Imaging of Pediatric Renal Tumors: a COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper Focused on Wilms Tumor and Nephrogenic Rests

Abstract

Malignant renal tumors account for approximately 6% of pediatric malignancies, with Wilms tumor (WT) representing approximately 90% of pediatric renal tumors. This manuscript provides consensus-based imaging guidelines for the initial evaluation of a child with a suspected WT and follow up during and after therapy co-developed by the Children’s Oncology Group (COG) Diagnostic Imaging and Society for Pediatric (SPR) Radiology Oncology Committees. The guidelines for Wilms tumor imaging in the Society of International Pediatric Oncology (SIOP) are briefly discussed to highlight some of the differences in imaging approach.

Introduction

Malignant tumors of the kidney comprise approximately 6% of all childhood cancers ¹. Wilms tumor (WT) is the most common renal cancer in children younger than 15 years of age while renal cell carcinoma is the most common in older children ^2,3. Since WT accounts for the majority of pediatric renal tumors, this white paper will focus on WT. While the majority of WTs are sporadic, approximately 10% are associated with underlying genetic predisposition such as WT1-related WT, WAGR (Wilms, aniridia, genitourinary anomalies and retardation) syndrome, Denys-Drash syndrome, and 11p15.5-related WT syndromes such as Beckwith-Wiedemann syndrome ^4,5. Most WTs are solitary at presentation with 10% being multifocal in one kidney and 5-7% having bilateral synchronous tumors. Genetically-predisposed WT tends to be more often multifocal and/or bilateral ⁴. Favorable histology (FH) WT is much more common than anaplastic WT.

Sporadic WT is typically detected as an abdominal mass in an otherwise healthy child. These tumors can, however, present with abdominal pain, fever, anemia, hematuria, and hypertension in up to 25%-30% of affected children ⁷. Genetically-predisposed WTs are often detected during sonographic surveillance. Sonographic surveillance is recommended to be performed every 3 months for up to 7 years of age in children with genetic variants that are associated with >5% risk of WT ^4,8.

In this white paper, we provide a consensus of imaging recommendations by experts in the Diagnostic Imaging Committee from the Children’s Oncology Group (COG) and the Oncology Committee from the Society for Pediatric Radiology (SPR) for the initial evaluation and follow up during and after therapy of a child with a suspected WT. International Society of Paediatric Oncology (SIOP) guidelines, provided by representatives (JNB, JPS and ASL) of the Renal Tumor Study Group (RTSG) who did not participate in the COG/SPR consensus of recommendations, are briefly summarized in a separate section at the end of this manuscript. This white paper was funded in part by the National Clinical Trials Network Operations Center Grant U10CA180886. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Imaging in Wilms tumor staging

Imaging plays a key role in WT staging, specifically, regarding the evaluation of locoregional disease, contralateral kidney, and detection of distant metastases. GRADE A. SOR 1 (very strong recommendation) WT staging in North America follows the COG system. Staging in this system relies heavily on surgical and pathologic findings following up-front nephrectomy. Stage V disease (i.e. bilateral WT +/− nephrogenic rests - NRs) is treated similarly in both COG and SIOP staging systems by administering pre-operative chemotherapy to potentially facilitate nephron-sparing surgery ⁹.

Although the COG staging system is based on surgical and pathological assessment, there are key imaging findings that are important to include in the interpretation of initial studies as they impact both locoregional and distant staging. Key COG staging features that rely solely on imaging include synchronous contralateral lesions and distant metastasis (lung and liver being most common). It is important to note that imaging assessment for bilateral disease has replaced routine intraoperative exploration of the contralateral kidney ¹⁰. GRADE A, SOR 1.11 (very strong recommendation)

Locoregional and distant staging of WTs has been shown to significantly impact prognosis, in addition to tumor biology. In the presence of pulmonary metastasis, 4-year event free survival (EFS) is reported at 85.4% and overall survival (OS) at 95.6%, for WT patients with FH ¹¹. In children with bilateral WT, 4-year EFS is currently around 82.1 % and OS around 95% ¹².

