Efficacy analysis of multidisciplinary treatment for Wilms tumor in a single center

To analyze the efficacy of multidisciplinary treatment for Wilms tumor (WT) in Kunming Children’s Hospital, and investigate the risk factors affecting the prognosis of WT. The clinic-pathological data were collected and analyzed in patients with unilateral WT treated in Kunming Children's Hospital from January 2017 to July 2021. Research subjects were selected according to inclusion criteria and exclusion criteria. The risk factors and independent risk factors that affect the prognosis of patients with WT were determined by Kaplan–Meier survival analysis and Cox proportional hazards model, respectively. A total of 68 children were included in this study, and the 5-year overall survival (OS) rate was 87.4%. Kaplan–Meier survival analysis results showed that ethnicity (P = 0.020), the tumor volume of resection (P = 0.001), histological type (P < 0.001), and postoperative recurrence (P < 0.001) were the risk factors affecting the prognosis of children with WT. The results of the Cox proportional hazards model showed that only the histological type (P = 0.018) was the independent risk factor for the prognosis of WT. The efficacy of multidisciplinary treatment for WT was satisfying. The histological type has important predictive value for the prognosis of WT, and the patient with unfavorable histology has a poor prognosis.


Background
Wilms tumor (WT) is the most common kidney tumor in childhood, accounting for 90% of childhood kidney tumors [1]. WT is a malignant tumor of embryonic origin, whose histology and gene transcription are closely related to the early kidney [2]. Mutations in WT1 [3], TP53 [4], WTX [5], and MYCN [6] genes are associated with the pathogenesis of WT. WT was named after Carl Max Wilhelm Wilms, who first reported pathological character on the disease in 1899 [7]. WT mainly occurs within 5 years after birth. The incidence of sex (female vs. male) and position (left vs. right) are similar, and the incidence of bilateral WT is about 5-9% [8,9]. Most children attend to hospital with an asymptomatic abdominal mass, and some children may present abdominal pain, hematuria, or high blood pressure [10].
Two major international collaborative organizations for renal tumors, Children's Oncology Group (COG) and the International Society of Pediatric Oncology (SIOP), have different staging systems and treatment strategies on WT. The main controversy is whether preoperative chemotherapy is needed before nephrectomy: COG recommends surgery as a priority to accurately assess tumor stage, biology, and histology, followed by adjuvant therapy. Conversely, SIOP insists that preoperative chemotherapy can reduce tumor volume, surgical difficulty, and the risk of tumor rupture [11][12][13].
Fengming Ji, Chengchuang Wu and Ye Li have contributed equally to this work.
China is a multi-ethnic country with 56 ethnic groups, 55 of which are ethnic minorities. Yunnan is the province with the largest concentration of ethnic minorities in China and has 25 ethnic minorities with a population of more than 4000. It provides a natural advantage for studying public health issues among various ethnic groups. The socioeconomic status, demographic and physiological characteristics, lifestyle, environmental factors, and genetic susceptibility of diseases of different races and ethnic groups are diverse in the incidence of many chronic diseases [14][15][16].
Multidisciplinary treatment is currently recognized as a good tumor treatment model [17]. In this study, clinico-pathological and prognostic data of single-center and relevant literature were analyzed respectively, aiming to summarize and share WT multidisciplinary treatment experience for clinicians' reference.

Patients
All clinico-pathological data of WT children who were diagnosed with postoperative pathology in Kunming Children's Hospital from January 2017 to July 2021 were collected. Study cases were screened according to inclusion and exclusion criteria, and the included cases were followed up. Inclusion criteria: (1) Preoperative chemotherapy, operation and, postoperative chemotherapy were all completed in Kunming Children's Hospital. (2) All patients underwent radical resection and were confirmed as WT by postoperative pathology. Exclusion criteria: (1) Bilateral WT in patients, (2) Relative data were incomplete, and (3) Lost to follow-up.

Treatment and follow-up
All patients' protocols were decided by a multidisciplinary team. The team consisted of experienced urologist、onco logist、radiologist、anesthetist、pathologist、nephrolo gist and ICU doctors. Patients who received upfront surgery were staged according to the COG staging system, and patients who received preoperative chemotherapy were staged according to the SIOP staging system. The children were followed up by telephone and outpatient, and the follow-up deadline was September 1st, 2022.

Research methods
Tumor volume of onset (TVO) was calculated according to abdominal enhanced CT measurement results before any treatment: TVO = length × width × height × 0.52 (ml).
Tumor volume of resection (TVR) was calculated based on the ruler measurement results after intraoperative tumor resection: TVR = length × width × height × 0.52 (ml).The optimal cut-off values of TVO and TVR were determined by receiver operating characteristic (ROC) curves. To determine the factors influencing the prognosis of WT, the variables, including gender, age, blood type, ethnicity, tumor location, WT-1 mutation, TVO, TVR, preoperative chemotherapy, postoperative radiotherapy, histological type, lymph node metastasis and vascular metastasis, and recurrence, were analyzed. The Kaplan-Meier survival analysis and Cox proportional hazards model were carried for univariate and multivariate analysis to determine the risk factor and independent risk factor. There were significant differences when p-values were < 0.05, using two-tailed tests. Statistical analyses were performed using SPSS ver. 20.0.

The general information
A total of 68 children were included in this study, including 33 males and 35 females. The median age of the patients was 36 months (6-264 months), and 22 of them were younger than 24 months. A total of 32 patients received preoperative chemotherapy, and all of them received radical nephrectomy with tumor volume ranging from 16.36 to 1912.08 ml. Postoperative chemotherapy was performed in 1-9 courses according to tumor stage and histological type. Postoperative recurrence occurred in nine children, with a recurrence rate of 13.24%. By September 1, 2021, a total of six children died, and the 5-year overall survival (OS) rate was 87.4% ( Fig. 1).

