1. health and fitness
2. disease
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Cancer Detection and Prevention 32 (2008) 178–183
www.elsevier.com/locate/cdp
The prevalence of signs and symptoms of childhood leukemia and
lymphoma in Fars Province, Southern Iran
Mehran Karimi MDa,*, Davood Mehrabani PhDb, Hooman Yarmohammadi MDa,
Farideh Safaei Jahromi BSc
a
Hemostasis and Thrombosis Research Unit, Hematology Research Center, Department of Pediatrics, School of Medicine,
Shiraz University of Medical Sciences, Shiraz, Iran
b
Gastroenterohepatology Research Center, Nemazee Hospital, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
c
Faghihi Hospital, Medical Record department, School of medicine, Shiraz University of Medical Sciences, Shiraz, Iran
Accepted 5 June 2008
Abstract
Background: Leukemia and lymphomas are still the common childhood cancers in Iran. This study was undertaken to determine the
prevalence of signs and symptoms of these malignancies in children of Fars Province, Southern Iran. Methods: A total of 368 cases of children
who were less than 15 years old and diagnosed as acute lymphocytic leukemia (ALL, n = 211), acute myeloid leukemia (AML, n = 64),
Burkitt lymphoma (BL, n = 40), chronic myeloid leukemia (CML, n = 5), Hodgkin’s disease (HD, n = 33) or non-Burkitt-type, nonHodgkin’s lymphoma (NBNHL, n = 15) referring to the hospitals of Shiraz University of Medical Sciences from April 1997 to March 2002
were enrolled. A questionnaire was provided to record the age, median age at the onset of the disease, sex, type of malignancy and the signs
and symptoms at the time of presentation. Results: The common sign or symptoms were fever (74%), in ALL, AML, NHL, and BL patients,
hepatosplenomegaly (100%) in CML patients, and lymphadenopathy (54%) and fever (54%) in Hodgkin’s disease. Conclusion: Knowledge of
signs and symptoms and types of presentations of childhood leukemia and lymphoma may help a physician to improve the patient’s outcome.
This study revealed that attention to uncommon signs and symptoms in history taking and physical examination together with laboratory tests
may increase the physicians’ awareness and better diagnosis of pediatric malignancies and would also be beneficial for the patient.
# 2008 International Society for Preventive Oncology. Published by Elsevier Ltd. All rights reserved.
Keywords: Leukemia; Lymphoma; Prevalence; Southern Iran; Acute lymphoblastic leukemia; Acute lymphocytic leukemia; Acute myeloid leukemia;
Chronic myeloid leukemia; Burkitt lymphoma; Pediatric malignancies
1. Introduction
Leukemia and lymphomas, the most common malignant
diseases affecting children, account for approximately 30%
of childhood cancers [1,2]. About 32% of cancers in children
ages 0–14 years are leukemia [1]. The most common forms
of leukemia among children under 19 years of age is acute
lymphocytic leukemia (ALL). The incidence of ALL among
1–4-year-old children is more than nine times greater than
that of young adults (ages 20–24) [1]. Before the advent of
* Corresponding author at: Hematology research center, Department of
Pediatrics, Nemazee Hospital, School of Medicine, Shiraz University of
Medical Sciences, Shiraz, Iran. Tel.: +98 711 6470207; fax: +98 711 6470207.
E-mail address: [email protected] (M. Karimi).