Imaging Modalities

Sonography is the imaging modality of choice for the initial workup of suspected pediatric renal tumors ¹³. GRADE A, SOR 1.00 (strong recommendation) Sonography is also the imaging modality of choice for surveillance of children with genetic predisposition to WT. Doppler evaluation can assist in assessment of the vessels and differentiating between bland vs. tumor thrombus.

Once a renal mass is detected, contrast-enhanced computed tomography (CECT) or magnetic resonance imaging (MRI) with and without intravenous contrast of the abdomen and pelvis is essential for locoregional staging ¹⁴. Oral contrast is not necessary. MRI is the preferred imaging modality for bilateral/multifocal or genetically-predisposed WT. GRADE A SOR 1.22 (very strong recommendation)

Computed tomography (CT) of the chest is essential to evaluate for pulmonary metastasis. Use of iodinated intravenous contrast is preferred for baseline chest CT as it aids in the simultaneous evaluation of lung parenchyma, regional vasculature, and other mediastinal structures. GRADE C SOR 2.11 (moderate recommendation) Chest CT should be performed prior to renal intervention, to avoid obscuration of the lungs secondary to post-procedural pleural effusion/atelectasis.

The advantages and disadvantages of each modality are summarized in Table 1.

Table 1:

Advantages and limitations of each modality for the evaluation of pediatric renal tumor.

Modality	Timepoints	Advantages	Limitations
Sonography	Screening for suspected mass Surveillance of predisposed children Post-therapy surveillance	Availability Ability to use Doppler to assess for blood flow in small or compressed vessels No sedation/anesthesia in almost all cases	Limited field-of-view for evaluation of large mass Should not be used for staging or response assessment
CT	Initial diagnosis and staging Response assessment Post-therapy surveillance	Simultaneous evaluation of abdomen/pelvis and lungs Reduced sedation/anesthesia requirements More readily available than MRI	Exposure to ionizing radiation
MRI	Initial diagnosis and staging Response assessment Post-therapy surveillance	Superior soft tissue contrast and characterization Multiphasic imaging without ionizing radiation	Sedation/anesthesia usually necessary >6 months to < 6 years age Less readily available

Imaging at Diagnosis

If a renal mass is initially detected at sonography, the renal vein and inferior vena cava should be evaluated to exclude the presence of tumor thrombus, which can be present in up to 11% of cases ¹⁶. However, if a renal mass is detected by CT/MR, additional imaging with doppler sonography is not required in every case and should be reserved for cases where CT/MR is equivocal for tumor thrombus ¹⁷. GRADE A SOR 1.33 (very strong recommendation) The contralateral kidney should also be evaluated to exclude synchronous masses as this impacts tumor stage and surgical approach/therapy ¹⁰.

Cross-sectional imaging with CT or MRI of the abdomen/pelvis is essential for locoregional staging. GRADE A SOR 1.11 (very strong recommendation) A CECT in a portal venous phase is typically sufficient to assess the abdomen/pelvis. In addition to confirming the number and location of renal masses, cross-sectional imaging helps evaluate for findings of tumor rupture (i.e. ascites beyond the rectouterine/rectovesical pouch, perinephric fat stranding and/or retroperitoneal fluid), infiltration into adjacent organs, (which would make primary nephrectomy more challenging), presence of tumor thrombus (precludes primary nephrectomy, if extending into the intrahepatic inferior vena cava - IVC - or right atrium), and bulky retroperitoneal lymph nodes ¹³. The same can be accomplished with MRI with and without contrast.

Although MRI has shown to be equivalent to CT in diagnostic performance for WT, it provides both qualitative and quantitative information while CT only provides qualitative information ¹⁸. MRI enables better tumor characterization due to its superior soft tissue resolution, discerning between hemorrhagic, necrotic, and solid/cystic components, and offers potential non-invasive biomarkers with diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) mapping for the diagnosis and pre-operative risk classification of WT and other pediatric renal tumors ^19-21. In addition, ADC distributions can aid in the assessment of chemotherapy response, particularly amongst WT with large necrotic components, in which post-treatment size may not be significantly reduced ¹⁸. New MRI sequences and technical advances, along with other strategies such as child life support and other distraction techniques, currently allow for the acceleration of imaging acquisition while mitigating potential risks associated to the use of sedation/general anesthesia, particularly, amongst patients younger than 6 years of age ²².

