Жамият ва инновациялар –
Общество и инновации –
Society and innovations
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General
information
about
childhood
kidney
tumors
(nefroblastoma)
Daniyar NISHANOV
1
, Ramon MATRASULOV
2
Specialized Scientific and Practical Medical Center of Oncology and Radiology
Urgench Branch of the Tashkent Medical Academy
ARTICLE INFO
ABSTRACT
Article history:
Received June 2021
Received in revised form
20 June 2021
Accepted 15 July 2021
Available online
15 August 2021
Nephroblastoma is a high-risk embryonic tumor that arises
from the developing kidney tissue. The disease is a common
malignant tumor of the urogenital tract in children under 5 years
of age and occurs equally in boys and girls. The relationship
between the mother’s age and the likelihood of having a baby
with Wilms nephroblastoma can often be accompanied by birth
defects. For nephroblastoma, hematogenous and lymphogenous
metastases are characteristic, and lymphogenous metastases
occur early. Most often, the lymph nodes located in the region of
the portal renal, para-aortic and hepatic gates are affected.
Hematogenously, they mainly metastasize to the lungs, less often
to the liver.
2181-1415/© 2021 in Science LLC.
This is an open access article under the Attribution 4.0 International
(CC BY 4.0) license (https://creativecommons.org/licenses/by/4.0/deed.ru)
Keywords:
nephroblastoma,
tumors in childhood,
nephroblastoma in children,
incidence of
nephroblastoma in
childhood,
malignant tumors,
epidemiology of
nephroblastoma.
Болалардаги буйрак ўсмалари ҳақида умумий маълумотлар
(нефробластома)
АННОТАЦИЯ
Калит сўзлар:
нефробластома,
болаликдаги ўсма,
болалардаги
нефробластома,
болаликдаги
нефробластома частотаси,
хавфли ўсмалар,
нефробластома
эпидемиологияси.
Нефробластома – бу юқори хавфлиликка эга бўлган
эмбрионал ўсма бўлиб, буйракнинг ривожланаётган
тўқималаридан келиб чиқади. Касаллик 5 ёшгача бўлган
болаларда сийдик-таносил трактининг кенг тарқалган
хавфли ўсмаси бўлиб, ўғил болалар ва қиз болаларда бир
хилда тарқалган бўлади. Бу касаллик онанинг ёши ва
болани Вильмс нефробластомаси билан туғилиш эхтимоли
орасидаги муносабатлар кўпинча туғма нуқсонлар билан
бирга келиши мумкин. Нефробластома учун гематоген ва
1
Republican Specialized Scientific and Practical Medical Center of Oncology and Radiology, Tashkent, Uzbekistan.
2
Urgench Branch of the Tashkent Medical Academy, Urgench, Uzbekistan.
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Special Issue – 7 (2021) / ISSN 2181-1415
180
лимфоген
метастазланиш
хос
бўлиб,
лимфоген
метастазланиш эрта юзага келади. Кўпинча буйрак
дарвозаси, парааортал ва жигар дарвоза соҳасида
жойлашган лимфа тугунлар жароҳатланади. Гематоген
метастазланиш ҳолатлари асосан ўпкага, кам ҳолларда
жигарга метастаз беради.
Общая
информация
о
детских
опухолях
почек
(нефробластома)
АННОТАЦИЯ
Ключевые слова:
нефробластома,
опухоли в детском
возрасте,
нефробластома у детей,
частота нефробластомы в
детском возрасте,
злокачественные опухоли,
эпидемиология
нефробластомы.
Нефробластома – это эмбриональная опухоль высокого
риска, которая возникает из развивающейся ткани почки.
Заболевание
представляет
собой
распространенную
злокачественную опухоль урогенитального тракта у детей
до 5 лет и в равной степени встречается у мальчиков и
девочек. Связь между возрастом матери и вероятностью
рождения ребенка с нефробластомой Вильмса часто может
сопровождаться врожденными дефектами. Гематогенные и
лимфогенные метастазы характерны для нефробластомы, а
лимфогенные метастазы возникают рано. Чаще всего
поражаются лимфатические узлы, расположенные в
области
воротного
почечного,
парааортального
и
печеночного ворот. Гематогенным путем в основном
метастазируют в легкие, реже – в печень.
Dramatic improvements in survival have been achieved for children and
adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased
by more than 50% [1]. For children younger than 15 years with Wilms tumor, the 5-year
survival rate has increased over the same time from 74% to 88% [12]. Childhood and
adolescent cancer survivors require close monitoring because cancer therapy side effects
may persist or develop months or years after treatment.
