Renal tumors in children and adolescents (primary diagnostics based on a pilot study)
E.A. Karavaeva1, T.E. Taranushenko2, A.V. Morgun2, M.V. Borisova1, T.G. Kadricheva1, T.I. Bulava1, N.A. Gonchar1, E.A. Guseynova1
1Krasnoyarsk Regional Clinical Center for Maternal and Child Welfare, Krasnoyarsk, Russian Federation
2Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, Krasnoyarsk, Russian Federation
Aim: to assess the rate of detection and epidemiology of renal tumors in children of the Krasnoyarsk Krai and to specify some tumor characteristics during primary diagnostics.
Patients and Methods: retrospective exploratory (pilot) dynamic single-center study was conducted. A group of 46 children and adolescents with renal tumors who were admitted to the Department of Hematological Malignancies for examinations and treatment in 2011–2019. All data were obtained from hospital register.
Results: renal tumors account for 6.4% of hematological malignancies first diagnosed in children. 9-year primary incidence of renal tumors in children was, on average, 0.87 per 100,000 children, alternating between the increase and decrease in the detection rate. Renal tumors rank 4th among hematological malignancies in the Krasnoyarsk Krai children. The mean age was 4.1±0.5 years. No gender differences were revealed. In a pre-hospital setting, renal tumors were suspected in 24 children (52%). The most common complaints were abdominal pains (34 patients, 74%) and enlarged abdomen (30 patients, 65%). Most renal tumors (40 out of 46) were nephroblastoma as demonstrated by histology. The distribution by prognostic risk (the likelihood of recurrence and/or other unfavorable outcome) has shown that most patients have intermediate (n=25, 54%) or high (n=19, 42%) risk.
Conclusions: our findings illustrate that children with renal tumors require more attention of pediatricians in a pre-hospital setting (cancer vigilance about abdominal pains and enlarged abdomen in children) to reduce the time to diagnosis and to increase the use of renal ultrasound during checkups or in suspicious renal tumors.
Keywords: nephroblastoma, Wilms tumor, renal tumors, children, epidemiology, prevalence, primary diagnostics.
For citation: Karavaeva E.A., Taranushenko T.E., Morgun A.V. et al. Renal tumors in children and adolescents (primary diagnostics based on a pilot study) . Russian Journal of Woman and Child Health. 2021;4(2):162–167. DOI: 10.32364/2618-8430-2021-4-2-162-167.
Renal tumors rank 4th among malignancies in children (after hematological cancers, CNS tumors, and lymphomas), and account for 5.5% to 7.0% of childhood cancers . In Russia, the primary oncological morbidity is 15 per 100,000 children while the incidence of nephroblastoma (Wilms' tumor, WT) is 0.4 to 1.0 per 100,000 children (on average, 0.6 per 100,000 children) . The mean incidence of renal tumors in children in Finland, Sweden, the USA, Australia, Italy, Netherlands, and Great Britain is 0.7 per 100,000 children. The maximum (0.95 per 100,000) and minimum (0.51 per 100,000) incidence is reported in Finland and Great Britain, respectively [3–5].
A great experience in the treatment of renal tumors in children (in particular, WT) has been accumulated worldwide. The efficacy of the treatment of renal tumors demonstrates a significant treatment success and a more favorable prognosis, primarily owing to the close cooperation of multidisciplinary teams of various countries. In many countries, studies conducted by the International Society of Pediatric Oncology were the key to the development of treatment strategies. Thus, in Northern America, the National Wilms Tumor Study Group (NWTSG) has brought great advances in studying WT. The United Kingdom Children's Cancer Study Group (UKCCSG) and the Brazilian collaborative group (Grupo Cooperativo Brasileiro para o Tratamento do Tumor de Wilms, GCBTTW) also contributed greatly to the study of scientific and practical aspects of childhood nephroblastoma . It is now generally accepted that a multimodal approach that includes surgery, chemotherapy, and radiotherapy provides the best outcomes.
WT (nephroblastoma) has received its name on the surname of the German surgeon Max Wilms who first described this disease at the end of the 18th century. The exact causes of WT development remain elusive. Most scientists suggest that this tumor originates from abnormally proliferated metanephric blastema and is referred to as "persistence of nephric blastema" or "nephrogenic rests" [6, 7].
