The Role of Ultrasonography forDiagnosing Wilms Tumor in Developing Country.

Background: Overall five-year survival rate of Wilm's Tumor (WT) in developing countries is still poor. Delayed diagnosis is one of the contributing factors, whereas early diagnosis is an important thing for the outcome. It is caused by the WT burden in developing countries that was not comparable with the number of facilities for diagnosis and treatment. Ultrasonography (USG) is the mandatory first-line imaging modality in children with a suspected abdominal mass and an overall sensitivity of 76%. Additionally, it can be found in many health facilities at a lower cost, quick, non-invasive, and carries no risk of radiation. Therefore, the relationship between USG and histopathology should be measured. Materials and
Methods: A cross-sectional study with an analytical approach was performed in pediatric (0 untill 18 year of age) renal malignancy and neuroblastoma that admitted to Dr. Hasan Sadikin Hospital, Bandung between 2015-2018. Data were collected from medical records. Statistical analyses using Fisher exact test were done to determine the significance of the relationship between USG and histopathology.
Results: Forty-three samples were obtained based on inclusion criteria, such as WT (n=33), neuroblastoma (n=6), renal clear cell carcinoma (n=2) and no specific type of renal malignancy (n=2). Fisher exact test revealed no-significant relationship between USG and histopathology with p-value > 0.05
Conclusion: There is no significant relationship between USG and histopathology. Therefore, centralized unity for USG interpretation is recommended.

Introduction

Nephroblastoma or Wilms Tumor (WT) is the most common renal malignancy in children (85% cases)[   1 ],[   2 ]. It accounts for 5% of all childhood malignancies[   3 ]. Data from Dr. Hasan Sadikin General Hospital stated 24 children with WT during 2014-2016[   4 ]. Patients usually come to hospitals at an advanced stage[   5 ]. Currently, most high-income countries reported that survival at 5 years is more than 90% for children with localized disease and 70% for distant metastatic disease[   6 ],[   7 ]. However, the outcome in developing countries is still poor (5-year survival less than 50%[9]).

Delayed diagnosis is one of the contributing factors for low survival rate in developing countries, whereas early diagnosis is an important factor for the outcome. It is caused by lack of facilities for diagnosis and treatment, lack of multidisciplinary collaboration, long distances to treatment centers, and also lack of parental awareness about early signs and symptoms of childhood malignancy[   10 ],[   11 ],[   12 ]. Other causes of the low survival rate include refusal and abandonment of treatment, preference for alternative medicine, financial difficulties coupled with lack of health insurance[   13 ],[   14 ].

WT patient is diagnosed sequentially by history taking, physical examination, laboratory investigation followed by imaging and histopathologic examinations. The physician usually uses Ultrasonography (USG) and CT scan as an imaging examination. CT scan is important for diagnosis because it is relevant and accurate to determine the staging of WT.[   15 ] But practically it is not yet available in many health facilities, expensive and contain radiation effect.[   16 ],[   17 ] Therefore, ultrasonography (USG) is needed as an alternative imaging examination with the overall sensitivity of 76%[   18 ],[   19 ].

According to UMBRELLA SIOP–RTSG 2016 protocol, USG is the mandatory first-line imaging modality in children with a suspected abdominal mass. USG is enough to evaluate whether the abdominal mass originates from the kidney or not and whether the component is solid or cystic. Additionally, ultrasonography in plays a vital role in developing countries because it can be found in many health facilities at a lower cost, quick, non-invasive, and carries no risk of radiation[   20 ],[   21 ]. If the study is significant, the umbrella protocol can be used as a new protocol to diagnose WT. Hopefully, it can improve the survival rate, especially in developing countries.

Currently, the study report on ultrasonography examination for WT patients in Indonesia does not yet exist. The aim of this study is to find relationship between USG with histopathology findings as a gold standard for the diagnosis of WT.

MATERIALS AND METHODS

A cross-sectional medical record study was conducted with an analytical approach. The sample was collected in August-October 2019 using medical records from inpatient, outpatient, Hospital Information System (SIRS), and Bandung Pediatric Cancer Registry. All children (0-18 years old) representing with renal malignancy and neuroblastoma at Dr. Hasan Sadikin General Hospital from January 1st, 2015 until December 31th, 2019 were included. The exclusion criteria were incomplete data (never done USG and/or histopathology examination), lost medical record data, inaccessible data and lack of renal malignancy or neuroblastoma in the results of histopathology examination.