Childhood kidney cancers account for about 7% of all childhood cancers. Most
childhood kidney cancers are Wilms tumor, but in the 15- to 19-year age group, most
tumors are renal cell carcinoma. Wilms tumor can affect one kidney (unilateral) or both
kidneys (bilateral). Less common types of childhood kidney tumors include rhabdoid
tumors, clear cell sarcoma, congenital mesoblastic nephroma, Ewing sarcoma of the
kidney, primary renal myoepithelial carcinoma, cystic partially differentiated
nephroblastoma, multilocular cystic nephroma, primary renal synovial sarcoma, and
anaplastic sarcoma. Nephroblastomatosis of the kidney is a type of nonmalignant
neoplasia [23].
Wilms tumor is the most frequent tumor of the kidney in infants and children. The
incidence of Wilms tumor is 8.2 cases for every 1 million children younger than 15 years,
or one case per 10,000 infants [1]. Approximately 650 cases of Wilms tumor are diagnosed
in the United States each year. The incidence is substantially lower in Asians [12, 27].
The male to female ratio in unilateral cases of Wilms tumor is 0.92 to 1.00, but in
bilateral cases, it is 0.60 to 1.00. The mean age at diagnosis is 44 months in unilateral cases
and 31 months in bilateral cases of Wilms tumor [11, 25] About 10% of children with
Wilms tumor have an associated congenital malformation syndrome [18].
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Wilms tumor is the most frequent tumor of the kidney in infants and children. The
incidence of Wilms tumor is 8.2 cases for every 1 million children younger than 15 years,
or one case per 10,000 infants.[12] Approximately 650 cases of Wilms tumor are
diagnosed in the United States each year. The incidence is substantially lower in Asians
[27].
The male to female ratio in unilateral cases of Wilms tumor is 0.92 to 1.00, but in
bilateral cases, it is 0.60 to 1.00. The mean age at diagnosis is 44 months in unilateral cases
and 31 months in bilateral cases of Wilms tumor. About 10% of children with Wilms tumor
have an associated congenital malformation syndrome. [11, 25].
Wilms tumor typically develops in otherwise healthy children without any
predisposition to developing cancer; however, approximately 10% of children with Wilms
tumor have been reported to have a congenital anomaly [17, 18]. In patients with
congenital anomalies and Wilms tumor, nephrogenic rests have been reported in 60% of
cases. Of 295 consecutive patients with Wilms tumor seen at the Institut Curie in Paris,
52 (17.6%) had anomalies or syndromes, 43 of which were considered major, and 14 of
which were genetically proven tumor predisposition syndromes [19].
Wilms tumor may arise during embryogenesis on the background of an otherwise
genomically normal kidney, or it may arise from nongermline somatic genetic precursor
lesions residing in histologically and functionally normal kidney tissue. Hypermethylation
of H19, a known component of a subset of Wilms tumors, is a very common genetic
abnormality found in these normal-appearing areas of precursor lesions [21].
One study performed genome-wide sequencing, mRNA and miRNA expression, DNA
copy number, and methylation analysis on 117 Wilms tumors followed by targeted
sequencing of 651 Wilms tumors. The tumors were selected for either favorable histology
(FH) Wilms that had relapsed or those with diffuse anaplasia. The study showed the
following: Wilms tumors commonly arise through more than one genetic event, Wilms
tumors show differences in gene expression and methylation patterns with different
genetic aberrations, Wilms tumors have a large number of candidate driver genes, most of
which are mutated in less than 5% of Wilms tumors, Wilms tumors have recurrent
mutations in genes with common functions, with most involved in either early renal
development or epigenetic regulation (e.g., chromatin modifications, transcription
elongation, and miRNA) [2].
Approximately one-third of Wilms tumor cases involve mutations in WT1, CTNNB1,
or WTX. [13, 20] Another subset of Wilms tumor cases results from mutations in miRNA
processing genes (miRNAPG), including DROSHA, DGCR8, DICER1, and XPO5. [6, 9, 22, 29].
Other genes critical for early renal development that are recurrently mutated in Wilms
tumor include SIX1 andSIX2 (transcription factors that play key roles in early renal
development) [9, 29.] Of the mutations in Wilms tumors, 30% to 50% appear to converge
on the process of transcriptional elongation in renal development and include
the genesMLLT1, BCOR, MAP3K4, BRD7, and HDAC4 [2]. Anaplastic Wilms tumor is
characterized by the presence of TP53 mutations.