ROC results
The results showed the area under the TVO ROC curve was 0.372, so the TVO has no predictive value for the prognosis in this study ( Fig. 2A). The area under the TVR ROC curve was 0.890, P = 0.002, with a 95% CI of 0.760-1000 (Fig. 2B). The maximal Youden Index (sensitivity + specificity − 1) showed the optimal cut-off value of TVR was 492.15 ml, and the sensitivity and specificity were 83.30% and 87.10%, respectively.

Prognostic factors for WT
In this study, 68 WT patients had a median survival time of 36.5 months and a 5-year OS rate of 87.4%.

Discussion
WT is one of the most common solid tumors in children. The incidence of North America and Europe are higher than East Asia [18]. A multi-center study during 1996-2015 from Kanata et al. [19] showed that in the centers of the investigation, there were 1395 patients from the UK and 537 from Japan, and Japanese patients have a significantly younger median age at diagnosis than those in the UK (28 months vs 39 months).
In recent years, with the development of tumor multidisciplinary treatment models, such as surgery, chemotherapy, radiotherapy, and immunotherapy, the 5-year OS rate of WT has increased dramatically from 25 to 90% [20,21]. The difference between the SIOP and COG strategy for WT is whether preoperative chemotherapy is needed. At present, there is a certain consensus that is preoperative chemotherapy has no significant effect on the WT prognosis [22]. In the results of this study, whether preoperative chemotherapy was not a risk factor affecting the OS as well (P = 0.457). However, preoperative chemotherapy can reduce tumor volume, staging, complications, and postoperative treatment intensity [23,24]. Moreover, preoperative chemotherapy can thicken tumor capsule and reduce the tumor's blood supply, effectively reducing the risk of tumor rupture during operation. The results of previous studies of SIOP have shown that the incidence of tumor rupture in patients without preoperative chemotherapy are about 25%, and patients who have received preoperative chemotherapy are about 5% [25]. However, the 4-6week preoperative chemotherapy time increases the risk of tumor invasion and metastasis, chemotherapy drugs also cause necrosis, suppuration, hemorrhage, or fibrosis of tumor tissues and lymph nodes. It affects the surgeon's judgment of intraoperative lymph node tissue, and tumor staging in the postoperative pathological examination, which does not reflect the true involvement of tumor and lymph node [26]. Therefore, whether to perform preoperative chemotherapy and the protocol should be determined by the multidisciplinary treatment team after a comprehensive evaluation. According to COG recommendations, preoperative chemotherapy should be performed for WT of the isolated kidney, bilateral WT, tumor invading adjacent organs, inferior vena cava tumor thrombus above the level of the hepatic vein, or unresectable WT. Secondly,  Rutigliano et al. [27] also pointed out that for children with ruptured WT, preoperative chemotherapy is conducive to the limitation of the ruptured tissue and avoids further local metastasis. It is also helpful to reduce the risk of intraoperative tumor rupture and the area of local radiotherapy after the operation.
In this study, the difference in prognosis between Han and ethnic minorities was a risk factor affecting the OS of WT. This finding provides a new perspective for the research of WT.
The histological type of WT is divided into favorable histology (FH) and unfavorable histology (UFH). FH  includes blastemal, stromal, epithelial and mixed, and the classification based on the ratio of the three tissue types, blastemal, stromal and epithelial, on the broadest section of the tumor [28]. About 7-10% of the histological type are UFH type, also called anaplasia, whose typical characteristics are large and deep stained nuclei, and have atypical mitotic features [29]. UFH is a vital risk factor for WT [30,31]. In our study, histological type was the only independent risk factor of OS and the histological types of all five patients were UFH. UFH can be divided into focal anaplasia (FA) and diffuse anaplasia (DA). FA and DA also have significant differences in the prognosis of WT, and the 4-year EFS was 74.9% (95% CI 59.9-85.0%) and 54.9% (95% CI 46.2-62.7%), respectively [32]. Anaplasia in WT is extremely rare before 2 years old, and the incidence gradually increases after the age of 4, and the anaplasia rate of tumor tissues above stage III are also significantly higher than the stages I and II [33]. There is no correlation between preoperative chemotherapy and anaplasia [34]. Research by Maschietto et al. [23] found that tissue anamorphosis is related to mutations in the TP53 gene, and the 5-year event-free survival (EFS) rate of wildtype TP53 patients is 80%, while the 4-year EFS rate of mutant TP53 patients is only 44% [35].
In our center, the choice of preoperative chemotherapy depends only on tumor volume, distant metastasis, tumor activity, and the presence of inferior vena cava cancer thrombus, and the long-term survival rate of patients with WT is significantly improved with a multidisciplinary treatment model. Therefore, all departments should work closely together to develop individualized treatment protocols, screen and closely follow-up high-risk patients to improve overall survival. Meanwhile reducing long-term complications also needs to be further improved.
Author contributions FMJ collected, analyzed data, and drafted the original manuscript; CCW and YL collected data and participated in to amend the manuscript; HCHZ collected and analyzed data; JRL and LL analyzed data; BY and ZY designed present study and amended the manuscript.

Data Availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.

Conflict of interest
The authors declare that they have no conflict of interest.
Ethics approval and consent to participate The study was confirmed by Kunming Children' Hospital Ethics Committee.