Most authors report that WT is diagnosed mainly in children aged 0-4 years without any significant gender differences [8, 9].
Nephroblastoma is a congenital embryonic malignant renal tumor whose histology is highly diverse. Microscopically, classic nephroblastoma is represented by three types of cells, i.e., blastemic, stromal, and epithelial. Each cell type is represented in varying degrees or even missing. The severity of any histological sign is characterized by a different prognostic value [10, 11]. WT usually occurs sporadically but is familial in 2%. Bilateral nephroblastoma is identified in 4-10% among all nephroblastomas in children .
WT is commonly accompanied by congenital birth defects but is also a part of a genetic syndrome predisposing to nephroblastoma. 12-15% of children with WT are diagnosed with birth defects of the urinary tract (hypoplasia, dystopia, shape abnormalities, one or duplicated kidney, abnormal blood vessel position, hypogonadism, etc.). A high (>20%) risk of WT is typical for patients with WT1-associated syndromes (including WAGR and Denys-Drash syndrome), Perlman syndrome, mosaic variegated aneuploidy syndrome, and Fanconi anemia with biallelic BRCA2 mutation .
Cell precursors of nephroblastoma are unknown. Currently, the hypothesis of the genetic nature of malignancies is generally accepted. This hypothesis is based on the presence of suppressor genes that inhibit tumor growth (mutation in WT1 gene located on the 11th chromosome). 11p15 mutation results in the loss of tumor-specific heterozygosis and leads to tumor progression while TP53 mutation results in the loss of tumor growth suppressor preventing clonal progression. Defects of these genes (which are classified into two groups, gatekeepers and caretakers) determines tumor growth progression [14, 15].
Nephroblastoma is the most common primary renal cancer in children accounting for 85% of all renal tumors . Malignancies are staged using the SIOP (Stockholm) Working Classification of Renal Tumors of Childhood after their removal. There are three risk groups (i.e., low, intermediate, and high) that determine the prognosis depending on tumor structure .
Mesoblastic nephroma, clear cell renal sarcoma, and rhabdoid renal cell carcinoma are separated tumors that do not belong to nephroblastoma but are typical for children and included in the SIOP (Stockholm) Working Classification of Renal Tumors of Childhood. Less common renal tumors which emerge at any age (including childhood) are also registered in the Nephroblastoma Trial Office since they provide useful information on the nature of renal tumors.
In addition to tumor histology, clinical staging is of great importance for management, treatment selection, outcomes, and prognosis. Currently, there are two systems of postoperative staging, i.e., SIOP (mainly used in Russia) and NWTS. The SIOP classification implies staging after preoperative polychemotherapy followed by surgery while the NWTS classification implies staging after initial surgery . The TNM classification (1987) is currently not applied in pediatric oncology.
Malignancy of nephroblastoma is generally known to be determined by rapid tumor growth and metastasis. In primary diagnosis, 40-45% of WT are referred to as stage 1, 20% to as stage 2, 20-25% to as stage 3, 10% to as stage 4 (with metastases), and 5-10% to as stage 5 (bilateral tumor) . Adjacent lymph nodes, lungs, and liver are usually affected followed while bones (in clear cell renal sarcoma) and brain (in rhabdoid renal cell carcinoma) are affected less commonly [1, 3, 4].
Despite significant advances in studying pediatric nephroblastoma, this disease is still an important issue for healthcare due to several factors:
· comparative assessment of oncological care quality in various regions and health facilities providing specialized and highly skilled care is required;
· dynamic evaluation of morbidity, disease pattern, age and gender specificity, clarification of the risk of recurrence and poor outcomes, and assessment of life expectancy in WTs are important;
· comparative analysis of novel (and conventional) therapeutic diagnostic approaches in pediatric renal tumors and the utility of the comparison of the results of individual hospitals and other centers in terms of providing care to these patients are important.
Aim: to assess the rate of detection and epidemiology of renal tumors in children of the Krasnoyarsk Krai and to specify some tumor characteristics during primary diagnostics.
Patients and Methods
A retrospective exploratory (pilot) dynamic single-center study to determine the occurrence and to specify early diagnostic aspects of renal tumors in 2011-2019 was conducted.
The study design was based on the retrospective analysis of a group of 46 children and adolescents who were admitted to the Department of Hematological Malignancies for examinations and treatment. All patients resided in the Krasnoyarsk Krai.