chemotherapy in the 1960s, these malignancies were usually
fatal. However, treatment with new agents resulted in
approximately 79% of pediatric cases with 5-year survival
[1–3]. Lymphoid, myeloid and monocytic leukemia were
reported to be 0.5%, 0.8% and 0.0% in Qidong County of
China in 1992 and 39, 29 and 3 cases in Goiania, Brazil in
1993. The figures for non-Hodgkin’s and Hodgkin’s
lymphoma were 1.6% and 0.0% in Qidong, China and 62
and 36 cases in Goiania, Brazil [4]. There are some studies
showing a correlation between the prognosis and various
clinical and laboratory findings at the time of diagnosis, such
as organ infiltration (especially liver, spleen, thymus, and the
lymph nodes) [5], the white blood cell (WBC) count [6], age
[7,8], race [9], sex [10–12], cytogenetic alterations [13] and
specific immunophenotypes [14,15]. The initial presentation
0361-090X/$30.00 # 2008 International Society for Preventive Oncology. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.cdp.2008.06.001
M. Karimi et al. / Cancer Detection and Prevention 32 (2008) 178–183
179
of leukemia usually has non-specific signs and symptoms
and relatively brief duration such as anorexia, fatigue and
irritability. Bone marrow involvement and infiltration of
blast in bone marrow may be followed by pallor, fever,
bleeding tendency, bone pain, lymphadenopathy (LAP),
hepatosplenomegaly and arthritis [1,16].
In lymphoma, lymphadenopathy, abdominal and mediastinal masses were reported to be the most common presenting
signs [17,18]. Signs and symptoms in non-Hodgkin’s
lymphoma vary with the disease site and its progression
and in turn differ with histological subtypes [18].
A thorough history taking and complete physical
examination have always been and still are the first tools in
the diagnosis of the diseases; however, with progressive
development of laboratory instruments, the significance of
traditional history taking and examinations have unfortunately
lost their significance for most physicians. Nowadays most
physicians progressively rely on laboratory tools. However, in
order to have an adequate degree of alertness, one must always
keep in mind the signs and symptoms of important diseases,
otherwise they may easily be misdiagnosed and mismanaged.
The present study was undertaken to determine the
prevalence of signs and symptoms of leukemia and
lymphoma in children in Fars Province, Southern Iran in
order to help physicians a faster and more accurate diagnosis
and also to prevent delayed treatment and management.
signs and symptoms when they were admitted to the
hospital. Splenomegaly, hepatomegaly, fever, upper respiratory tract infections (URI), lymphadenopathy, abdominal
mass, pallor, arthritis, arthralgia and any other rare
presentations were checked by two pediatric hematologists
separately. Epistaxis, gum bleeding, hematuria, gastrointestinal bleeding, menorrhagia, petechial hemorrhage, and
echymoses were all catagorized as bleeding tendency. In
hepatosplenomegaly, the size of the liver and spleen were
determined by ultrasonography. The abdominal mass was
recorded only when the patient had a positive sonography or
CT. The common signs and symptoms included pallor, fever,
bleeding tendency, bone pain, respiratory difficulty. Modified Ann Arbor classification was used for Hodgkin’s
disease and Murphy classification for non-Hodgkin’s
lymphoma.
When any rare presentation was detected, the patient was
checked by two pediatric hematologists, a radiologist, and a
pathologist. Other concomitant diseases were ruled out and
the diagnosis along with the rare presentations were
recorded. If anemia was diagnosed, the patient was checked
for thalassemia and other causes that are common cause of
anemia in Iran.
The results were statistically analyzed using Chi-square
test and a P value of less than 0.05 was considered
significant.
2. Materials and methods
3. Results
In a study of 368 patients under 15 years of age referred to
three hospitals of Shiraz University of Medical Sciences
(Faghihi, Dastgheyb and Nemazee hospitals as reference
hospitals in Southern Iran), from April 1997 to March 2002,
the International Classification of the Diseases for Oncology
(ICD-O) was employed to standardize data. We studied
patients diagnosed as ALL (n = 211), acute myeloid
leukemia (AML, n = 64), Burkitt lymphoma (BL, n = 40),
chronic myeloid leukemia (CML, n = 5), Hodgkin’s disease
(HD, n = 33) or non-Burkitt-type, non-Hodgkin’s lymphoma
(NBNHL, n = 15). No case of chronic lymphocytic leukemia
(CLL) included in our study. Our diagnosis of leukemia was
based on a complete blood count and bone marrow
examination including histochemistry, immunophenotyping
and cytogenetics. In relation to lymphoma, lymph node or
mass biopsy was performed for histopathological and
cytologic studies. Immunohistochemistry assay was applied
in selected cases of lymphoma to differentiate the disease
from other small round cell tumors.
