagnoses per system affected in 103 patients

53

with solid malignant neoplasms presenting to (RIC-K) &

KTH between Sept. 2004-Jan.2005

Figure 2:

Distribution of sex in 103 patients with solid malignant

54

neoplasms presenting to (RIC-K) & KTH between Sept.

2004-Jan.2005

Figure 3:

The age distribution of 103 patients with solid malignant

55

neoplasms presenting to (RIC-K) & KTH between Sept.

2004-Jan.2005

Figure 4:

Tumor percentage in bleeding in 103 patients with solid

56

malignant neoplasms presenting to (RIC-K) & KTH between

Sept. 2004-Jan.2005

Figure 5:

Tumors percentage in haematuria in 103 patients with solid

57

malignant neoplasms presenting to (RIC-K) & KTH between

Sept. 2004-Jan.2005

Figure 6:

Tumor percentage in jaundiced patients among the 103

58

patients with solid malignant neoplasms presenting to (RICK) & KTH between Sept. 2004-Jan.2005

Figure 7:

Surgical intervention performed in 103 patients with solid

59

malignant neoplasms presenting to (RIC-K) & KTH between

Sept. 2004-Jan.2005

Figure 8:

The Hb level in 103 patients with solid malignant neoplasms

60

presenting to (RIC-K) & KTH between Sept. 2004-Jan.2005

Figure 9:

The percentage of types of anaemia encountered in 103

61

patients with solid malignant neoplasms presenting to (RICK) & KTH between Sept. 2004-Jan.2005

Figure 10:

The incidence of platelet changes in 103 patients with solid

malignant neoplasms presenting to (RIC-K) & KTH between
Sept. 2004-Jan.2005

11

62

INTRODUCTION
The term cancer, neoplasia and malignancy are usually used
interchangeably in both the technical & popular literature.
Cancer has 4 characteristics:
1. Clonality = it originate from single stem cell which proliferates to
form a clone of malignant cells.
2. Autonomy = uncontrolled growth.
3. Anaplasia = lack of normal, coordinated cell differentiation.
4. Metastasis = dissemination to other parts of body.
Malignant disease is widely prevalent and in the west, almost third of the
population will develop cancer at some time during their life. It is second to
cardiovascular disease as the cause of death. Although the mortality of
cancer still high, many advances had been made, both in treatment and in
understanding the biology of the disease at the molecular level.
"Is it a cancer?" is a question we frequently ask ourselves in front of some
symptoms, signs or laboratory results like weight loss, anemia, high
erythrocyte sedimentation rate (ESR) or thrombocytosis . The aim of this
study is to assess the impact of hematological changes in the diagnosis and
treatment of solid malignant neoplasms.
Up to 75% of patients with cancer experience anemia during the
course of their disease, either due to cancer itself (tumor infiltration of the
bone marrow and/or anemia of chronic disease) or to the myelosuppressive
effects of chemotherapy or radiation therapy

12

(65)

It has a considerable

impact on outcome. Health-related quality of life of cancer patients is

significantly inhibited by anemia and other haematological complications.
Several lines of evidence indicate that aggressive treatment of anemia
is an important aspect of cancer therapy (36).
Treatment of anemia with recombinant human erythropoietin can
improve health-related quality-of-life outcome. However, despite this
knowledge, anemia remains under-recognized and under-treated in the
cancer patient population.
Many issues may be determinants of sub- optimal management of
anemia. They include ; limitations of current therapies for anemia, varying
practice strategies, and the lack of guidelines on how to treat anemia.
Additionally, clinicians may underestimate the importance of health-related
quality of life of their patients.
It is critical that these factors be addressed and that emerging and future
approaches are incorporated into clinical practice to maximize the future
treatment of anemia in the cancer patient.
In addition to anemia , there are other important hematological changes
that occur in platelet, W.B.C. or coagulation state. It may alert physician
to diagnose cancer early. These haematological changes need to be evaluated
properly for best treatment and better cancer outcome.

13

LITERATURE REVIEW
HAEMATOLOGICAL MANIFESTATIONS ASSOCIATED WITH
MALIGNANT SOLID NEOPLASMS IN SUDANESE PATIENTS

BACKGROUND:
Anaemia and other blood disorders are common presentations for a
great deal of diseases, especially the chronic ones.
Many patients with cancer have complication that are not due to
direct invasion of adjacent tissues by the tumour or its metastases. The
tumour produces hormones or cytokines, which are responsible for
symptoms at a remote site, so it provokes an immunological reaction
resulting in PARANEOPLASTIC SYNDROMES (See table 1-1) .
It is important to be aware of paraneoplastic syndromes in cancer
medicine because their appearance may be the first sign that malignant
disease is present. HAEMATOLOGICAL SYNDRME is one of these
important paraneoplastic syndromes and it will be reviewed in this study.
Table

(1-2) will show the principal haematological changes in

malignant disorders and their related tumours.

14

Table (1-1):

15

Table (1-2):

Principal haematological changes in malignant disorders

16

By far the most common hematological finding in malignant disease

is the anaemia of chronic disorders, which frequently complicates the course
of a cancer, and while it may be a presenting sign of malignancy

(1)

, more

often it is consequence of a patient's antineoplastic therapy or progressive

disease.
It is clear that anaemia is a common occurrence in cancer patients and has a
significant impact on clinical and health related quality of life (HRQOL)
outcomes. It is, therefore, important to understand the underlying etiology of
anaemia in cancer in order to provide the correct and most effective
treatment for individual patients.

17

As with anaemia in general, three broad categories should be considered

when assessing causes of anaemia in patients with malignancies:
Red blood cell (RBC) losses from the body (blood loss anaemia)
Increased RBC destruction (haemolytic anaemia)
Decreased red blood cell production (hypoproliferative anaemia)
While one or more of these three mechanisms must be responsible when
anaemia is present, some causes are relatively specific for patients with
malignancy. These include:
Direct effects of the neoplasm.
Products of the neoplasm.
Effects of treatment directed against the neoplasm.

*ANEMIA FROM DIRECT EFFECTS OF NEOPLASMS:

External bleeding Intraluminal neoplasm (i.e., malignancies arising from
or metastasis to the gastrointestinal or genitourinary tract) may bleed,
producing blood loss anaemia. When evaluating cancer patients who have
anaemia, stool and urine samples should be examined for evidence of
blood(2).

18

Impaired iron absorption While iron deficiency most commonly

arises from bleeding, it may occasionally result from impaired iron
absorption. Iron malabsorption should be considered in patients whose
malignancies involve the mucosa of the duodenum and/or upper jejunum,
the sites of maximal iron absorption. (see figure a )
This effect can be direct, as in gastrointestinal lymphoma

[2]

, or

indirect, as in amyloidosis from plasma cell myeloma.

Chronic bleeding of this type is often associated with a mild thrombocytosis.

Internal bleeding Occasionally, there may be significant bleeding into

the body of the tumour, resulting in acute anaemia. Most patients suffering
this complication have hepatocellular carcinoma, and spontaneous liver
rupture can arise with catastrophic consequences

[3]

. Other malignancies

associated with haemorrhage into the tumour, with risk of massive internal
bleeding include:
Malignant hepatic epithelioid hemangioendothelioma [3]
Peliosis hepatis and liver cell adenomas (4)
Liver metastases, especially from cutaneous or ocular melanomas(5)
Splenic hemangiosarcomas (6)
Stromal ovarian tumors or cancers metastatic to the ovary(7)
Retroperitoneal tumors with retroperitoneal hemorrhage(8)

Other causes of bleeding Not all bleeding episodes will be related to

direct effects of the patient's malignancy, and other causes (for example,
peptic ulcer disease and mucosal erosive disease) should be considered.
Additionally, coagulopathies can enhance bleeding risk, and correlation of

19

patients' hemorrhagic tendencies should be made with laboratory tests

assessing

the

patient's

haemostatic

competencies

(platelet

count,

prothrombin time, activated partial thromboplastin time, thrombin time and

fibrinogen.