Differentiation between NRs and small WTs continues to be challenging with all cross-sectional modalities ¹⁹. GRADE B SOR 1.66 (strong recommendation) Imaging findings supportive of a diagnosis of perilobar NRs include peripheral subcapsular location, ovoid/elliptical shape, and homogeneity ^19,20.^19,20. Intralobar NRs are more difficult to differentiate from small WT due to location within the renal parenchyma and heterogeneity of these lesions.

Chest CT is essential to evaluate for pulmonary metastasis. GRADE A SOR 1.00 (strong recommendation) Use of intravenous contrast is not required for pulmonary staging but can be helpful to evaluate for other key findings on chest imaging including tumor thrombus extension into high IVC/right atrium, pulmonary embolism, and mediastinal lymphadenopathy. In patients undergoing sedated/anesthetized MRI of the abdomen and pelvis, chest CT should always be performed prior to MRI to avoid obscuration of the lung parenchyma due to sedation/general anesthesia induced atelectasis GRADE A SOR 1.00 (strong recommendation).

Imaging at Follow-up

CT or MRI can be used as imaging modalities for follow-up of the primary tumor. GRADE A SOR 1.22 (very strong recommendation) Imaging parameters for either modality remain similar to recommended protocols at time of diagnosis. Notably, a solitary kidney is not a contraindication to the administration of intravenous contrast if the renal function is within normal limits. Follow up for pulmonary metastatic disease requires CT, which can be performed without intravenous contrast, especially if the baseline scan showed no evidence of vascular thrombus, embolism or mediastinal lymphadenopathy.

Tumor Response Assessment

Response assessment is needed for the primary unilateral renal tumor only if primary nephrectomy is not performed. CT or MRI can be used to assess any change in renal mass size. This is especially important in children with bilateral/multifocal or genetically-predisposed WT to determine feasibility of nephron-sparing surgery, typically performed at week 6 and week 12 of chemotherapy ¹². If the reason for delayed nephrectomy was the presence of intra-caval/intra-atrial tumor thrombus, CT/MRI have a complementary role to sonography with Doppler and echocardiography for complete vascular assessment of residual thrombus (bland or tumor) GRADE C SOR 2 (strong recommendation) as this impacts surgical approach (i.e. potential need for cardiopulmonary bypass, thoracotomy or cavotomy).

In children with pulmonary metastasis, follow up chest CT (either with or without intravenous contrast) at week 6 is needed to determine response to treatment.

Imaging Off Therapy/Surveillance

The primary purpose of surveillance/off therapy imaging in WT patients is to detect asymptomatic disease recurrence with the aim for high salvage. GRADE A SOR 1 (very strong recommendation) About 15% of children with WT relapse ²³. Exact surveillance guidelines depend on tumor biology and initial staging, though a recent study has shown that surveillance of unilateral FHWT with chest radiographs and abdominal ultrasound (US) is sufficient²⁴.

Advances in Imaging

Newer imaging techniques that have become available over the last two decades include contrast-enhanced sonography, dual-energy CT, MRI-based DWI, dynamic contrast-enhanced imaging, arterial spin labeling, intravoxel incoherent motion (an alternative DWI model), blood oxygenation level-dependent, and CT/MRI-based radiomics, among others ²⁵. Of these, DWI has made it to routine clinical care and can aid with lesion detection but not necessarily with determining renal tumor histological grade or differentiating between NRs and WT ^20,26,27. The other techniques have been explored for characterization and subtyping of adult renal tumors with limited applications in pediatric renal tumors to date.

In the era of precision medicine, radiomics has become a promising emergent field that focuses on the extraction of mineable quantitative data, beyond the human eye, from imaging modalities such as CT and MRI performed in oncology patients ^28,29. The application of radiomics for evaluating pediatric renal tumor biology is currently being evaluated.