All data were obtained from the hospital register to specify the diagnosis and course of nephroblastoma (passport data, anamnesis, complaints, results of physical examination, laboratory and instrumental tests, and imaging, type, and extent of surgery, histology, and immunology).
This study is a part of global research to focus on the primary data of patients with renal tumors.
Statistical analysis was performed using the MS Excel 2016 (Microsoft Corporation, USA) and Statistica 8.0 (StatSoft Inc., USA) software. Qualitative parameters studied are reported as absolute values and percentages. The estimates are reported as the mean ± the standard deviation (M ± σ), the median, the first and the third quartiles (Ме [Q1; Q3]).
Results and discussion
As Table 1 illustrates, renal tumors rank 4th after hematological cancers, CNS tumors, and lymphomas. Their rate is slightly higher than that of soft tissue tumors and bone tumors. Renal tumors account for 6.4% of all cancers first diagnosed in childhood (in 3 to 7 children per year in 2011-2019, i.e., in different years, the rate of this disease varies greatly).
Our findings demonstrate that the primary incidence of renal tumors in children and adolescents of the Krasnoyarsk Krai varies from year to year being 0.5 to 1.26 per 100,000 children. As a result, a group of 46 children was recruited over 9 years (see Table 2).
The calculation of a rough (non-standardized) incidence was characterized by the alternation of a significant rise (1.26 and 1.12 per 100,000 children in 2012 and 2018, respectively) and a reduction to minimal values (0.55 and 0.5 per 100,000 children in 2011 and 2016, respectively). Our findings are in line with the Russian and European statistics.
Published data  demonstrate that the mean age of children by the time of diagnosis is 0-4 years. According to our findings, the mean age was 4.1±0.5 years (3,24 [1,64; 5,56]). Most children (n = 33, 72%) were aged between 1.5 and 5.5 years. The youngest patient was a 2-month-old infant and the oldest patient was a 16-year-old girl.
Neither gender differences (24 girls and 22 boys) nor family history of nephroblastoma were revealed.
We also addressed the clinical features of renal tumors in the primary referral. The most common complaints were abdominal pains (34 patients, 74%), enlarged abdomen (30 patients, 65%), constipation (8 patients, 17%), fever (7 patients, 15%), growth retardation (4 patients, 9%), and hypertension (1 patient, 2%). In a pre-hospital setting, the most common misdiagnosis was urinary infection (3 patients, 7%), vesicoureteral reflux (3 patients, 7%), suspected bowel dysfunction (2 patients, 4%), parasitic diseases (2 patients, 4%), and no formulated preliminary diagnosis (3 patients, 7%).
In a pre-hospital setting, renal tumors were suspected in 24 patients (52%). In 4 patients (9%), imaging techniques revealed abnormalities of the urinary tract (double renal artery, renal aplasia, horseshoe kidney, vesicoureteral reflux). Bilateral nephroblastoma was identified in 4 patients (9%).
All patients were admitted to an oncohematological department and underwent a complex therapeutic diagnostic algorithm that included surgery, pharmacotherapy, and radiotherapy.
Histologically, most tumors (40 out of 46) were nephroblastoma. In addition, clear cell renal sarcoma (n = 4) and metanephric blastema (n = 2) were identified. These findings are in line with published data which demonstrate that nephroblastoma is the most common solid tumor in preschool children (nephroblastoma accounts for 85% of all primary renal cancers in children) .
To address treatment strategy, risk groups and disease stages were specified. All patients were allocated to prognostic risk groups (the likelihood of recurrence and/or other unfavorable outcomes) based on histological types of renal tumors: the low-risk group included 2 patients (4%), the intermediate-risk group included 25 patients (54%), and the high-risk group included 19 patients (42%). The predominance of children with intermediate- and high-risk is in line with published data.
The following disease stages (tumor grade and metastases) were diagnosed based on the pattern of tumor growth: stage 1 was identified in 6 children (13%), stage 2 in 16 children (35%), stage 3 in 9 children (19%), stage 4 in 11 children (24%), and stage 5 in 4 children (9%). More than half of children (stage 3 to 5) were characterized by unfavorable disease course and poorer outcomes and required more aggressive treatment.
The mean time from the appearance of first symptoms to the start of a specialized treatment was 3.8 ± 3.4 (3 [2; 4]) months.