The study was approved by the Health Research Ethics Committee of Universitas Padjadjaran, Bandung through a letter of approval number 808/UN6.KEP/EC/2019 and was permitted by the Medical Research Ethics Committee of Dr. Hasan Sadikin General Hospital with a letter Number LB.02.01/X.2.2.1/12581/2019. This study was also acknowledged and approved by Pediatrics Department and Pathology Anatomy Department of Dr. Hasan Sadikin General Hospital and Hospital Information System (SIRS).

Data analysis includes demographic characteristics such as age and gender, USG finding,histopathology finding, treatment protocol, and tumor distribution. USG finding was classified based on location (intrarenal and extrarenal) and type (solid, cystic and mix) of mass. Histopathology finding was classified based on histological subtypes into blastemal, epithelial and stromal. Treatment was classified based on first treatment that given to patients such as preoperative chemotherapy (SIOP 2001 protocol) or nephrectomy (COG/NWTSG protocol). And tumor distribution was classified into localized and metastatic tumors based on Toronto guidelines.[   22 ]

The statistical analysis was performed using Microsoft® Excel 2016 and Statistical Package for Social Sciences (IBM® SPSS® Statistics Data Editor version 23). USG and histopathology relationship analyzed by Fisher Exact Test and p<0.05 considered statistically significant.

Results

Seventy-eight children with renal malignancy and neuroblastoma were admitted to Dr. Hasan Sadikin General Hospital during the period of study and among them, 43 data fulfilled the inclusion criteria of this study. 30 data were excluded because there were no USG and/or histopathology findings. Thirty-three children who diagnose WT were included in the case group and 10 children who diagnose renal malignancy (except WT) or neuroblastoma were included in the control group.

Patient characteristics are presented in Table 1, the age of WT patients ranges between 0-13 with the median age at diagnosis was approximately 3 years. Most WT patients were male and the male to female ratio was 6:5.

Table 1

Characteristics of the patient

Variable	Wilm’s Tumor n=33	n on - Wilm’s Tumor n=10
Age at diagnosis, yearsMedianRange	3.000-13	3.000-16
Gender          • Male             • Female	18 (41.9)15 (34.9)	4 (9.3)6 (13.9)

Distribution of renal mass type in accordance with histopathology findings of intrarenal mass

Distribution of renal mass type in accordance with histopathology findings of extrarenal mass

Histopathology findings in table 2 showed a subtype component, but 20 samples were unidentified. Preoperative chemotherapy becomes the majority primary treatment for WT patients used by physicians in Dr. Hasan Sadikin General Hospital. And also in mass distribution showed patients with localized mass (87.9%) more than patients with metastasis (12.1%).

Table 2

Histopathology Findings, Primary Treatment and Mass Distribution in Wilms Tumor

Variable	n (%)
Histopathology examination•      Blastemal + stromal +epithelial•      Blastemal + stromal•      Blastemal + epithelial•      Unidentified	7 (21.2)4 (12.1)2 (6.1)20 (60.6)
Treatment Protocol        •     Preoperative chemotherapy (SIOP)        •     Nephrectomy (COG/NWTSG)        •     Unidentified	15 (45.4)10 (30.3)8 (24.3)
Mass Distribution        •      Localized        •      Metastasis	29 (87.9)4 (12.1)
Total	33 (100)

Table 3 illustrated the relationship between ultrasonography and histopathology. All children who diagnose Wilms Tumor based on histopathology findings were 33 patients, and the majority were positive WT in USG findings with p-value = 0.177.

Table 3

Cross tabulation USG and histopathology examination

USG	Wilms Tumor (Histopatologi)		Total n (%)	P-value
	Positive Wilm’s Tumor n (%)	Negative Wilm’s Tumor n (%)
Positive Wilm’s Tumor	28 (65.1)	6 (14)	34 (79.1)	0.177*
Negative Wilm’s Tumor	5 (11.6)	4 (9.3)	9 (20.9)
Total	33 (76.7)	10 (23.3)	43 (100.0)

Fisher’s Exact Test

Discussion

This study reveals the age of WT patients ranges between 0-13 with the median age at diagnosis was approximately 3 years. Most WT patients were male with male to female ratio is 6:5. This finding was similar to a study from Soyemi SS et al. (2013) who reported that 44 patients with WT in Lagos State University Teaching Hospital, Nigeria have the median age of 3 years at diagnosis               23 . Another study conducted by F Rais et al. (2016) at Department of Hemato-oncology in Children Hospital of Rabat also stated that WT in children were frequent in male with the ratio of male to female (10:9)    24 .