Hemophagocytosis
It is characterized by ingestion of RBCs by macrophages or cancer cells.
While the hemophagocytic syndrome is most commonly seen in association
with infection, particularly Epstein Barr virus (EBV) infection, this disorder
can complicate certain malignancies, producing anemia in the absence of
documented infection(9).
Cancer types most commonly associated with this syndrome are the
leukemias and the lymphomas. The latter are usually of T-cell lineage,
although B-cell proliferations causing hemophagocytosis have also been
described (10).
Rarely, solid tumours demonstrate hemophagocytosis(11). Detection of
hemophagocytosis is often made by bone marrow biopsy, which reveals
macrophages or cancer cells with ingested whole RBCs. Therapy is
treatment of the underlying malignancy, but prognosis is poor.

20

Bone marrow replacement -Solid tumours can also produce anaemia

by involving the bone marrow space through metastasis seen in cases of
disseminated malignancy resulting in leukoeythroblastosis .

Leukoerythroblastosis- which can arise also from haematopoietic

malignancies

(12)

and it is characterised by the presence in the blood of

immature myeloid cells together with some nucleated red cells and,
sometimes, a mild reticulocytosis. The red cells often show a moderate
degree of anisocytosis and poikilocytosis. This finding is very commonly
accompanied by the presence of tumour cells in the bone marrow.
Clinically, it can cause confusion with the diagnosis of primary
myelosclerosis; splenomegaly is unusual in patients with disseminated
carcinoma.
Solid tumour types most commonly resulting in this disorder are prostatic
and gastric carcinomas.
21

*ANEMIA FROM PRODUCTS OF NEOPLASMS:

Haemolysis
It is defined here as a shortening of RBC survival to less than 100
days, may occur in various malignancies. Two different mechanisms may
be involved:
Production of autoantibodies which recognize red cell membrane
antigens and cause an autoimmune hemolytic anemia.
Microangiopathic changes, which cause fragmentation hemolysis.

Autoimmune hemolytic anemia

Autoimmune hemolytic anemia (AIHA) is usually associated with the
presence of immunoglobulin (IgG) or complement (C3d) on the surface of
circulating RBCs, as detected by the direct Coombs' test. The presence of
spherocytic RBCs on the peripheral smear, along with increased serum
concentrations of indirect bilirubin and lactate dehydrogenase (LDH) are

22

the hallmark findings. While cancer-associated AIHA is most frequently

noted in patients with chronic lymphocytic leukemia, other associated
tumors include non-Hodgkin's lymphoma, Hodgkin's disease, carcinomas,
multiple myeloma, Waldenstrom's macroglobulinemia, acute myelogenous
leukemia, angioimmunoblastic lymphadenopathy with dysproteinemia,
acute lymphoblastic leukemia, and myelodysplasia.

Microangiopathic hemolysis
In microangiopathic hemolytic anemia (MAHA), Coombs' testing is
negative, and schistocytes (RBC fragments) are the hallmark peripheral
blood smear finding. MAHA in malignancy may be a consequence of
disseminated

intravascular

coagulation

(DIC)(13)

or

thrombotic

thrombocytopenic purpura- hemolytic uremic syndrome (TTP-HUS)(14).

Most patients with cancer-related MAHA have already been diagnosed
with cancer, although it can occasionally be a presenting sign of
malignancy

(15)

. However, many disorders other than cancer may trigger

MAHA, particularly DIC

(16)

. Hence, implicating cancer as the cause of

MAHA requires exclusion of these other causes.

Both solid tumours and haematological malignancies may give rise to

MAHA (15). However, in contrast to leukaemia-associated MAHA, which

is generally DIC with risk of hemorrhage from consumptive coagulopathy
(as in acute promyelocytic leukemia), solid tumor-associated MAHA is
generally thrombotic, with an increased risk for thrombotic complications
and renal failure. The solid tumors most commonly associated with
MAHA are mucinous adenocarcinomas of the gastrointestinal tract
(especially gastric and pancreatic) or prostate
as a consequence of antineoplastic therapy.
23

(16)

, MAHA may also arise

Mechanisms responsible for cancer-triggered

MAHA are

uncertain. However, investigations have yielded several insights,

particularly in cancer-associated DIC. For example, tissue factor, the
activator of factor VII, has been shown to be expressed on the surface of
certain tumor cells(17).
In addition, tumor necrosis factor and interleukin-6, proinflammatory
cytokines associated with the malignant state, may dysregulate
anticoagulant and antifibrinolytic mechanisms (18).

24

Inflammation
Certain cytokines (for example, interferon-alpha, interferon-beta ,
interferon-gamma , TNF-alpha , TGF-beta , IL-1 and IL-6), produced in
response to malignancy, may result in anemia by mediating a block in iron
utilization, inhibiting erythropoietin mRNA synthesis, and exerting other illdefined suppressive effects on erythropoiesis (19).

Anaemia of chronic disoders:

It is typically normochromic, normocytic, and hypoproliferative
anemia, which may occur together with localized or widespread
malignancy and is sometimes associated with an elevated erythrocyte
sedimentation rate (ESR), it can also be the result of cancer therapy(19). It
is found in patients with practically every type of carcinoma or reticulosis
and it is refractory to haematinics, but may respond to successful removal
of a primary tumour and recently to (Recombinant human erythropoietin).

PATHOGENESIS It is thought to reflect a reduction in red blood cell

(RBC) production by the bone marrow. There may also be mild shortening
of RBC survival. Three factors are thought to contribute to the
hypoproliferative state (20):
Trapping of iron in macrophages, making it relatively unavailable for
new hemoglobin synthesis.
Inability of the morphologically normal marrow to increase
erythropoiesis in response to the anemia. EPO levels are somewhat
elevated in ACD but there is virtually no increase in erythropoiesis (20,21).
25

 A relative decrease in EPO production. Patients with ACD have lower

levels of EPO than do patients with iron deficiency and a similar degree of
anemia.

LABORATORY FINDINGS The anemia in ACD is of variable

severity. Many patients have a mild anemia, with a hemoglobin
concentration of 10 to 12g/dL. However, more severe anemia can be seen
with a hemoglobin concentration below 8 g/dL occurring in approximately
20 percent of cases. The absolute reticulocyte count is frequently low
(<25,000/L), a reflection of the decrease in RBC production.

Amyloid Amyloid, either primary (AL) or secondary (AA), may deposit

in a variety of organs including bone and rarely causes bone marrow
replacement.
Although disorders causing secondary (AA) amyloid are chiefly chronic
inflammatory and infectious diseases, but also malignant diseases giving
rise to AA amyloid have been reported, including Hodgkin's disease, nonHodgkin's lymphoma, macroglobulinemia, and renal cell carcinoma (22).

*ANEMIA FROM EFFECTS OF CANCER TREATMENT

Most commonly, anemia in patients with cancer is the consequence of
effects relating to cancer therapy. Ionizing radiation, encompassing sites
of marrow hematopoiesis, results in depletion of hematopoietic stem cells.
However, systemic antineoplastic therapy contributes more to anaemia
development than radiotherapy e.g.Tamoxifen ,Busulfan and others .

26

Other mechanisms by which chemotherapy may result in anemia include:

Suppression of hematopoietic growth factor synthesis, especially

erythropoietin .
Oxidant damage to mature hematopoietic cells .
Induction of immune-mediated hematopoietic cell destruction (e.g.,
cisplatin, teniposide) .
Induction of microangiopathic hemolytic anemia, as in mitomycin Cinduced hemolytic uremic syndrome .
Acute bone marrow stromal damage with intramedullary serofibrinous
exudate and hemorrhage, particularly from high-dose chemotherapy
Management Management of anemia from chemotherapy-induced
myelosuppression includes transfusion of packed red blood cells and the
administration of recombinant erythropoietin .
LESS COMMON FORMS OF ANAEMIA ASSOCIATED WITH
CANCER:

1-Pure red cell aplasia :

While a variety of drugs, chemicals and non-malignant conditions
may be responsible for the development of acquired pure red cell aplasia
(PRCA), this profound hypoproliferative anaemia, characterized by
markedly decreased or absent erythroid progenitors in the bone marrow,
marked reticulocytopenia, and normal leukocyte and platelet counts, can be
a consequence of malignancy.