A written informed consent was obtained from each
patient or their parents at the time of admission.
Among the 368 studied cases, the male to female ratio
was more than 1.5 in all malignancies. ALL was more
common in the age range of 3–8 years, while this range was
10–12 years for AML.
The common sign or symptom in ALL, AML, NHL, and
BL patients were fever (74%); for CML patients it was
hepatosplenomegaly (100%), and for Hodgkin’s disease,
lymphadenopathy (54%) and fever (54%). In AML and ALL
patients, mediastinal mass, superior vena cava syndrome and
arthritis were more common in older age ranges in AML
patients (10.5 years) (Table 1). They were more prevalent in
older age children. The common sign among the patients
were fever, mediastinal mass, superior vena cava syndrome
and arthritis that were also more common in older age ranges
(7–7.5 years) (Table 1). The prevalent median ages at onset
of signs and symptoms of the diseases were demonstrated in
Table 1. No correlation was observed between the subtypes
of the diseases and geographical regions of our area.
2.1. Questionnaire
3.2. Specific signs and symptoms
Data provided from medical charts included variables of
age, age at onset of disease, type of malignancy, sex, and
There was one female case with huge abdominal mass
whose fine needle aspiration showed granulocytic sarcoma
3.1. Signs and symptoms
180
M. Karimi et al. / Cancer Detection and Prevention 32 (2008) 178–183
Table 1
The prevalence of signs and symptoms of leukemia and lymphoma among patients under 15 years of age in Fars Province, Southern Iran
Signs and symptoms
ALL
AML
CML
a
a
a
Age
Fever
Pallor
Bleeding tendency
Upper Respiratory infection
Lymphadenopathy
Hepatomegaly
Splenomegaly
Bone pain
Arthritis (Juvenile Rheumatoid)
Abdominal mass
Abdominal pain
Abdominal protrusion
Mediastinal mass
Superior vena cava syndrome
a
5
4
4
4.5
6
6
5.5
6
7
–
–
–
7.5
7.5
%
Age
74
42
16
20
38
25
19
19
6
–
–
–
3.8
3.8
9
8
9
8
10
10
9
8
11
–
–
–
10
10
%
Age
70
44
32
20
18
15
13
9
4.5
–
–
1
3.1
3.1
13
–
–
12
13
13
–
–
–
–
–
–
–
HD
NBNHL
%
a
Age and
stage
%
40
–
–
20
1260
100
100
–
–
–
–
–
–
–
9.5, II
–
–
10.0, III
9.0, II
10.5, IV
10.5, IV
11.0, IV
–
9.0, III
8.5, III
–
10.0, II
–
54
–
–
15
54
9
9
12
–
18
5
–
5
–
BL
a
Age and
stage
%
Agea and
stage
%
15,
–
–
14,
10,
–
–
10,
–
11,
11,
–
12,
12,
III
40
–
–
20
20
–
–
13
–
40
15
–
50
20
14, III
11, IV
11, IV
10, III
9, III
12, IV
11, III
9, IV
–
10, III
10, III
11, III
–
–
60
10
2.5
2.5
35
17.5
12.5
5
–
45
45
22.5
–
–
III
III
IV
III
III
III
III
The prevalent median age at onset of the disease.
(chloroma) and was diagnosed as AML. There were also
four cases of leukemia (three ALL and one AML) presented
with Miculitz syndrome, three cases of isolated microcytic
hypochromic anemia and three cases of prolonged chronic
diarrhea that included uncommon presentations. In HD
patients, pleural effusion (one case) and isolated splenomegaly (one case) were observed while in NHL cases,
pleural effusion (three cases), bone mass (one case), hard
palate mass (one case) and jaw mass (three cases) were
noticed. Other rare presentations in leukemic patients were
presented in Table 1.
