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 . 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) . 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 . 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) , the white blood cell (WBC) count , age [7,8], race , sex [10–12], cytogenetic alterations  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 . 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 . 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% . 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 . 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% . In Iran the results are quite different to these reports and similar to developed countries showing that leukemia is the most prevalent one . Childhood leukemia is reported to have increased fivefold during the 20th century , 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 . 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%) . 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 . 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 . 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 . 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 . 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 . 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. 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