27

In older series, thymomas accounted for as many as 50 percent of

PRCA cases, with the incidence of PRCA in patients with thymomas
ranging from 1 percent to 15 percent

(23)

. More recent series, however,

implicate thymomas less frequently (24-25).

However, in a Mayo Clinic series of 47 adults with acquired pure red
blood cell aplasia, CGL leukemia was the most common underlying
cause(26). While non-hematologic solid tumors have also been reported in
association with PRCA, a cause-and-effect relationship between the patient's
solid tumor and their PRCA has not necessarily been established in all cases.
Mechanisms causing cancer-associated PRCA include (27,28):
Immunoglobulin inhibitors of erythropoietin responsive cells
Immunoglobulin-mediated cytotoxicity of erythroblasts
T-cell inhibition of erythropoietin-responsive cells.

Parvovirus B19 infection Now widely recognized as a cause of

acquired PRCA, parvovirus B19, which selectively invades erythroid
progenitors, can cause profound erythroid hypoplasia with erythroid
maturation arrest, particularly with protracted infections arising in patients
with altered immunity

(29)

. Since patients with cancer are often

immunosuppressed, either primarily by their malignancy or secondarily by

therapy for their disease, parvovirus B19 infection must be considered as a
possible cause of hypoproliferative anemia in such patients.

28

2-Pernicious anaemia :
Which should be remembered as an associated factor with carcinoma of
the stomach and a patient may present with a megaloblastic anaemia
associated with a malignancy of this type.

3-Sideroblastic anaemias:
Are occasionally found in patients with carcinoma; in one series of 62
patients who presented with a sideroblastic anaemia, 10 were found to have
an underlying malignancy.
29

**

According to a European multicentre study on 15 000 cancer

patients, the percentage of anaemia exceeded 66% during the development

of solid tumours and 72% during development of other malignancies(30).
A quantitative review of published data from patients with cancer suggests
that anemia may be an independent prognostic factor for survival, with a
65% overall estimated greater relative risk of death (31).

** Anaemia as a PROGNOSTIC FACTOR:

Several studies have demonstrated that anemia is not only linked to an
impaired quality of life but to prognosis as well. Albain et al.

(32)

found a

Hb% level of bellow 11 g\dl as a significant independent prognostic factor

associated with shorter survival of chemotherapeutically treated non small
cell lung cancer (NSCLC)patients. The same applies to Hb% level
bellow12.7g\dl for radiotherapeutically treated (NSCLC)patients according
to a study by CARO JJ ,SALAS Met Al (31).

Managing Anemia in the Cancer Patient: Old Problems,

Future Solutions
Rationale for Treatment of Cancer-Related Anemia:
To correct anaemia, clinicians have several options; the preferred therapy for
anemia is correction of the underlying disorder.
Although red blood cell transfusion is also a treatment option for anemia, its
associated problems include the potential for transmission of infections, limited
availability of adequate blood supplies, and short-term resolution of symptoms.
30

Epoetin alfa is more convenient to administer, reduces infectious risks, and

maintains more constant steady-state Hb levels. It has been suggested that rHuEPO
and darbepoetin alfa may decrease the number of days cancer patients with anemia
spend in hospital . But their high cost limits their use in some centers.

Erythropoietin (EPO):
It is a haematopoietic growth hormone that regulates survival, proliferation, and
differentiation of erythroid progenitor cells(33). A reduction in tissue oxygenation
stimulates EPO production, through a complex feedback mechanism. Patients with
cancer-related anaemia have an inadequate EPO response that is further impaired by
cancer treatments such as chemotherapy.
Cancer-related anaemia substantially impairs patient functioning and may
contribute to poor treatment outcomes. A significant number of studies demonstrates
that treatment of anemia in cancer patients using recombinant human EPO
(rHuEPO, epoetin alfa) significantly increases haemoglobin (Hb) levels, reduces
transfusion requirements, and improves quality of life, particularly by relieving
fatigue. Recent data also show that epoetin alfa therapy may improve cognitive
function in patients receiving chemotherapy. In addition, the correction of anemia
may prolong survival by enhancing tumor oxygenation, thus increasing tumor
sensitivity to chemotherapy or radiation(34).
The indicated dose of epoetin alfa is 150-300 IU/kg three times per week, but it is
commonly dosed at 40,000-60,000 IU once weekly based on trial data and extensive
clinical use(34). Determining the timing of initiation of epoetin alfa is a clinical
judgment; however, data suggest that patient functioning declines and the risk of
transfusion increases when the Hb level falls under 12 g/dL.

31

Clinical practice guidelines issued by the American Society of Hematology and

the American Society of Clinical Oncology have recommended epoetin alfa as the
standard treatment option for patients with chemotherapy-related anemia and
hemoglobin (Hb) levels 10 g/dl

(35)

. For patients with Hb levels >10 g/dl but 12

g/dl, the use of epoetin alfa is optional, depending on clinical circumstances (35,36). In
contrast, the National Comprehensive Cancer Network recommends the use of
erythropoietic agents for the treatment of cancer-related or treatment-related anemia
in patients with Hb levels 11 g/dl (36).
In this setting, measurement of the plasma EPO concentration may be helpful.
Patients with ACD due to cancer, rheumatoid arthritis, or AIDS who have EPO
levels below 500 IU/mL (although some authors suggest a cut-off of 100 mU/mL)
will frequently respond to the administration of recombinant human EPO.

Potential Direct Effects of Epoetin Alfa on EPO-R-Expressing Tumors:

Because some cancer cells express EPO-R, treatment with epoetin alfa
could produce a variety of direct effects on tumors. For example, it has been
suggested that, in certain tumor cell lines and xenografts that express both
EPO and EPO-R, EPO signaling may promote cancer progression (37,38,39). In
cell lines of colon carcinoma, the Ewings sarcoma family of tumors, and
neuroblastoma, EPO reduced chemotherapy-induced apoptosis through
upregulation of antiapoptotic genes (40).
Overall, data from more than 10 years of epoetin alfa use in millions
of patients indicate that the drug is safe and beneficial for use in cancer(41),
with no evidence of associated tumor progression reported in clinical trials.
As discussed, limitations in current therapies for anemia, which include
RBC transfusions, iron supplementation, and rHuEPO, lack of global
32

guidelines for treatment, and an under appreciation of the impact of anemia

may contribute to this situation. It is critical that these factors be addressed
and that emerging and future approaches are incorporated into clinical
practice to maximize the future treatment of anemia in the cancer patient.