Elevated rates of Wilms tumor are observed in patients with a number of genetic
disorders, including WAGR (Wilms tumor, aniridia, genitourinary anomalies, and mental
retardation) syndrome, Beckwith-Wiedemann syndrome, hemihypertrophy, Denys-Drash
syndrome, and Perlman syndrome [8]. Other genetic causes that have been observed in
familial Wilms tumor cases include germline mutations in REST and CTR9 [4, 14].
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The genomic and genetic characteristics of Wilms tumor are summarized below.
The WT1 gene is located on the short arm of chromosome 11 (11p13). WT1 is a
transcription factor that is required for normal genitourinary development and is
important for differentiation of the renal blastema [28]. WT1 mutations are observed in
10% to 20% of cases of sporadic Wilms tumor [20, 26, 28].
Germline WT1 point mutations produce genetic syndromes that are characterized
by nephropathy, 46XY disorder of sex development, and varying risks of Wilms tumor.
Studies evaluating genotype/phenotype correlations of WT1 mutations have shown that
the risk of Wilms tumor is highest for truncating mutations (14 of 17 cases, 82%) and
lower for missense mutations (27 of 67 cases, 42%). The risk is lowest for KTS splice site
mutations (1 of 27 cases, 4%). Bilateral Wilms tumor was more common in cases with
WT1-truncating mutations (9 of 14 cases) than in cases with WT1 missense mutations
(3 of 27 cases) [1, 3].
A second Wilms tumor locus, WT2, maps to an imprinted region of chromosome
11p15.5; when it is a germline mutation, it causes Beckwith-Wiedemann syndrome. About
3% of children with Wilms tumor have germline epigenetic or genetic changes at the
11p15.5 growth regulatory locus without any clinical manifestations of overgrowth. Like
children with Beckwith-Wiedemann syndrome, these children have an increased
incidence of bilateral Wilms tumor or familial Wilms tumor [16].
Approximately one-fifth of patients with Beckwith-Wiedemann syndrome who
develop Wilms tumor present with bilateral disease, and metachronous bilateral disease
is also observed. [7, 10, 24]. The prevalence of Beckwith-Wiedemann syndrome is about
1% among children with Wilms tumor reported to the National Wilms Tumor Study
(NWTS) [10, 25].
Approximately 80% of patients with Beckwith-Wiedemann syndrome have a
molecular defect of the 11p15 domai [15]. Various molecular mechanisms underlying
Beckwith-Wiedemann syndrome have been identified. Some of these abnormalities are
genetic (germline mutations of the maternal allele of CDKN1C, paternal uniparental
isodisomy of 11p15, or duplication of part of the 11p15 domain) but are more frequently
epigenetic (loss of methylation of the maternal ICR2/KvDMR1 or gain of methylation of
the maternalICR1) [5, 16].
Several candidate genes at the WT2 locus comprise the two independent imprinted
domains IGF2/H19 and KIP2/LIT1 [5]. LOH, which exclusively affects the maternal
chromosome, has the effect of upregulating paternally active genes and silencing
maternally active ones. A loss or switch of the imprint for genes (change in methylation
status) in this region has also been frequently observed and results in the same functional
aberrations [5, 15, 16].
A relationship between epigenotype and phenotype has been shown in Beckwith-
Wiedemann syndrome, with a different rate of cancer in Beckwith-Wiedemann syndrome
according to the type of alteration of the 11p15 region [30].
The aim of our study is to improve modern diagnostic methods in the study of
pathomorphological changes developing in the kidneys in children with nephroblastoma.
The main objectives of the study are to identify macroscopic and microscopic
changes in renal tissues in nephroblastoma in children, to study changes in renal tissues
that develop in nephroblastoma in children, using the immunohistochemical method, to
substantiate the criterion of the relationship between pathomorphological and
immunohistochemical changes during development nephroblastomas in children.
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When assessing the pathomorphological features of nephroblastoma, data on
autopsies are given, as well as general characteristics of the research methods used. In this
study, a retrospective analysis of extracts from case histories, data obtained during
autopsy, copies of materials obtained during laboratory studies, the results of clinical and
laboratory studies that were obtained during autopsy in the pathomorphology department
of the Republican Specialized Scientific and Practical Medical Center of Oncology and radio
logic from 2008 to 2021.