The specificity of our findings (compared to the average Russian values) was a diagnosis on stages 2 and 4 that is potentially accounted for by several reasons, e.g., late diagnosis of renal tumors due to a large territory of the Krasnoyarsk Krai, late referral for medical care, the lack of cancer vigilance among pediatricians, and ignoring of imaging techniques at early stages of outpatient care outside specialized oncological departments.
Our study first conducted in the Krasnoyarsk Krai provided data on the prevalence of renal tumors and referral rate in children and adolescents and addressed some tumor specificity based on disease stage and risk groups. These findings are generally in line with published data [3, 5]. Meanwhile, our study illustrates that children with renal tumors require more attention from pediatricians in a pre-hospital setting (cancer vigilance about abdominal pains and enlarged abdomen in children) to reduce the time to diagnosis and to increase the use of renal ultrasound during checkups or in suspicious renal tumors.
Low diagnostic relevance of family history, the severity, and diversity of clinical symptoms of renal tumors (e.g., hypertension is unusual) account for optimization of diagnostic techniques using genetic tests (in particular, in suspected bilateral renal lesions).
About the authors:
Elena A. Karavaeva — pediatric oncologist of the Department of Oncology & Hematology, Krasnoyarsk Regional Clinical Center for Maternal and Child Welfare; 2A, Academician Kirenskiy str., Krasnoyarsk, 660074, Russian Federation; ORCID iD 0000-0002-8835-2806.
Elena E. Taranushenko — Doct. of Sci. (Med.), Professor, Honored Doctor of Russian Federation, Principal Pediatric Endocrinologist of the Ministry of Health of the Krasnoyarsk Krai, Head of the Department of Pediatrics, Institute of Postgraduate Education, Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University; 1, Partizan Zheleznyak str., Krasnoyarsk, 660022, Russian Federation; ORCID iD 0000-0003-2500-8001.
Andrey V. Morgun — Doct. of Sci. (Med.), assistant of the Department of Pediatrics, Institute of Postgraduate Education, Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University; 1, Partizan Zheleznyak str., Krasnoyarsk, 660022, Russian Federation; ORCID iD 0000-0002-9644-5500.
Marina V. Borisova — Cand. of Sci. (Med.), Head of the Department of Oncology & Hematology, Krasnoyarsk Regional Clinical Center for Maternal and Child Welfare; 2A, Academician Kirenskiy str., Krasnoyarsk, 660074, Russian Federation; Head Extrabudgetary Pediatric Oncologist and Hematologist of the Ministry of Health of the Krasnoyarsk Krai, associate professor of the Department of Children’s Diseases, Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University; 1, Partizan Zheleznyak str., Krasnoyarsk, 660022, Russian Federation; ORCID iD 0000-0003-4338-4940.
Tatyana G. Kadricheva — Cand. of Sci. (Med.), hematologist, pediatric oncologist of the Department of Oncology & Hematology, Krasnoyarsk Regional Clinical Center for Maternal and Child Welfare; 2A, Academician Kirenskiy str., Krasnoyarsk, 660074, Russian Federation; ORCID iD 0000-0001-9697-806Х.
Tatyana I. Bulava — hematologist, pediatric oncologist of the Department of Oncology & Hematology, Krasnoyarsk Regional Clinical Center for Maternal and Child Welfare; 2A, Academician Kirenskiy str., Krasnoyarsk, 660074, Russian Federation; ORCID iD 0000-0003-2565-6076.
Nadezhda A. Gonchar — hematologist, pediatric oncologist of the Department of Oncology & Hematology, Krasnoyarsk Regional Clinical Center for Maternal and Child Welfare; 2A, Academician Kirenskiy str., Krasnoyarsk, 660074, Russian Federation; ORCID iD 0000-0002-9202-0038.
Evgeniya A. Guseinova — hematologist, pediatric oncologist of the Department of Oncology & Hematology, Krasnoyarsk Regional Clinical Center for Maternal and Child Welfare; 2A, Academician Kirenskiy str., Krasnoyarsk, 660074, Russian Federation; ORCID iD 0000-0002-9201-0138.
Contact information: Elena A. Karavaeva, e-mail: firstname.lastname@example.org. Financial Disclosure: no authors have a financial or property interest in any material or method mentioned. There is no conflict of interests. Received 12.07.2020, revised 04.08.2020, accepted 27.08.2020.
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