POLYCYTHAEMIA: (Erythrocytosis ):
Defined as an increase in haemoglobin, PCV and red cell count. It
has been found in patients with renal tumours, hepatomas, hamartomas of
the liver, uterine fibroids, vascular tumours and cystic adenomas of the
cerebellum, and carcinoma of the lung.
Ectopic production of erythropoietin by cancer cells causes most
paraneoplastic erythrocytosis. The ectopically produced erythropoietin
stimulates the production of red blood cells in the bone marrow and raises
the hematocrit. Other lymphokines and hormones produced by cancer cells
may stimulate erythropoietin release but have not been proven to cause
erythrocytosis.
Most patients with erythrocytosis have an elevated hematocrit
(>52% in men; >48% in women) that is detected on a routine blood count.
Approximately 3% of patients with renal cell cancer, 10% of patients with
hepatoma, and 15% of patients with cerebellar hemangioblastomas have
erythrocytosis. In most cases the erythrocytosis is asymptomatic.
Patients with erythrocytosis due to a renal cell cancer, hepatoma, or
central nervous system cancer should have measurement of red cell mass. If
the red cell mass is elevated, the serum erythropoietin level should then be
measured. Patients with an appropriate cancer, elevated erythropoietin
levels, and no other explanation for erythrocytosis (e.g., a hemoglobinopathy
that causes increased O2 affinity,) have the paraneoplastic syndrome.
33

TREATMENT OF ERYTHROCYTOSIS:
Successful resection of the cancer usually resolves the erythrocytosis.
If the tumor neither can be resected nor treated effectively with radiation
therapy or chemotherapy, phlebotomy may control any symptoms related to
erythrocytosis.
CHANGES IN THE PLATELETS AND BLOOD COAGULATION:
An otherwise unexplained THROMBOCYTOSIS may be the first
indication of an underlying malignancy. It is important to remember that this
is not always associated with chronic blood loss; other carcinoma may
present in this way.
Thirty-five percent of patients with thrombocytosis (platelet count
>400,000/uL) have an underlying diagnosis of cancer. IL-6, a candidate
molecule for the aetiology of paraneoplastic thrombocytosis, stimulates the
production of platelets in vitro and in vivo. Some patients with cancer and
thrombocytosis have elevated levels of IL-6 in plasma. Another candidate
molecule is thrombopoietin(42), a peptide hormone that stimulates
megakaryocyte proliferation and platelet production

(43)

. The aetiology of

thrombocytosis has not been established in most cases.

Patients

with

thrombocytosis

are

nearly

all

asymptomatic.

Thrombocytosis is not clearly linked to thrombosis in patients with cancer. It

is present in 40% of patients with lung and gastrointestinal cancers, 20% of
patients with breast, endometrial, and ovarian cancers, and 10% of patients
with lymphoma. Patients with thrombocytosis are more likely to have
advanced-stage disease and have a poorer prognosis than patients without
thrombocytosis.
Paraneoplastic thrombocytosis does not require treatment(42).
34

BLEEDING:
Hemorrhaging occurs in approximately 6%10% of patients with
advanced cancer (44).
When visible, it can be particularly distressing to patients and their
caregivers (45,46),in some patients, it may be the immediate cause of death.

AETIOLOGY AND CLINICAL PRESENTATION:

Bleeding may result from local vessel damage and invasion or from
systemic processes such as disseminated intravascular coagulopathy (DIC)
or abnormalities in platelet functioning and number.
The underlying causes of these abnormalities are varied and include
liver

failure,

medications

such

as

anticoagulants,

chemotherapy,

radiotherapy, surgery, and the cancer itself (47).

Occasionally,

concurrent

diseases,

such

as

idiopathic

thrombocytopenia, may be responsible.

Hemorrhaging may manifest in a variety of ways, including
hematemesis, hematochezia, melena, hemoptysis, hematuria, epistaxis,
vaginal bleeding, or ulcerated skin lesions (48).
It may also present as echymoses, petechiae, or bruising. Hemorrhage
may occur as an acute catastrophic event, episodic major bleeds, or ongoing

35

low-volume oozing. These characteristics provide clues as to the underlying

cause and guide management.
Management should focus on identifying the underlying cause(s) and,
where possible, controlling the bleeding. A comprehensive history and
examination is self-evident. A review of concurrent medications and other
illnesses may be helpful in identifying the etiology or contributing factors,
such as the concurrent use of nonsteroidal anti-inflammatory drugs, which
may exacerbate or precipitate bleeding through their actions on the
gastrointestinal tract and platelet functioning (48).
MANAGEMENT :
Local interventions: Packing, Hemostatic Agents, and Dressings
Vasoconstricting or cauterizing agents provide an alternative modality to
managing localized, capillary-based bleeding. Epinephrine may be used, but
its liberal use is discouraged. Prostaglandins E2 and F2 have been used to
control intractable hemorrhagic cystitis bladder spasms, however, may limit
their utility(49).

Radiotherapy:
External-beam radiotherapy has been shown to decrease haemoptysis
caused by lung cancer, with control occurring in up to 80% of patients(50).
Systemic treatments are also available, particularly for more
generalized

bleeding

or

oozing,

such

as

vitamin

K,

vasopressin/desmopressin, octreotide/somatostatin, antifibrinolytic agents

(tranexamic acid and aminocaproic acid), and blood products.

36

The majority of these treatments are supported only by case reports

and series in the setting of advanced cancer. Comparative and controlled
trials are lacking in this patient population.
Generalized haemostatic failure may occurs with disseminated
carcinoma. Some bleeding disorders associated with cancer seem to be due
to selective impairment of coagulation, from the treatment of the tumor by
cytotxic agents. This may result from pathological inhibitors of different
parts of the coagulation system or from isolated factor deficiencies. The
mechanism is unknown. However, in a patient with a bleeding disorder
associated with cancer, which is not characterized by consumption of
clotting factors or fibrinolysis, a detailed analysis of the activities of the
intrinsic and extrinsic pathways must be made in case a correctable lesion is
present (51).
Pathogenesis of the hypercoagulable state associated with malignancy:
Many patients with cancer are in a hypercoagulable state.
Table (1-3): Selective impairment of coagulation in cancer

37

The spectrum of manifestations ranges from abnormal coagulation tests

in the absence of symptoms attributable to thrombosis, to massive
thromboembolism. Thrombotic episodes may precede the diagnosis of
malignancy by months or years and can present in one of the following
ways(52).
Migratory superficial thrombophlebitis (Trousseau's syndrome)(53).
Idiopathic deep venous thrombosis and other sites of venous thrombosis
Nonbacterial thrombotic endocarditis.
Disseminated intravascular coagulation (DIC)
Thrombotic microangiopathy (e.g., thrombotic thrombocytopenic
purpura)
THROMBOPHLEBITIS:
Deep venous thrombosis and pulmonary embolism are the most
common thrombotic conditions in patients with cancer(54). Migratory or
recurrent thrombophlebitis may be the initial manifestation of cancer.
Approximately 15% of patients who develop deep venous thrombosis or
pulmonary embolism have a diagnosis of cancer. The coexistence of
peripheral venous thrombosis with visceral carcinoma, particularly
pancreatic cancer, is called Trousseau's syndrome.
Pathogenesis: Patients with cancer are predisposed to thromboembolism
because of many factors:

38

Release of procoagulants which promote clotting.

These are substances that have been isolated from animal and human
tumors with procoagulant activity that

fall into two major categories:

tissue factor-like procoagulant and cancer procoagulant (55,56).

1) Tissue factor
Tissue factor forms a complex with factor VII to activate factor IX
and factor X, thereby initiating blood coagulation.
It is a transmembrane protein expressed by some normal human
parenchymal and connective tissue cells and many malignant counterparts
such as sarcoma, melanoma, neuroblastoma, lymphoma, pancreatic cancer,
and acute promyelocytic leukemia (APL) (57).
2) Cancer procoagulant
Cancer procoagulant (CP) is a calcium-dependent cysteine protease
which has been found in malignant and fetal tissue, but not normally
differentiated tissue (58). It activates factor X directly, independently of the
tissue factor/factor VIIa complex

(58)

, Cancer procoagulant is present in

extracts of cells obtained from patients with acute promyelocytic leukemia,

malignant melanoma, and cancers of the colon, breast, lung, and kidney(59).
An immunoassay has been developed and there are data suggesting that
CP might be useful as a tumor marker (60).
Platelets
Increased platelet reactivity secondary to either clonal abnormalities
(eg, myeloproliferative disorders) or tumor-platelet interactions could
contribute to hypercoagulability.