In our studies, based on the results of the study, we study the relationship of
pathomorphological changes that develop in the kidneys with nephroblastoma in children
and between death. A full-fledged and comparative analysis of the relationship between
pathomorphological and immunohistochemical changes in renal tissues is carried out.
Diagnosis of Wilms’ tumor. If, after an external examination of the child and in the
medical history, the pediatrician has a suspicion of Wilms ‘tumor, then the doctor issues a
referral to the Children’s Cancer Hospital on suspicion of Wilms’ tumor, it is necessary to
carry out various tests and studies: firstly, to confirm the diagnosis, and secondly, to find
out the specific form of nephroblastoma and to find out how much the disease has already
spread throughout the div.
Having received answers to these questions, one can begin to plan the optimal
treatment tactics and give a prognosis. An important role (after external examination) for
the diagnosis is played by such diagnostic methods based on images as ultrasound studies
(ultrasound), magnetic resonance imaging (MRI) and computed tomography (CT). With
their help, Wilms’ tumor can be distinguished from other diseases (for example,
from neuroblastoma, from lymphoma or from neuroblastomatosis) with a certainty
of up to 95%.
Also, according to the images, you can accurately estimate the size of the tumor and
the degree of its prevalence throughout the div. But the condition for the most accurate
diagnosis is the high quality of the technique and the extensive experience of the doctor
who performs diagnostics based on the images. This is especially important here. Because
in Germany, microscopic (histological) confirmation of the diagnosis, that is, when a tumor
sample is taken and then examined under a microscope, is usually done after the initial
course of chemotherapy. Clarification of the diagnosis and search for metastases.
Sometimes it happens that it is impossible to accurately distinguish Wilms’ tumor from
other diseases, for example, from neuroblastoma, using the images.
Then an additional examination is prescribed. For example, MIBG scintigraphy is
done to distinguish nephroblastoma from neuroblastoma. Or, the div is looking for
certain tumor markers that can be found if a child has neuroblastoma. With
nephroblastoma, they are not in the div. Other studies should confirm or exclude
metastases in the div. Therefore, in order to find metastases in the lungs, an x-ray or
computed tomography of the chest is always prescribed.
Morphological diagnostics. As with all other malignant tumors, the diagnosis of
nephroblastoma is based on a morphological conclusion. However, with regard to
nephroblastoma, an exception is allowed from the rule of biopsy before starting
chemoradiation therapy. During the biopsy, a violation of the integrity of the
pseudocapsule occurs, and the tumor detritus enclosed in the pseudocapsule, which has a
mushy character, is scattered along the abdominal cavity or along the needle, which
increases the spread of the tumor, changes the clinical stage of the disease (automatically
translates into stage 3) and worsens the prognosis of the disease.
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Therefore, in patients> 6 months and <16 years, the diagnosis of nephroblastoma
is established with conservative examination. This is facilitated by the presence of clear
diagnostic signs of nephroblastoma, which reduce diagnostic errors to a minimum. The
histological diagnosis is made after preoperative chemotherapy. Confirmation of the
diagnosis in a reference laboratory is mandatory. At the same time, some foreign protocols
suggest the initial removal of the kidney with the tumor or its biopsy, even with doubtful
tumor resectability.
In accordance with the NWTS strategy, this approach avoids the error of
conservative diagnostics and conducts a thorough revision of the abdominal organs,
excluding or detecting metastatic lymph nodes and a tumor of the opposite kidney
(according to NWTS, in 30% of cases of bilateral nephroblastoma, a tumor of the second
kidney is not visualized by conservative diagnostic methods). Diagnosis of a primary
tumor is based on the identification of typical signs of nephroblastoma and the exclusion
of other diseases.
The range of differential diagnoses includes malformations of the kidney,
hydronephrosis, neurogenic tumors and other tumors of the retroperitoneal space, liver
tumors, hamartoma. Diagnosis of nephroblastoma and stage determination includes
laboratory studies and instrumental ones. Laboratory tests include: a clinical blood test, a
general urinalysis, a biochemical blood test, and a study of catecholamines in urine and
blood serum (to exclude neuroblastoma) [13].
Thus, the review of the literature showed that the issue under study has not been
sufficiently studied in the domestic and foreign literature. Nephroblastoma is one of the
most serious diseases in children among oncopathology, which requires dynamic
monitoring of hemodynamic parameters and timely prescription of both pharmacological
and mechanical means of prophylaxis. Prevention of the development of Wilms’ tumor is
one of the important steps to increase the survival rate of children with nephroblastoma.
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