4. Discussion
In Europe and the United States, cancer is a major cause
of death among children aged 5–14 years [19]. Leukemia
and lymphoma are among the most common malignancies
of the childhood age [1,2]. During 1996–2002, the 5-year
relative survival rates for ALL were 65.2% and 90.5%
overall and in children under 5 respectively while the figures
for AML were 20.4% and 53.1% overall and in children
under 15. The rate for CLL was reported 74.2% and for CML
42.3% [1]. The prevalence of the disease in Jordan was
28.7% for lymphoma and 19.6% for leukemia, which was
reported to be similar to Iranian neighbouring countries like
Iraq, Saudi Arabia and Kuwait [20,21]. The annual
incidence rate of pediatric AML is now 10 per million in
Japan, against 5–9 million in the USA and Europe [22,23].
The 5-year event-free survival of nearly 80% of childhood
ALL achieved in the 1990s attested to the effectiveness of
risk-directed therapy developed in clinical trials [24]. Initial
leucocytosis, presence of t(9;22) and t(4;11) translocations
and poor response to steroid therapy or induction
chemotherapy are still included as poor risk factors. From
1981 to 1986, children with ALL and initial WBC above
50,000 mm 3, were significantly associated with worse
treatment results than children with lower WBC: over 6-year
disease-free survival were respectively 33% and 60% [25].
In Iran the results are quite different to these reports and
similar to developed countries showing that leukemia is the
most prevalent one [26]. Childhood leukemia is reported to
have increased fivefold during the 20th century [27], while
this increase was greater in Southern Iran due to probably 8
years of war with Iraq and contamination of the area with
chemical weapons which affected the persons exposed to
these chemicals in the region. New medical graduates have to
be familiar with signs and symptoms of these malignancies for
proper diagnosis and treatment (Table 2). Although ocular
involvement by adult T-cell leukemia-lymphoma is extremely
rare, ATLL can first present in the orbit, and only the results of
a biopsy can provide definitive information for its diagnosis
[28]. Leukemia cutis was observed in two patients with ALL
which is a rare presentation (Table 2). Neoplasms associated
with paraneoplastic pemphigus (PNP) were reported in
patients with non-Hodgkin lymphoma (38.6%) and CLL
(18.4%) [29]. In addition, in leukemia and lymphoma, the
coagulopathy is typically acute DIC that can lead to systemic
and brain hemorrhages and is especially common in AML.
The clinical signs of cerebral hemorrhage are fulminant and
may be fatal [30]. Familiarity with the most common signs
and symptoms of these diseases would be one of the most
important factors in faster diagnosis, better treatment and
controlling of the disease and would increase the survival rate
of the patients.
In our study, fever was one of the most common signs. So,
the patients with fever of unknown origin (FUO) during the
childhood should not be neglected. Based on this finding,
bone marrow aspiration and biopsy were included in the
work ups of patients with FUO [5].
In this study, in all CML patients, hepatosplenomegaly
was noticed at the time of presentation of the disease and as
M. Karimi et al. / Cancer Detection and Prevention 32 (2008) 178–183
181
Table 2
Some uncommon presentations of leukemia among leukemic patients in Fars Province, Southern Iran
Signs or symptoms
ALL (no)
ALL (%)
AML (no)
AML (%)
Renal involvement
Meningitis
Leukemia cutis
Aplastic anemia
Megaloblastic anemia
Superior vena cava and mediastinal syndrome
Pleural effusion
Pericardial effusion
Gum hypertrophy
Proptosis
Ovarian mass
Cyclic neutropenia
Lupus erythromatosis
Huge abdominal mass (granulocytic sarcoma)
Eosinophilia
Osteomyelitis
Pericarditis
1
1
2
8
–
8
2
1
–
2
–
2
1
–
2
1
–
0.5
0.5
1
3.8
–
3.8
1
0.5
–
1
–
1
0.5
–
1
0.5
–
–
–
–
1
1
2
–
–
5
4
2
–
–
1
–
–
1
–
–
–
1.6
1.6
3.2
–
–
7.9
6.3
3.2
–
–
1.6
–
–
1.6
the number of patients with CML was not significant, the
analysis could not be considered reliable (Table 1).