Most USG findings were intrarenal mass (n=34) and the majority showed solid type masses (n=19). This study was in line with an article from Lisa H. Lowe, MD about the variety of pediatric renal masses that explained the characteristics of WT, which mostly appear as large solid mass, often vascular invasion, in children25. Ellen M. Chung et al also explained that the margin was smooth and well-defined margin formed a pseudocapsule. Areas of necrosis and cystic appear hypoechoic and/or anechoic while hemorrhagic, fat and calcification appear hyperechoic   26 ,   21 .

Histopathology is performed after Fine Needle Aspiration Biopsy (FNAB) and/or Nephrectomy. Only 13 samples that explained the subtype of histopathology findings in this study and 20 samples were unidentified. Triphasic component was the most component (21.2%), followed by blastemal+stromal (12.1%) and blastemal+epithelial (6.1%). This result was similar to a study from Soyemi SS et al (2013) in which 100% of patients(n=44) with WT who did not receive neoadjuvant chemotherapy exhibited triphasic histological pattern.   27  But, another study from Innocent et al. (2019) found that the most common subtype was blastemal monophasic (43%), followed by triphasic type (35%) and blastemal-stromal (22%)   28 .

According to SIOP 2001, triphasic type (blastemal+epithelial+stromal) is a classical pattern in histopathology of WT   2 . Blastemal component presume the most malignant component   29 . Neoadjuvant chemotherapy may modify the histopathological patterns; therefore, patients who performed nephrectomy before chemotherapy were susceptible to have triphasic pattern   30 . Chemotherapy destroyed blastemal and epithelial element, while induced maturation in stromal component. Differentiation of stroma cell in the form of well-differentiated smooth or skeletal muscle cells, fat tissue, cartilage, bone and even glial tissue is present in some cases. The presence of blastemal after preoperative chemotherapy indicated that it does not respond to chemotherapy   2 .

Treatment protocol in WT patients divided into SIOP 2001 protocol (preoperative chemotherapy) and COG protocol (primary surgery). SIOP protocol cannot be performed for a patient under 6 months old, while COG protocol cannot be used for bilateral WT   31 . In this study, neoadjuvant chemotherapy was given to 15 patients (45.4 %) and nephrectomy was the initial treatment in 10 patients (30.3 %). A reduction in tumor component was resulted in two patients with WT bilateral who were given neoadjuvant chemotherapy before surgery.

Mass distribution in this study showed more patients with localized mass (87.9%) compared to patients with metastasis (12.1%). This study was in line with the previous study conducted by Atteby Jean-Jacques Yao et al (2019) which revealed children with localized mass (n=158) more than children with metastasis (n=11)   32 .

Both USG and histopathology examinations are performed for the diagnosis of WT. According to Umbrella Protocol, USG is first choice investigation in suspected WT and sufficient to WT diagnosis    21 . This study reported that 28 of 33 children who were diagnosed with Wilms Tumor based on histopathology findings had positive WT in USG findings. The USG is positive if the tumor comes from the kidney and negative if the tumor is located outside of the kidney. There were 5 patients that were histopathologically positive, but were negative in USG findings due to some cases of extrarenal WT. Moreover, 6 out of 10 patients with negative WT had positive results in USG because WT only constitute 85% of all renal malignancies. Additionally, neuroblastoma from intra-abdominal masses sometimes invade the kidney and show an intrarenal mass in USG findings   33 .

This study revealed that there is no significant relationship which was different from the Umbrella Protocol statement in which USG was sufficient for the diagnosis of WT. The researcher suggested that the no-significant results were influenced by USG findings which were not centralized from Dr. Hasan Sadikin General Hospital only. USG was operator-dependent, so it is probable to have different perceptions and interpretations   34 .

Limitations of this study were difficulty of access to results of USG and histopathology examination because not all results noted and placed in the medical records, especially for referral patients. Besides, the researcher could not obtain the data before 2014 because they were unavailable.

CONCLUSION

In conclusion, there is no significant relationship between USG and histopathology for the diagnosis of WT because the data were collected from various operators and health facilities whose data were missing or incomplete.