39

Endothelial cells
Endothelial cells may become procoagulant under the influence of
inflammatory cytokines and other peptide products.
Co morbid factors
A number of clinical factors may contribute to the thrombotic
tendency in cancer patients. These include vascular stasis due to obstruction
of blood flow by the tumor or patient immobility, hepatic involvement and
dysfunction, sepsis, advanced age, other comorbid conditions, and certain
antineoplastic agents.
Clinical Manifestations: Patients with cancer who develop deep venous
thrombosis usually develop swelling or pain in the leg, and physical
examination reveals tenderness, warmth, and redness. Patients who present
with pulmonary embolism develop dyspnea, chest pain, and syncope, and
physical examination shows tachycardia, cyanosis, and hypotension.
Approximately 5% of patients with no history of cancer who have a
diagnosis of deep venous thrombosis or pulmonary embolism will have a
diagnosis of cancer within 1 year. The most common cancers associated
with thromboembolic episodes include lung, pancreatic, gastrointestinal,
breast, ovarian, and genitourinary cancers, lymphomas, and brain tumors.
Patients with cancer who undergo surgical procedures requiring general
anesthesia have a 20 to 30% risk of deep venous thrombosis.
Diagnosis: The diagnosis of deep venous thrombosis in patients with cancer
is made by impedance plethysmography or bilateral compression
ultrasonography of the leg veins.

40

Patients without a diagnosis of cancer who present with an initial

episode of thrombophlebitis or pulmonary embolus need No additional tests
for cancer other than a careful history and physical exam.
In light of the many possible primary sites, diagnostic testing in
asymptomatic patients is wasteful
However, if the clot is refractory to standard treatment or is in an
unusual site, or if the thrombophlebitis is migratory or recurrent, efforts to
find an underlying cancer are indicated.
TREATMENT
Patients with cancer and a diagnosis of deep venous thrombosis or
pulmonary embolism should be treated initially with intravenous
unfractionated heparin or low molecular weight heparin for at least 5 days
and coumadin started within 1 or 2 days. The Coumadin dose should be
adjusted so the INR is 2 to 3. Patients with proximal deep venous thrombosis
and a relative contraindication to heparin anticoagulation (hemorrhagic brain
metastases or pericardial effusion) should be considered for placement of a
filter in the inferior vena cava (Greenfield filter) to prevent pulmonary
embolism. Coumadin should be administered for 3 to 6 months. Patients
with cancer who undergo a major surgical procedure should be considered
for heparin prophylaxis or pneumatic boots. Breast cancer patients
undergoing chemotherapy and patients with implanted catheters should be
considered for prophylaxis (1 mg Coumadin per day) (61).

41

Among the tumour related bleeding problems are D.I.C., primary

fibrinolysis, thrombocytopenia (1-chemotherapy-related. 2-bone marrow
infiltration), acquired platelet dysfunction, and circulating inhibitors or
anticoagulants (62).
DISSEMINATED INTRAVASCULAR COAGULATION (DIC):
Resulting from generalized activation of the coagulation system and
it is the most common coagulopathy associated with malignancy.
Malignancy is the third most frequent cause of DIC after infection
and trauma, accounting for approximately 7 percent of clinically evident
cases. DIC, which may be occult, has been reported in as many as 15
percent of patients with advanced disease and in most patients with acute
promyelocytic leukaemia (APML) (63).
Acute DIC Acute, overt DIC is rare in most malignancies, most often
occurring with APML and adenocarcinomas.
Carcinoma of the prostate also may be associated with hemorrhagic
symptoms. However, the mechanism is different from DIC, being due to
activation of fibrinolysis. Laboratory evaluation in DIC reveals a typical
constellation of findings. These include prolongation of the prothrombin
time (PT), activated partial thromboplastin time (aPTT), thrombin time
and reptilase time; thrombocytopenia; and reductions in plasma
concentrations of fibrinogen and factors V and VIII. The most useful
confirmatory test is the demonstration of increased levels of fibrin
degradation products (FDPs).

42

Chronic DIC Chronic forms of DIC are more common in patients with
cancer, particularly those with solid tumours
WHITE-CELL ABNORMALITIES:
Apart from the leukaemoid reaction caused by widespread carcinoma,
there are several white-cell changes that should make the clinician think
about an underlying malignancy (64).
GRANULOCYTOSIS :
Approximately

30%

of

patients

with

solid

tumours

have

granulocytosis (granulocyte count >8000/uL). In about half of patients with

granulocytosis and cancer, the granulocytosis has an identifiable
nonparaneoplastic etiology (infection, tumour necrosis, glucocorticoid
administration, etc.). The other patients have proteins in urine and serum that
stimulate the growth of bone marrow cells. Tumors and tumor cell lines
from patients with lung, ovarian, and bladder cancers have been documented
to produce granulocyte colony-stimulating factor (G-CSF), granulocytemacrophage colony-stimulating factor (GM-CSF), and/or IL-6. However,
the etiology of granulocytosis has not been characterized in most patients.
Patients with granulocytosis are nearly all asymptomatic, and the
differential white blood cell count does not have a shift to immature forms of
neutrophils. Granulocytosis occurs in 40% of patients with lung and
gastrointestinal cancers, 20% of patients with breast cancer, 30% of patients
with brain tumors and ovarian cancers, and 10% of patients with renal cell
carcinoma. Patients with advanced-stage disease are more likely to have
granulocytosis than those with early-stage disease, (Prognostic factor ).
43

Paraneoplastic granulocytosis does not require treatment. The

granulocytosis resolves when the underlying cancer is successfully treated.
EOSINOPHILIA :
Eosinophilia is present in 10% of patients with lymphoma (tumors and
tumor cell lines from patients with lymphomas or leukemia may produce
IL-5, which stimulates eosinophil growth), 3% of patients with lung cancer,
and occasional patients with cervical, gastrointestinal, renal, and breast
cancer. Patients with eosinophilia are typically a symptomatic however those
with markedly elevated eosinophil counts (>5000/uL) can develop shortness
of breath and wheezing. A chest radiograph may reveal diffuse pulmonary
infiltrates from eosinophil infiltration and activation in the lungs.
TREATMENT:
Definitive treatment is directed at the underlying malignancy: tumors
should be resected or treated with radiation or chemotherapy. In most
patients who develop shortness of breath related to eosinophilia, symptoms
resolve with the use of oral or inhaled glucocorticoids.
LYMPHOPENIA:
Persistent lymphopenia may occur in patients with Hodgkin's disease.

44

STUDTY OBJECTIVES
MAIN OBJECTIVE:

To determine the prevalence of haematological changes in patients

with malignant solid neoplasms.

SPECIFIC OBJECTIVES:

To determine the association of solid tumours with certain types of

anaemia.
To identify the clinical haematological complications associated with
malignant solid neoplasms.

45

MATERIALS AND METHODOLOGY

A literature review was used to identify the weight of the
haematological changes in the relation to cancer the following sites were
used (Pubmed, The oncologist, Emedicine and Medline), using the following
search strategy www.pubmed.com .
Other resources are Oxford textbook of medicine, Up-to-date CD and
Harrison textbook of medicine.
A number of 103 patients, who proved to have malignant solid tumours
were selected randomly from (RIC-K) and Khartoum Teaching Hospital and
asked to join the study.
INCLUSION CRITERIA:
Patients who was already diagnosed as having malignant solid tumour and
agreed to join the study.
EXCLUSION CRITERIA:
Patients with haematological tumours.
Patients who received chemotherapy and/or radiotherapy.

STUDY DESIGN:
It is a prospective descriptive study held in a period from 01/09/2004
to 01/01/2005.

46

Data collection:
The researcher will interview all participants and a standard questionnaire
will be filled by him or medical personnel (medical registrar, medical officer
or house officer).
History was taken from the patient or a relative, in some cases it was
obtained from the hospital s file.
A blood sample will be drawn, for analysis.
All patients who agree to join the study will undergo the following
laboratory tests before receiving any treatment:
1)

HB %

2)

PCV

3)

MCV

4)

MCH

5)

MCHC

6)

ESR

7)

TWBC

8)

PLATELET COUNT

9)

PERIPHERAL BLOOD PICTURE.