In our study, fever was significantly more prevalent in
advance stages of BL and NBNHL (Table 1). So, it is
important to start medications more rapidly for these
patients with fever. Fifty percent of the patients with
NBNHL had a mediastinal mass and when compared to
previous studies, the rate seems to be surprisingly higher
[30–35]. In our study, the mean age for HD patients was 10.5
years old, which was lower than those reported in western
countries [30–37]. High incidence viral infections may
explain the occurrence of the disease in this age group.
Usually, two peaks of 15–35 years and above 55 years of age
were reported to be the most prevalent ages [30–37]. As seen
in Table 1, jaw hypertrophy was not a common presentation
in our patients with BL. Instead, they presented themselves
mostly with abdominal mass. This differs from what was
reported for endemic BL, in which jaw hypertrophy was the
common type of presentation [35]. Pallor, bleeding
tendency, hepatomegaly, and bone pain were significantly
more prevalent as the signs in advanced stages (stage IV) of
patients with BL ( p < 0.05). Hepatosplenomegaly and bone
pain were also significantly more prevalent in advanced
stages of HD ( p < 0.05) indicating prompt and aggressive
therapy. The common presentations observed in our study
were also reported in previous studies [34,35]. Our results
showed that patients with leukemia presented with
completely unusual signs and symptoms, however, these
presentations were significant when were persistent. The
results in Table 2 presents uncommon signs and symptoms
of the diseases such as isolated microcytic hypochromic
anemia as the most common manifestation of irondeficiency anemia in Iran which may be misdiagnosed.
Anemia and B cell lymphoma symptoms were additionally
predictive of poor overall survival in patients with B cell
lymphoma [38]. Prevalence of anemia in patients with
hematologic malignancies is high and increases with
chemotherapy. The current practice of anemia management
in these patients leaves room for improvement [39]. Isolated
huge abdominal masses with normal bone marrow aspiration
which were observed in our leukemic patients may be
misdiagnosed with neuroblastoma or other solid tumors and
finally parotid swelling (Miculitz’s syndrome) due to
infiltration of blasts into the parotid gland which may also
be misdiagnosed with mumps. In Iran, measles is the only
routine vaccine in vaccination protocol of the Ministry of
Health of our country.
The immunophenotype and cytogenetic evaluation of
childhood leukemia have recently been established in our
center while in the past, just complete blood count and bone
marrow morphologic evaluation (FAB classification) were
performed for diagnosis. The reliance on laboratory testing
to investigate the prevalence of signs and symptoms would
be reliable if they are supported by a precise physical
examination and a thorough history taking because rare
presentations may be missed if a precise physical examination is not preformed. Therefore, a thorough history taking
together with a complete physical examination of highly
suspicious patients may prevent delayed diagnosis, unsuccessful treatment and decreased survival rate.
Our results showed that some difficulties were noticed in
rapid diagnosis of lymphoma. Familiarity with common and
uncommon signs and symptoms of lymphoma as well as
precise physical examination and history taking would be
very valuable for rapid detection of the diseases in early
stages that would lead to an increase in survival rate of the
patients. This study showed the importance of common
signs and symptoms of leukemia and lymphoma as a
common pediatric disease in Iran based on a thorough
history taking and physical examination as well as rare
presentation of these diseases which may be misdiagnosed
by physicians and do not seem to be replaced with laboratory
examinations or other interventions. Chronic cough, facial
edema, upper respiratory tract infections and joint pain
182
M. Karimi et al. / Cancer Detection and Prevention 32 (2008) 178–183
should not be neglected as rare presentations in differential
diagnosis of the disease. Pericardial effusion, abdominal
pain and presence of skin nodules should also be considered
as rare presentations in leukemic patients. As a result, rare
presentations, if present, can play an important role for
suspicion to unusual presentations of childhood leukemia
and lymphoma. This study showed that physicians’
awareness of uncommon signs and symptoms in physical
examination together with laboratory tests and a thorough
history taking may be beneficial for the patient’s outcome of
a better and more rapid diagnosis and treatment.
Acknowledgments
The authors would like to thank the Office of Vice
Chancellor for Research of Shiraz University of Medical
Sciences for financial support.
Conflict of interest
None declared.
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