SIOP Approach to Imaging

In the SIOP approach, all WT cases undergo chemotherapy prior to nephrectomy. The SIOP- RTSG does not advocate for invasive procedures for histopathological confirmation before starting pre-operative treatment, except when a non-WT is suspected based on unusual clinical presentations and/or imaging findings. Although COG and SIOP approaches show comparable survival rates, the differences in treatment protocols have implications in the imaging assessment of WT patients.

The SIOP-RTSG developed the UMBRELLA treatment protocol with updated imaging guidelines that were implemented in 2016 ³⁰. According to these guidelines, after initial evaluation of a suspected WT is completed with US, the protocol favors imaging assessment with contrast-enhanced abdominopelvic MRI (including DWI) ¹⁸ along with a non-contrast chest CT ³¹ rather than a CECT of the chest, abdomen and pelvis. Abdominopelvic MRI is also preferred for pre-operative assessment, after initial chemotherapy, and for follow-up while abdominopelvic CECT is only accepted when MRI is not feasible.

Table 2:

Suggested CT abdomen/pelvis protocol for initial evaluation and follow-up of WT. Images should be reconstructed in axial, coronal and sagittal planes. Thin- and thick-section images between 0.5-1.5mm and 3-5mm, respectively, should be provided according to institutional preference.

Contrast Phase	Positioning and Coverage	Contrast Timing	Comments
Portal venous	Position supine with arms raised. Abdomen and pelvis; chest (if indicated)	55-60 seconds after injection	Evaluate: Renal mass Retroperitoneal lymph nodes Vascular structures Distant metastasis (most common, liver and lungs) Chest, abdomen and pelvis can be performed in one breath hold

Table 3:

Suggested MRI abdomen and pelvis protocol for initial evaluation and follow-up of WT. Magnet strength 1.5 or 3 Tesla. Patient positioned supine with anterior torso coil and posterior spine coils. Coverage: Entire peritoneal cavity - lung bases through ischial tuberosities; all slice thickness 5mm or less. Use of motion correction techniques such as respiratory triggering, radial acquisition strongly recommended. GRE = gradient recalled echo; TSE = turbo spin echo; FSE = fast spin echo; DWI = diffusion weighted imaging

Plane	Sequence	Contrast phase	Required Or Optional	Comment
Coronal	T2	Pre-contrast	Required	TSE or FSE sequence; usually without fat suppression
Axial	T2	Pre-contrast	Required	TSE or FSE sequence; with and without fat suppression
Axial	DWI	Pre-contrast	Required	Use low (50-100 s/mm2) and intermediate-to-high (600-800 s/mm2) b-values
Axial	Dixon-type Water/Fat and In/Out Phase	Pre-contrast	Optional
Axial	Axial T1 Fat Suppressed	Pre-contrast	Required	3D volumetric GRE sequence
Axial	T1 Fat Suppressed	Arterial	Optional	16-20 seconds after injection
Axial	T1 Fat Suppressed	Portal Venous	Required	45-60 seconds after injection
Axial	T1 Fat Suppressed	Delayed	Required	2-5 minutes after injection
Coronal	T1 Fat Suppressed	Delayed	Required	3D volumetric GRE sequence

Glossary

WT

Wilms tumor

COG

Children’s Oncology Group

SPR

Society for Pediatric Radiology

SIOP

International Society of Pediatric Oncology

WAGR

Wilms, aniridia, genitourinary anomalies and retardation syndrome

FH

Favorable histology

RTSG

Renal Tumor Study Group

NRs

Nephrogenic rests (nephroblastomatosis)

EFS

Event free survival

OS

Overall survival

CECT

Contrast-enhanced computed tomography

MRI

Magnetic resonance imaging

CT

Computed tomography

IVC

Inferior vena cava

DWI

Diffusion-weighted imaging

ADC

Apparent diffusion coefficient

FHWT

Favorable histology Wilms tumor

US

Ultrasound

SIOP- RTSG

International Society of Pediatric Oncology - Renal Tumor Study Group

GRE

Gradient recalled echo

TSE

Turbo spin echo

FSE

Fast spin echo