For some specific cases further investigations will be done e.g. :

1.

Coagulation profile.

2.

Bone marrow study.

3.

Coomb,s test .

47

NORMAL VALUES = BLOOD INDICES

HB%=13-16gm/dL male 12-15 gm/dL female
ESR= 0-10 mm/1st hour
MCV=75-95 fl
MCH=27-32 pg
MCHC=32-36%
PCV=0.40-0.54
RBCs=4.5-6 mill. Male 0.35-0.47 mill.
PLATELET COUNT= 150000 - 400000/L
WCC= 4000-8000 Cu/mm
For all patients their records will be checked and if they have all required
investigations no further analysis will be conducted, unless indicated.
Results were used for the benefit of the patients and for the study.
DATA ENTRY AND ANALYSIS:
Were done using SPSS and conducted by two independent persons.
Results will be expressed in the form of figures, tables and graphs.
LIMITATIONS:
Lack of National Sudanese studies made it difficult to interpret our
findings in comparison to the international findings.
Additional investigations could have been more useful but lack of
funding and limited financial capacity of the patients made it un-achievable.

48

RESULTS
Personal Data:
This is a prospective study conducted over five months in The
Radiation and Isotopes Centre Khartoum and Khartoum Teaching Hospital.
In this prospective study 103 cases of solid malignant tumours were
studied for associated hematological disorders (Table 1).
The percentages of tumours represented as follows: 12.6% breast,
5.8% musculoskeletal (fibrosarcoma, skin), female genital organs
(uterus,

ovary

and

cervix)

,7.8%

urinary

(renal,

9.7%

bladder),27.2%

gastrointestinal (oesophagus, stomach, colon, rectum, cholangiocarcinoma),

7.8% HCC ,8.8% glands(thyroid, parotid and pancreas), 6.8%prostate, 6.8%
respiratory (lung ,larynx), 4.9% unknown primary carcinoma.(Figure 1).
Sex distribution in the study is 56.3% male and 43.7% female
(Figure 2), and their age group varies from each other, the commmonest age
group affected is those who aged >50years 58.3% followed by 20-49years
age 36.9% and the younger one (<20years)4.9% .(Figure 3).
Malignant tumours showed predominance of male sex in all age
groups, being 80% to 20% male to female respectively in patients aged < 20
years, 52.6 % to 47.4% in age group between 20 -50years and 34% to 26% in
those who aged > 50 years. (Table 2)
CLINICAL PRESENTING SYMPTOMS AND SIGNS:
In the study patients presented with different clinical pictures and
remarkable and heterogeneous groups of symptoms and signs were reported
(Table 3).
49

Pallor was noted in 73.8% of patients those who had Hb. > 12gm/dl
clinical pallor was detected in 6 patients 24% and 82% in those with Hb. 1012gm/dl and 95.5% when Hb. is less < 10 gm/dl. (P=0.00001) this is
statistically significant. (Test is significant if < 0.05) (Table 4).
19.2% of all cases presented with bleeding in a form of frank rectal or
vaginal bleeding, epistaxis, haemoptysis, melaena or haematuria.
Bleeding was encountered in all cases of rectal and cervix carcinoma,
37.5% in HCC, 28,6% ovarian and 14.3% in prostatic cancer.(Figure 4)
Haematuria stated in 8.7%of all cancers evaluated, all bladder
tumours ,12.5% HCC, 42.9% prostate and 40% of renal cases .(Figure 5)
( P=0.00001) .
Fatigability considered as a major symptom of anaemia and it does
affect the life style of patient , here 55.3% of our patients were found to
have this cardinal manifestation of malignancy and it was encountered in
almost all types of malignancy. (P value=0.094 ) this is statistically
insignificant.
Other common clinical presentations of the studied population were:
masses 36.9% (p value 0.00), pain 44.7% (P value 0.003) , weight loss
25.2% (P value 0.007 ).
Less common clinical presentation which depend mainly on the type
of tumour were represented as follows ; vomiting in 17 patients(16.5%)
mainly in

GI. malignancy, 10.7% dysphagia, 11.7% cough ,8.7%

dysuria,7.8% anorexia ,fever 4.9%. and

shortness of breath 4.9%.

(P

0.001)this is statistically significant.

Physical examination of patients revealed that 30 patients ( 29.2%)
have lymphadenopathy with

involvement of different groups.(P-value

0.106) insignificant test (Table 5).

50

Jaundice is seen in 12.6% of patients, encountered in 25% of

pancreatic tumors, 50% HCC and 20% in thyroid cancer. (P 0.01) this is
statistically significant (Figure 6).
Liver is affected in 31.1% of patients either primary or secondary due
to metastasis, kidneys were abnormal in 6.8%, spleen was affected in 5.8%
and chest abnormality found in 21.4%.
Deep vein thrombosis of lower limbs was observed in 7.8% (cervix,
ovary, prostate and renal cancers), one case had Inferior Vena Cava
thrombosis evident by CT-scan. (Table 5)
In reviewing the surgical history of our patients we found that,82.5%
of them underwent surgery for a diagnostic purpose compared to 52.4%
who underwent therapeutic surgical intervention . (P value=0.052) this is
statistically significant (Figure 7)
INVESTIGATIONS:
The study showed anaemic changes in 75.7% of all analyzed samples.
33% of them revealed moderate anaemia and 42.7% of patients presented
with severe anaemia regardless the stage of their disease.(Figure 8)
Severe anaemia was noted in 11.4% of breast cancer, 11.4%female
genital, 25% gastro intestinal ,18.2% glands ,6.8% HCC ,6.8% lung ,4.5
unknown primary carcinoma and 6.8% in urinary cancers, mild anaemia
occurred as well in these cancers 8.8%, 11.8%, 41.2%,11.8%,5.9%,2.9%
,5.9% and 8.8% respectively.
The most common type of anaemia shown in the study is anemia of
chronic disease 50.5%, the second one was leukoerythroblstic anemia in
13.6% then iron deficiency anemia in 11.7%. (Figure 9)
Anaemia of chronic disease was detected commonly in every type of
malignancy e.g. 83.3% in musculoskeletal cancers ,46% in breast, 66.7% in
51

lung, 39.3% in GI. cancers, 62.5 in glands, 25% in HCC ,40% in unknown
primary carcinoma and 75% of urinary cancers. (Table 6)
While iron deficiency anaemia was encountered in 20% of female
genital cancers, 25% in GI.

malignancy, 25%

HCC

and in

20%of

unknown primary carcinoma .

Leukoerythroblastic anaemia was detected in 15.4% breast, 10%
genital, 21.4% GI, 18.8% glands, 12.5% HCC and in 20% of unknown
primary.
Our

study

revealed

that

18.4%

had

high

platelet

count

(thrombocytosis) , and commonly it is found in GI. malignancy e.g.(colon

66.7 , stomach 66.7% , 28.6% rectum , 33.3% pancreas , 16.7% oesophagus)
and in other tumours e.g. 15.4% breast, 16.7% lung , 20% renal , 20%
unknown primary carcinoma. (Table 7)
Compared to 9.7% who had thrombocytopenia (drug induced or bone
marrow

infiltration

by

tumour

which

per

say

found

in

2.9%)

.thrombocytopenia was detected in 33.3% of bladder cancer , 25% in HCC,

42.9% in prostate

and 28.6% in

rectal carcinoma . (P value=0.084)

(Figure 10)
Hypercoagulable state was observed in 10.7% of the study population.
Polycythamia was detected in two patients with renal carcinoma (1.9%)
(Table 8)
The study revealed that 32% had E.S.R. <49 , 51.5% had moderately
elevated ESR 50-99mm/h ,16.5%had had very high ESR >100mm/h e.g.
7.7% breast cancer ,20% female genital organ ,25% HCC ,18.8%
prostate,42.9% lung cancer 12.5% urinary cancers and 20% unknown
primary carcinoma. ( P value=0.472 ) (Table 9)

52

It is also shown by the study that 41.7% of our patients have high
TWBC, demonstrated in majority of cancers compared to 3.9% who had low
count ,25% thyroid and 20% in unknown primary carcinoma.(P=0.5)
insignificant. (Table 10)
Other tools of investigation which assisted the diagnosis in addition to
tissue biopsy were CT-scan done in 21.5% , C.X.R. done in 7.9% and
others.

