Imaging for Metastatic Renal Cell Carcinoma

Patients with renal cell carcinoma may develop metastases after radical nephrectomy, and therefore monitoring with imaging for recurrent or metastatic disease is critical. Imaging varies with specific suspected site of disease. Computed tomography/MRI of the abdomen and pelvis are mainstay modalities. Osseous and central nervous system imaging is reserved for symptomatic patients. Radiologic reporting is evolving to reflect effects of systemic therapy on lesion morphology. Nuclear medicine studies compliment routine imaging as newer agents are evaluated for more accurate tumor staging. Imaging research aims to fill gaps in treatment selection and monitoring of treatment response in metastatic renal cell carcinoma.

Key points

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Imaging modalities for metastatic renal cell carcinoma offer synergistic soft tissue characterization for staging evaluation.
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Clinical suspicion for osseous or central nervous system metastasis remains the recommended driver for imaging specific to these organ systems.
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Imaging criteria for tumor assessment during systemic therapy and for likelihood of response to first-line antiangiogenic agents may need to account for markers of vascularity rather than size alone for prognostication.

Introduction

Renal cell carcinoma (RCC) accounts for approximately 5% of adult cases of cancer in men and 3% in women and is the second most common urologic neoplasm found in both sexes. Approximately 33% to 50% of patients have metastatic disease at the time of detection. In addition, 20% to 40% of patients with RCC develop metastatic disease after radical nephrectomy. ^, Approximately 25% to 50% of those treated for localized disease develop metastatic disease. Monitoring for metastatic disease development and progression relies mostly on imaging. The increasing use of diagnostic imaging has resulted in tumors being diagnosed incidentally at an earlier stage and smaller size, but dedicated staging protocols may still be needed to provide accurate staging evaluation once RCC is suspected. The stage of disease is the most important factor in determining prognosis and determining the risk of relapse.

Imaging plays a key role in surveillance and assessment of treatment response after the diagnosis of metastatic disease by aiding clinicians in tailoring treatments. Systemic therapies for metastatic RCC have evolved from the earliest forms in the 1980s based on adoptive immunotherapy. By the early 1990s, interleukin-2, interferon, or a combination of the two were widely adopted. Immunotherapy with interferon or interleukin-2 was the standard of care, but with response rates of only 10% to 20%. ^, However, with newer agents, such as tyrosine kinase inhibitors, patients have partial response rates of 4% to 40% and more than 75% demonstrate minor response or stabilization of disease. Randomized trials have also shown promising results with vascular endothelial growth factor inhibitors and anti–programmed death ligand in molecular targeted therapies. ^, With such treatment advances, imaging evaluation of response may play an increasingly crucial role in decision-making about available systemic therapies. This review article provides updates on the role of imaging in metastatic RCC and describes newer techniques under investigation for staging and treatment response.

Role of diagnostic radiology in evaluation for metastatic disease: computed tomography and MRI

Abdominal computed tomography (CT) and MRI are the mainstay of staging the primary tumor at initial diagnosis, including evaluation for locoregional nodal or abdominal visceral metastases. Protocols are designed to fully evaluate the extent of the primary tumor and for metastatic RCC. The recommended CT technique for the initial staging evaluation includes arterial and nephrographic/portal venous phases to identify hypervascular tumors and also delineate arterial and venous structures. Imaging is acquired at 15 to 30 and 80 to 90, seconds, respectively, to capture these phases.

Clear cell carcinoma is the most common subtype of RCC and demonstrates avid arterial enhancement as opposed to papillary or chromophobe subtypes ( Fig. 1 ). These differences are related to intratumoral vascularity. Therefore, clear cell metastases generally also demonstrate avid arterial enhancement and can be undetectable in nephrographic phases. However, non–clear cell subtypes may enhance to a lesser degree and are better detected on nephrographic phases. The nephrographic/portal venous phase is used to evaluate the venous system to evaluate for invasion and/or surgical planning. Additional delayed excretory phase images, captured at 180 seconds, can also be obtained if there is concern for extension into the collecting system. Excretory images are helpful in detecting identifying filling defects in the ureters and can supplement routine surveillance when there is a clinical concern. Other helpful study components include multiplanar reformatted images and three-dimensional volume-rendered images, with the latter helpful in visualization of the relationships of structures for preoperative planning. In addition, these images can help assess tumor stage, delineating the tumor with particular attention to the relationship of the tumor to adjacent structures, including vascular relationships. Such reformations are best obtained with the thinnest possible images (typically <1.5-mm interval and 10%–50% overlap).

MRI is generally used when iodinated contrast is contraindicated or when further characterization of soft tissue is needed to determine disease extent. For MRI, protocols should include gadolinium-enhanced and noncontrast T1 sequences. Just as in CT, arterial phase imaging is useful in detection of clear cell type metastases. For example, one can see an avidly arterially enhancing focus in the left adrenal gland, which was biopsy proven as metastatic clear cell RCC. Arterial phase imaging can be used in initial staging and recurrence as commonly done with CT; tumor proximity vasculature is important in surgical planning. Other useful sequences in MRI can also help identify RCC metastases. For example, diffusion weighting is used to more easily identify lymph nodes in the retroperitoneum, which may be less conspicuous on other sequences; use of diffusion-weighted imaging can increase sensitivity to detect smaller lymph nodes and those that may have less contrast to abutting structures. RCC are cellular tumors that demonstrate diffusion restriction. In addition, they contain intravoxel fat, which occasionally is seen in metastasis. Papillary subtype to be specific may not demonstrate avid arterial enhancement but demonstrates diffusion restriction. Therefore, diffusion imaging aids in the detection of metastatic non–clear cell subtype RCC.

