Epidemiology of pediatric sarcoma in Iran

Abstract Background Pediatric sarcomas are divided into two major groups of soft‐tissue sarcomas (STSs) and malignant bone tumors (MBTs). Aims The aim of the present study was to determine the incidence and survival rate of STSs and MBTs in the Iranian population based on diagnosis date, gender, age, and histological types. Methods and Results Data was retrieved from Iran National Cancer Registry between 2008 and 2015. The dataset was classified according to the third edition of the International Classification of Childhood Cancer. The survival information was merely available for 291 (21% of total data), including 142 (49%) MBTs and 149 (51%) STSs. The age‐standardized incidence rates (ASIRs) and five‐year survival rates were calculated. Conclusion The present study is the first comprehensive study of pediatric sarcomas in Iran, in which a lower incidence and survival rate of MBTs and STSs compared with high‐income countries were found. However, the survival rates of these malignancies were higher in high‐income countries compared to Iran. This study showed the need to improve the quantity and quality of the population‐based registry in Iran for acquiring progress in the prevention and control of sarcomas.

EWS, accounting for 51%-69% and 29%-47% of all cases, respectively. [6][7][8][9] RMS could spread to several body parts such as the head, neck, and bladder. 1 OS is commonly located at the end of the long bone (91%), 2 and EWS generally affects the lower extremity (45%). [10][11][12] Men are more likely to develop both types of sarcomas compared to women. 13 The overall incidence of sarcoma cases has never been recorded, while the incidence of several histological subtypes of sarcomas has been indexed so far. 14 The annual incidence rate of RMS among children was recorded as 4.5 cases per million in the United States (U.S.) and 5.4 per million in Europe. 15,16 Plus, the OS rate was indexed in the range between 0.3 and 5.1 cases per million in various geographical areas. 17 The five-year survival rate for sarcoma cases has remained below 70%, despite improvements in survival for the majority of pediatric cancer cases over the last decades. 16,18 In Iran, patients with STS and MBT are primarily witnessed by general practitioners and orthopedists. They undergo radiological evaluation with Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) scans. Diagnosis is confirmed through histopathological evaluation. Patients are then referred to specialized centers, equipped with facilities for surgery, radiation therapy and chemotherapy. 19 In Iran, no comprehensive studies have been conducted on the incidence and survival rates of pediatric sarcomas to date. The aim of this study was to collect and report the pediatric incidence and survival rates of sarcomas as well as investigate the incidence patterns in Iran, from 2008 to 2015. Such studies help health administrators and policymakers to make better decisions in tackling this issue. Nearly half of the patients' registered contact information had been collected by INCR, but only 42% of those patients (21% of total data), including 142 (49%) MBTs and 149 (51%) STSs participated in the telephone interview. The first name, surname, father's name, type of cancer, status (deceased or alive), and death date of each patient were checked and collected during this interview.

| Study population
The initial evaluation of data quality was conducted by INCR in several steps as follows: In the first step, the consistencies of the topographical and morphological information of the patients were evaluated. If there were any inconsistencies, the data was re-examined and if there were any inaccuracies, the subject was omitted from the dataset. Subsequently, the agreement between the type of tumor and the approaches to cancer diagnosis was checked. In the next step, the accuracy of patients' birthday and the date of cancer diagnosis were checked to modify or remove any incorrect information from the dataset. The pathology (or cytology), clinical outcome, and DCO were used to identify the diagnosis of cancer.
Data cleaning procedures such as removing wrong histology codes and duplicate cases were applied. Duplicate cases were identified by checking ID number, first name, surname, gender, and father's name. Patients with the exactly matched records were excluded from the study as duplicates.

| Data variables
In the current study, ICCC-3 of the International Classification of Diseases for Oncology was considered as a reference for the identification of childhood cancer cases. 20 MBTs and STSs are considered to be among the 12 main categories of tumors and coded by ICCC-3. For each patient, gender, age, birth date, city of residence, phone number, date of diagnosis, and the ICCC-3 group have been registered.
The incidence rates reported in this study were calculated using data from 2005, 2009 and 2013 Iranian censuses, conducted by the Statistical Center of Iran. The study is based on age groups (0-4, 5-9, [10][11][12][13][14] according to the census data. The population of gap years was estimated by means of the growth rate between the two censuses.
Accordingly, the population of each year was calculated by multiplying the population of the previous year by the growth rate.