53

Table (1) :
The frequency of diagnosis in 103 patients with solid malignant neoplasms
presenting to (RIC-K) & KTH between Sept. 2004-Jan.2005
Diagnosis

Frequency

Breast

13

12.6

Stomach

8.7

HCC

7.8

Oesophagus

7.8

Prostate

6.8

Rectum

6.8

Ovary

6.8

Lung

5.8

Renal

4.9

Unknown primary

4.9

Pancreas

3.9

Thyroid

3.9

Bladder

2.9

Fibrosarcoma

2.9

Colon

2.9

Cervix

1.9

Naso-pharynx

1.9

Skin

1.9

Larynx

1.0

Osteosarcoma

1.0

Cholangiocarcinoma

1.0

Parotid

1.0

Uterus

1.0

Total

103

100.0

54

Table (2):
The relationship between sex and age in 103 patients with solid malignant
neoplasms presenting to (RIC-K) & KTH between Sept. 2004-Jan.2005
AGE
< 20 yrs

FEMALE

MALE

20%

80%

20 50 yrs

52.6%

47.4%

> 50 yrs

56.7%

43.3%

55

Table (3):
The common presenting symptoms in 103 patients with solid malignant
neoplasms presenting to (RIC-K) & KTH between Sept. 2004-Jan.2005

Frequency

Fatigue

57

55.3

Pain

46

44.7

Loss of weight

26

25.2

Vomiting

17

16.5

Bleeding

15

15.6

Cough

12

11.7

Dysphagia

11

10.7

Dysuria

8.7

Haematuria

8.7

Abdominal distention

7.8

Anorexia

7.8

Shortness of breath

4.9

Fever

4.9

Haemoptysis

1.9

Melaena

56

Table (4):
Presence of pallor according to hemoglobin level in 103 patients with solid
malignant neoplasms presenting to (RIC-K) & KTH between Sept. 2004Jan.2005
HEMOGLOBIN
> 12 gm/dl

YES

NO

24%

76%

10 12 gm/dl

82.4%

17.6%

< 10 gm/dl

95.5%

4.5%

57

Table (5):
The clinical finding on the examination of 103 patients with solid malignant
neoplasms presenting to (RIC-K) & KTH between Sept. 2004-Jan.2005

Frequency

Pallor

76

73.8

Jaundice

13

12.6

Lymphadenopathy

30

29.1

Chest abnormal findings

22

21.4

Enlarged liver

32

31.1

Enlarged kidneys

5.8

CNS abnormalities

11

10.7

Ascitis

14

13.6

Deep vein thrombosis

7.8

Ulcers

4.9

Masses

38

36.9

58

Table (7):
Distribution of platelet changes in tumours in 103 patients with solid
malignant neoplasms presenting to (RIC-K) & KTH between Sept. 2004Jan.2005

DIAGNOSIS

LOW

HIGH

BREAST

15.4 %

COLON

66.7%

25%

LUNG

16.7%

OESOPHAGUS

12.5%

OVARY

14.3%

PANCREAS

33.3%

PROSTATE

42.9%

14.3%

RECTUM

28.6%

28.6%

RENAL

20%

STOMACH

66.7%

UNKNOWN PRIMARY

20%

20%

UTERUS

100%

HCC

59

Table (8):
Other hematological changes seen in 103 patients with solid malignant
neoplasms presenting to (RIC-K) & KTH between Sept. 2004-Jan.2005

Frequency

Hyper coagulable state

11

10.7

Polycythaemia

1.9

60

Table (9):
The incidence of ESR changes in 103 patients with solid malignant neoplasms
presenting to (RIC-K) & KTH between Sept. 2004-Jan.2005

ESR

Frequency

0 49

33

32

50 99

53

51.5

100 mm/hour

17

16.5

61

Table (10):
The incidence of WBCs changes in 103 patients with solid malignant
neoplasms presenting to (RIC-K) & KTH between Sept. 2004-Jan.2005

WBCs

Frequency

Normal (4000-8000)

56

54.4

Low (<4000 )

3.9

High (>8000 Cu/mm3)

43

41.7

62

Table (6):
Incidence of types of anaemia in 103 patients with solid malignant neoplasms presenting to (RIC-K) & KTH between Sept.
2004-Jan.2005
RBCs Blood Picture
Anaemia of chronic disease
Iron deficiency anaemia

Diagnosis
Normal

Bladder
Breast
Cholangiocarcinoma
Colon
Cervix
Fibrosarcoma
Hepato cellular carcinoma
Larynx
Lung
Naso-pharynx
Oesophagus
Oeteosarcoma
Ovary
Pancreas
Parotid
Prostate
Rectum
Renal
Skin
Stomach
Thyroid
Unknown primary
Uterus
Total

No.
1
5
0
1
0
1
3
1
2
2
2
0
1
0
1
0
0
1
0
1
2
1
0
25

%
33.3
38.5
0
33.3
0
33.3
37.5
100.0
33.3
100.0
25.0
0
14.3
0
100.0
0
0
20.0
0
11.1
50.0
20.0
0
24.3

No.
2
6
0
0
2
2
2
0
4
0
4
1
3
4
0
5
1
4
2
6
1
2
1
52

63

%
66.7
46.2
0
0
100.0
66.7
25.0
0
66.7
0
50.0
100.0
42.9
100.0
0
71.4
14.3
80.0
100.0
66.7
25.0
40.0
100.0
50.5

No.
0
0
0
0
0
0
2
0
0
0
2
0
2
0
0
0
4
0
0
1
0
1
0
12

%
0
0
0
0
0
0
25.0
0
0
0
25.0
0
28.6
0
0
0
57.1
0
0
11.1
0
20.0
0
11.7

Leukoeryt hroblastic
anaemia
No.
0
2
1
2
0
0
1
0
0
0
0
0
1
0
0
2
2
0
0
1
1
1
0
14

%
0
15.4
100.0
66.7
0
0
12.5
0
0
0
0
0
14.3
0
0
28.6
28.6
0
0
11.1
25.0
20.0
0
13.6

64

65

66

67

68

69

70

71

72

73

DISCUSSION
Cancer is a common disease, the second largest cause of death after
cardiovascular disorders, it may present with signs and symptoms due to
direct effect of tumor or with other features secondary to hormonal or
immunological effects, anemia and blood disorders were overlooked in this
study.
The study showed that incidence of solid malignancy is increasing
with age being common in patients aged > 50 years with marked male
predominance in all age group, but not all cancers, 58 males and 44 females
were studied with M:F ratio of 1.3:1 , this results is similar to that obtained
in National Cancer Institute in U.S. , which revealed that the age is the most
common risk factor for malignancy.
A wide variety of clinical presentations of solid tumors were
encountered including masses, vomiting, abdominal distention, pain, cough
and weight loss. But the more common one detected

was fatigability in

55.3% which affect the patient quality of life as shown in other studies
(1) (36)

. More or less these finding in addition to other blood changes are used

as a predictive value for malignancy as shown in study held in Romania and

reported that among those admitted to their hospital with weight loss,
anemia and high ESR, one out of two has cancer, those with weight loss
and anaemia 44% have cancer and those with weight loss and high ESR one
out three has cancer (66).