RCC typically metastasizes to the lung, bone, lymph nodes, liver, adrenal glands, and brain. More rare sites include skeletal muscle, bowel, gallbladder, pancreas, and orbits ( Fig. 2 ). Depending on the organ system in which the metastasis may be suspected clinically, various imaging modalities are superior to others in detecting metastasis. CT and MRI play critical but distinctive roles in detection and surveillance of metastatic RCC. Guidelines slightly vary among the American Urologic Association (AUA), European Association of Urology, and National Comprehensive Cancer Network. AUA defines certain symptoms that should be followed by specific imaging. However, the European Association of Urology and National Comprehensive Cancer Network make general recommendations, stating that bone scan, brain CT, or MRI may be used in the presence of specific clinical or laboratory signs and symptoms ( Table 1 ). ^, The AUA also recommends specific time intervals for surveillance for metastatic disease based on the TNM stage of disease at presentation ( Table 2 ).

Table 1

Imaging recommendations based on clinical suspicion for metastatic RCC

Data from Campbell S., Uzzo R G., Allaf M E., et al., Renal Mass and Localized Renal Cancer: AUA Guideline. J Urol., 2017. 198(3); p. 520-529.

Symptom	Imaging Modality Recommended
Bone pain or elevated alkaline phosphatase	Bone scan
Pulmonary symptoms	Chest radiograph or CT chest
Neurologic symptoms	CT or MRI of the brain/spine

Table 2

The American Urologic Association categorizes follow-up imaging recommendations based on risk criteria

Data from Campbell S., Uzzo R G., Allaf M E., et al., Renal Mass and Localized Renal Cancer: AUA Guideline. J Urol., 2017. 198(3); p. 520-529.

Low Risk (pT1N0Nx)	Moderate/High Risk (pT2-pT4 N0, Nx, or Any Stage N+)
Baseline abdominal scan (CT or MRI) for nephron-sparing surgery and abdominal imaging (US, CT, or MRI) for radical nephrectomy within 3–12 mo after surgery Additional abdominal imaging (US, CT, or MRI) may be performed in patients with low-risk disease following a radical nephrectomy if the initial postoperative baseline image is negative Abdominal imaging (US, CT, or MRI) may be performed annually for 3 y in patients with low-risk disease following a partial nephrectomy based on individual risk factors if the initial postoperative scan is negative Those with history of low-risk RCC are recommended to have annual CXR to assess for pulmonary metastases for 3 y and only as clinically indicated beyond that time period	Moderate- to high-risk patients are recommended to have a baseline chest and abdominal scan (CT or MRI) within 3–6 mo following surgery with continued imaging (US, CXR, CT, or MRI) every 6 mo for at least 3 y and yearly thereafter to year 5 Site-specific imaging may be performed if clinical symptoms are suggestive of recurrence or metastatic spread In moderate- to high-risk patients, imaging (US, CXR, CT, or MRI) beyond 5 y may be performed at the discretion of the clinician Routine FDG-PET scan is not indicated in the follow-up for RCC

Low Risk (pT1N0Nx)

Moderate/High Risk (pT2-pT4 N0, Nx, or Any Stage N+)

Baseline abdominal scan (CT or MRI) for nephron-sparing surgery and abdominal imaging (US, CT, or MRI) for radical nephrectomy within 3–12 mo after surgery
Additional abdominal imaging (US, CT, or MRI) may be performed in patients with low-risk disease following a radical nephrectomy if the initial postoperative baseline image is negative
Abdominal imaging (US, CT, or MRI) may be performed annually for 3 y in patients with low-risk disease following a partial nephrectomy based on individual risk factors if the initial postoperative scan is negative
Those with history of low-risk RCC are recommended to have annual CXR to assess for pulmonary metastases for 3 y and only as clinically indicated beyond that time period

Moderate- to high-risk patients are recommended to have a baseline chest and abdominal scan (CT or MRI) within 3–6 mo following surgery with continued imaging (US, CXR, CT, or MRI) every 6 mo for at least 3 y and yearly thereafter to year 5
Site-specific imaging may be performed if clinical symptoms are suggestive of recurrence or metastatic spread
In moderate- to high-risk patients, imaging (US, CXR, CT, or MRI) beyond 5 y may be performed at the discretion of the clinician
Routine FDG-PET scan is not indicated in the follow-up for RCC

Abbreviations: CXR, chest radiograph; US, ultrasound.

Organ-specific evaluation for metastasis

Pulmonary

Pulmonary metastases account for 45% of metastatic RCC and are usually asymptomatic. Controversies exist as to whether and how to evaluate for the possibility of intrathoracic metastases based on stage of tumors. For small primary tumors (T1), where the risk of metastatic disease is small, simple chest radiography may be satisfactory. For stage T2 or higher primary tumors, and because small pulmonary metastases are missed on radiographs, chest CT should probably be performed. ^, Lesions on CT are usually small, well circumscribed, and in subpleural locations. However, in RCC, patients can have “cannonball” metastases that are large (>5 cm) rounded pulmonary metastases.

Bone

The second most common site of RCC spread is to bones. Compared with other malignancies, the distribution of bone metastases varies and common sites include the pelvis, spine, and ribs. Solitary bone metastases are rare. For bone metastases, compared with CT, MRI is useful in detecting smaller lesions and lesions adjacent to the bones. Bone scan is recommended for patients with bone pain or elevated increased alkaline phosphatase ( Fig. 3 ).