| Statistical analysis
The frequency and age-specific incidence rates (per million personyears) with 95% confidence interval (95% CI) were calculated for each ICCC-3 group and subgroups of MBTs and STSs by gender and age.
The age-standardized incidence rates (ASIRs) were calculated for ICCC-3 groups, using new world health organization (WHO) standard population estimates as the weights in the standardization method. 21 The Kaplan-Meier survival rate was used to estimate the 5-year survival rate by gender, age, and main ICCC-3 groups among MBTs and STSs. In addition, survival rates were calculated using the Kaplan-Meier method. 22 The difference in survival rate between groups was assessed using log-rank tests. 23 (Table S1). Five hundred and eighty-five (85.9%) MBT and 630 (89.49%) STS patients were diagnosed T A B L E 1 Frequencies, age-specific incidence rates, age-standardized incidence rates, and standardized rate ratio of malignant bone tumors by histology type and gender, 2008-2015.
The ASIR (per million) and male to female SRR of each ICCC-3 subgroup were also reported in the supplementary file (Tables S2   and S3).   It is hard to say that a population-based survival study was performed since the survival analysis was only conducted on 21% of the total dataset. Based on the study results, the distribution of demographic variables in the MBT and STS cases were identical in the total dataset and survival dataset. To the best of our knowledge, this is the first comprehensive epidemiological study of pediatric sarcoma, conducted in Iran based on the ICCC-3 histology subtypes.
There is a lack of pediatric referral centers in order to diagnose, manage and control the different malignancies in most of the provinces of Iran. These centers could provide and promote pediatric services including hematology/oncology, biopsy, MRI and CT scan. The highest incidence rate of STSs was observed in age groups of 0-4 and 10-14 years and the highest incidence rate of MBTs  26,27 In addition, the study performed by the Centers for Disease Control and Prevention in the U.S. confirmed the present findings. 28 Despite the variety of sample sizes, tools, study designs, and study protocols, there were considerable similarities across the findings of previous studies. [25][26][27][28] This study revealed that patients with STS who are less than 4 years old and those between 10 and 14 years old need to be further considered cancer diagnosis at an earlier time and treat it more successfully.
In the present study, the 95% C.I was reported for male-to-female SRR of MBTs and STSs subtypes. The findings revealed that while ASIR of MBTs was similar among men and women, the ASIR of STSs was significantly higher among men. The female to male incidence rate ratio has been reported in various studies, showing that the incidence rate of STSs in males was greater than in females. [29][30][31] Nevertheless, some studies indicate that women are more likely to be affected by MBTs subtypes than men. [32][33][34][35] This study manifested that OS was the most common type of MBTs, followed by EWS. In addition, the CS was the rarest type of all pediatric MBT types. This study's findings showed that the incidence  [7][8][9]13,[29][30][31]36 The present study revealed that the RMS was the most common type of STSs, which was partially in accordance with another study carried out on MENA countries. The median ASIRs of RMS reached 3.6 per million in the MENA countries, which was relatively greater than the ASIR of RMS in Iran. However, ASIR of FS and KS in Iran exceeded the median value of MENA countries. 9 The ASIR of fibroblastic, synovial sarcomas and miscellaneous STS ranked first among all STS subtypes in MENA countries. These subtypes were more frequent between the ages of 15 and 19 years. Based on the present study results, the ASIR of those subtypes was negligible when it comes to pediatric patients aged 0-14 years. 32 The low incidence rate in Iran does not necessarily mean that the cancers are more infrequent there. It may attribute to either a poor registry system or inconvenient medical facilities as for diagnosing and screening this type of cancer in Iran.
In this study, the incidence rate of unspecified MBTs and STSs exceeded 1 per million in accordance with the results of studies in West and East Asia (except Japan). [33][34][35]37 In European countries such as Italy and Germany, the rate dropped below 1 per million. 38 In Estonia, while the incidence rate had been more than 1 per million between 1970 and 1994, it fell below 1 per million from 1995 to 2016. 39 In the U.S., this rate was also recorded below 1 per million between 1975 and 1995. 5 The main reason for the difference between Asian and other aforementioned studies could be in view of accurate cancer registration systems in European and American countries, and also Japan. Accordingly, the type of patients' cancers in bone and soft tissue has been diagnosed accurately and precisely.
However, in this study, the results were not as precise as those of the studies carried out in countries with well-registered cancer data, which was due to the limitation of registered cancer cases in the program of cancer registry of the Iranian Ministry of Health.
In this study, the overall 5-year survival rate for MBTs in Iran was less than 30%, while this rate for OS and EWS patients was measured to 41.2% and 16.7%, respectively. According to recent reports, the OS and EWS rates were significantly lower than the survival rates in some countries such as Japan and Germany. In these countries, the 5-year survival rate for MBTs was between 70-76% for OS patients and 58%-70% for EWS ones. 13,30 Concerning the results of the study, it is proposed that the low 5-year survival rate might be as a consequence of the late diagnosis of MBT in children of 0-14 years, which is in accordance with the results of Nandra et al. 40 The strategy accounted in England suggests that the primary goal of Domain 1 of the National Health Service is to ensure that patients receive timely and appropriate treatment in order to prevent early death and improve the survival rate of these patients. 41 The current study showed that the 5-year survival rates of STS and its subgroups, RMS and FS, were about 50%, lower than those in Japan and Europe. 16,37 To be more specific, in another study of Europe, the survival rate of STS and its subgroup, RMS, was calculated about 65% while the 5-year survival rate of FS was 82%. 16 In Japan, the 5-year survival rate for STS patients was 68% while it was 59% for RMS. 37 Overall, the results indicated that the survival rate of STS in Iran was slightly lower than that of STS in high-income countries. The most likely reason may lie in better medical facilities and more up-to-date treatment protocols in these countries; accordingly, patients' survival rate increased significantly compared to low-income countries. and being impossible to evaluate the survival rate of patients who have undergone any treatment due to variable treatment methods.
In conclusion, the incidence rate of MBTs and STSs in this study was lower than those in high-income countries. Furthermore, it is required to determine how much the inconstancy of incidence rates is

CONFLICT OF INTEREST
The authors have stated explicitly that there are no conflicts of interest in connection with this article.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.

ETHICS STATEMENT
The current study was approved by the Ethics Committee of Research