74

Bleeding including all types of blood loss, was stated in 19.2% of our
patients and this represent high percentage compared to 6-10 % reported in
western countries studies (44), (45), (46).
Special types of blood losses were observed in our study e.g.
haematuria, which was seen in 8.7% of patients commonly in bladder,
prostate and renal cancers, and this was in keeping with literature (48).
Deep venous thrombosis and pulmonary embolism are the common
thrombotic conditions in patients with cancer, in the literature

(52,54)

it was

mentioned that approximately 15 %of patients with DVT or pulmonary

embolism have a cancer and 5% of them with no history of cancer will
develop this in one year, so the 7.8% incidence of DVT stated in our study
represent an important observation.
Anemia is a common presentation of malignant tumors in our study, it
was found in 75.7% of patients which is a percentage nearest to that proved
by European Hematology Association 72% (32).
Anemia was detected in majority of our patients in different
distribution, regardless the time of presentation and stage of disease so it can
be considered as prognostic factor as it demonstrated in lung cancer by
Albain et al. and others

(31) , (32 )

. Other significant associations , were those

with Hb and Karnofsky performance status (KPS) (67).

In our study four different entities of anaemia were described, the
most common one being anaemia of chronic disorders which was seen in
50.5% of patients, in almost all types of malignancy, finding similar to that
documented in literature (19), (20) and (21).
75

Iron deficiency anemia was encountered in 11.7% of all cases studied

and it is commonly seen in female genital, unknown primary carcinoma and
gastrointestinal malignancy (2).
Leukoerythroblastic anemia was detected in 13.6% of study
population a

percentage which cannot be ignored especially if we

considered the results published by Institute of Pathology, Queen Elizabeth

Hospital in Hong Kong by Wong KF.

(68)

, 2/3 of patients with

leukoerthroblastic picture will demonstrate malignant cells in bone marrow

study (12).
Platelet count was increased in 18.4% of our patients mainly in
gastrointestinal

malignancy, breast, lung 16.7% , renal and unknown

primary carcinoma , a result which fits with that done in Italy

(67)

in lung

cancer and stated 17% occurrence of thrombocytosis . In literature although

it is not clearly linked to thrombosis in patients with cancer but it may
represent poor prognostic factor, it was described in 40% of patients with
lung and gastrointestinal cancers, 20% breast, endometrial and ovarian
cancers, and 10% of patients with lymphoma (42) (43).
Hypercoagulable state which includes a spectrum of manifestation
ranges from abnormal coagulation test to massive thromboembolism was
seen in 10.7% of our patients which is proportional to other study done on
this

(53),(54) and (56-61)

It has been estimated that about 2 % of all patients with

hypernephroma have erythrocytosis, a study done in U.S.A.

(69)

, and it

mimics the finding 1.9% in our patients. Also in Hong Kong polycythaemia
was reported in 10% of workers with hepatocellular carcinoma, but this was
not so evident in our study.
76

ESR was found high in 68% of our patients so it can be considered as

alarming sign for malignant process if there is suspicious for that, and it is
importance in this issue was estimated in other studies (66).
Also high TWBC count was detected in 41.7% of cancer patients in
the study, this was considered high compared with 30% incidence reported
in literature (64).

77

CONCLUSION
The study showed that solid malignant tumors are more common in
patients > 50 years and males predominate.
The study proved that the prevalence of anemia in cancer patients
regardless of the type and stage of disease doesnt differ between
Sudan and other countries.
The most common type of anaemia which was seen frequently in the
majority of solid tumors was anaemia of chronic disease followed by
leukoerythroblastic anaemia which
marrow infiltration, furthermore

per say

may indicate

bone

iron deficiency anaemia

was

observed commonly in patients with gastrointestinal malignancy.

The incidence of other clinical hematological presentation is also high
compared with other studies done in western countries centers ,e.g.
bleeding which was detected in 19.2% of our patients
Thrombocytosis , hypercoagulable state and erythrocytosis may be
the presenting feature of cancer and in our study they were found in
high frequencies 18.4% , 19,7% and 1.9% respectively.
Laboratory changes in blood count like high ESR and high TWBCS
were seen in most types of tumors regardless of pathophysiology.

78

RECOMMENDATIONS

The principles of cancer management are of great importance for every

clinician so collaboration between oncologists and other specialists is
much needed to emphasize the magnitude of this problem for better
outcome.
As soon as cancer diagnosis is confirmed early treatment with surgery,
chemotherapy and/or radiotherapy is preferred to avoid complications.
Anaemia may be the main presenting feature of solid malignancy, so it
needs better evaluation especially in the elderly patients.
It is very important for clinicians to be able to identify a anemia of
chronic disease and to be alert of the possibility of serious disease in its
presence.
Anaemia can be used as a marker for cancer prognosis e.g. in (NSCLC),
bladder and cervix cancer so it should be studied thoroughly during the
disease course.
Early and proper treatment of anaemia is essential so as to improve the
patient quality of life (QOL) and survival.
Continued researching

into anemia and discussions between all

specialties to understand the impact of anemia on patient quality of life

and outcomes aiming for optimization of anemia management.

79

 RBC transfusions provide immediate correction of anemia, which is

of particular value in patients with life-threatening anemia, but
new methods of treatment like recombinant human erythropoitein
should be installed in our

practice to treat anaemia in cancer

patient . Further studies and discussions may focus on this issue.

80

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87

T.J.McGraw-Hill,NEW

University of Khartoum
Faculty of Medicine
Questionnaire on Hematological Manifestations associated with
malignant solid neoplasms
1. Demographic Data:

1.1. Name: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
....
1.2. Sex:

1. Male

2. Female

1.3. Age:

1. < 20 years

2. 20-50 years

2. Presentation:

3. >50 years .

Complain of ; 2.1/
2. 2/
2. 3/
2.4/
2.5/..

3. Physical Examination:

3.1. Pale:

1. Yes

2. No

3.2. Jaundice:

1. Yes

2. No

3.3. Cyanosed:

1. Yes

2. No

3.4. Lymphadenopathy: 1. Yes

If yes, specify group:
Cervical

2. No
Axillary

88

Epitrochlear

Inguinal

3.5. Chest:

1. Normal ..
2. Abnormal; Specify: . . . . . . . . . . . . . . . . . . . . . . . . . .

3.6. C.V.S.:

1. Normal .
2. Abnormal; Specify: . . . . . . . . . . . . . . . . . . . . . . . . . . .

3.7. Abdomen:
Normal

Abnormal; Specify: . . . . . . . . . . . . . . . . . . . .

3.7.2 Spleen: Normal

Abnormal; Specify: . . . . . . . . . . . . . . . . . . . .

3.7.1 Liver:
......

......

3.7.3 Kidneys: Normal

Abnormal; Specify: . . . . . . . . . . . . . . . . . . . .

......

3.7.4 Masses: No

Yes; Specify: . . . . . . . . . . . . . . . . . . . . . . . .

......

3.8.C.N.S.
1. Normal

2. Abnormal; Specify:
3.9. Other physical findings:
1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
.......
2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
........
3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
........

89

4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
........
5) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
........

4. Surgical Intervention:

3.1. Diagnostic:

No

Yes; Specify: . . . . . . . . . . . . . .

No

Yes; Specify: . . . . . . . . . . . . . .

..........

3.2. Therapeutic:
..........

5. Diagnosis:

6. Laboratory Results:

6.1 complete haemogram :

Hb: . . . . g/dl

P.C.V.: . . . . %
3

T.W.B.C : . . . . . /mm

MCV..fl

E.S.R.: . . . . . mm/hr

MCH ..pg
MCHC.%

Differential Count:
Neutrophils: (. . . .)%

Lymphocytes: (. . . .)%

Esinophils:

Monocytes:

(. . . .)%

90

(. . . .)%

Blood Picture:
R.B.C.s:
W.B.C.s:
Platelets:

6.2 Others :
..
.

91