Role of Imaging in Renal Cell Carcinoma: A Multidisciplinary Perspective

SA-CME LEARNING OBJECTIVES

After completing this journal-based SA-CME activity, participants will be able to:

• ■ Describe essential, important, and optional reporting elements used to characterize an indeterminate renal mass.

• ■ Discuss the role of advanced medical imaging in surgery, PA, TAE, AS, and SBRT for the management of RCC.

• ■ Review imaging findings associated with treatment of advanced RCC with antiangiogenic therapy or immunotherapy.

Introduction

Imaging has a crucial role in patients with renal cell carcinoma (RCC) for diagnosis, characterization, staging, treatment guidance, and posttreatment evaluation. We provide a multidisciplinary overview of the role of imaging for surgery, percutaneous ablation (PA), transarterial embolization (TAE), active surveillance (AS), stereotactic body radiation therapy (SBRT), and the evaluation of advanced RCC response after antiangiogenic target therapy or immunotherapy.

Image Evaluation of the Indeterminate Renal Mass

An indeterminate renal mass is any renal mass that cannot be diagnosed as benign or malignant at the time of discovery.

In patients with normal renal function, the most appropriate imaging modality to fully characterize an indeterminate renal mass is renal CT or MRI, without and with intravenous contrast material

The renal MRI acquisition protocol should include axial or coronal two-dimensional (2D) T2-weighted images, axial 2D T1-weighted in- and out-of-phase images, axial and/or coronal three-dimensional T1-weighted fat-saturated pre- and postcontrast (obtained after the administration of contrast material) images, and axial diffusion-weighted images for complete characterization of a renal mass (4). The purpose of renal mass CT or MRI is to characterize the renal mass and obtain information to assist with management. Up to 20% of indeterminate solid renal masses are ultimately found to be benign, with an increased incidence of benignity in small (<4 cm) renal masses (1,2).

Table 1 lists essential, important, and optional reporting elements used to describe the indeterminate renal mass.

There has been interspecialty consensus between radiologists and urologists that the following imaging features are essential reporting elements: tumor size, presence or absence of macroscopic fat, tumor characterization as solid or cystic, and tumor enhancement

Table 1: Reporting Elements for Indeterminate Renal Masses

The presence of macroscopic fat in a renal mass, particularly in the absence of calcification, is characteristic of an angiomyolipoma, a benign renal mass. Macroscopic fat at CT is best detected on noncontrast CT images and defined as a component or focus of the mass measuring less than 10 HU (9). Macroscopic fat on MR images is defined as a component or focus of the mass that shows signal intensity loss after application of fat suppression (not to be confused with signal loss comparing opposed-phase to in-phase dual-echo T1-weighted images) or as linear or curvilinear chemical shift artifact of the second kind causing India ink (etching) artifact within or at the periphery of the mass, while the central portion of the mass matches the signal intensity of subcutaneous or visceral fat (10). Conversely, microscopic fat on MR images is characterized by signal loss on the opposed-phase images compared with the in-phase dual-echo T1-weighted images and is not specific to fat-poor angiomyolipomas and can be found in some RCC subtypes, most commonly clear cell RCC but occasionally papillary RCC (10,11).

Cystic renal masses, defined as a renal mass with greater than 75% nonenhancing components, are less likely to be malignant than are solid renal masses, and malignant cystic renal masses are less aggressive than malignant solid renal masses (10,12). Cystic renal masses evaluated at renal CT or MRI without and with intravenous contrast material should be further categorized by the Bosniak classification system, version 2019 to improve the clarity of radiology reporting and stratify the risk of malignancy (10).

The majority of urologists prefer quantitative information on enhancement (eg, Hounsfield unit measurements in the noncontrast and each contrast-enhanced phase) rather than simply reporting the presence or absence of enhancement (8). Enhancement at CT is classically determined by an increase of 20 HU or more between noncontrast and contrast-enhanced phases obtained at 120 kVp, with an increase of 10–19 HU considered indeterminate (9). The role of dual-energy and spectral CT and iodine quantification to characterize renal masses is growing, although the need and best method for incorporation of dual-energy or spectral CT techniques into a renal mass CT protocol remain unclear (13,14). By comparison, MRI is more sensitive than CT for detection of enhancement, defined as a greater than 15% change in signal intensity between pre- and postcontrast T1-weighted images or subjective definitive enhancement on subtraction images.

Staging of RCC

The staging system most commonly used for kidney cancer is the American Joint Commission on Cancer (AJCC) TNM system (Tables 2, 3) (15). Clinical staging includes physical examination, biopsy, and imaging findings, although the final stage is determined by surgical staging (also referred to as pathologic staging).

Table 2: AJCC TNM Staging System

Table 3: Stage Groups for the AJCC TNM Staging System

The main strengths of imaging for clinical staging are its noninvasive nature, the wide availability of CT and MRI, the ability to measure tumor size, the detailed visualization of most of the critical landmarks for T staging, and the ability to aid in the detection of pathologic lymph nodes, venous invasion, and distant metastases

Figure 1.

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The renal capsule is tightly adherent to the kidney and is a critical landmark for staging but cannot be visualized at renal CT or MRI. Partially exophytic renal masses can push the capsule externally (T1a, T1b, or T2; Fig 2) or invade through the capsule (T3a; Fig 3), and the accuracy of CT for detecting invasion of the perirenal fat is poor at 32%–64% (16–18). Imaging findings associated with perirenal fat invasion include thickened perirenal fascia, perinephric fat stranding, and visualization of ill-defined margins between tumor tissue and the perinephric fat (16).

Figure 2a.

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Figure 3a.

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Perirenal fascia surrounds the perinephric fat and adrenal gland (Fig 1) and is commonly visualized on high-quality renal CT and MR images as a thin linear band. Renal tumors that contact or push the perirenal fascia externally (T1-T3), especially large tumors (Fig 4), can be difficult to differentiate from tumors that invade through the perirenal fascia (T4), unless there is obvious invasion of other organs or structures (Fig 5). Multiplanar reformatted images can be helpful for detecting invasion through the perirenal fascia, but it is sometimes surprising when a large renal mass displaces multiple structures and is ultimately found to be contained within the perirenal fascia at surgical pathologic analysis (Fig 4).

Figure 4a.

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Figure 5a.

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Appendices E1 and E2 and two structured report templates provide examples of standardized report templates designed for initial characterization, staging, and management planning for an indeterminate renal mass evaluated at renal CT or MRI, respectively. The structured report templates for CT and MRI are available at https://radreport.org/home/RPT50857 and https://radreport.org/home/RPT50856, respectively. Both the appendices and the structured report templates include information to determine the radius, exophytic or endophytic, nearness to collecting system or sinus, anterior or posterior, and location relative to polar lines (RENAL) nephrometry score, for surgical risk planning as described in more detail further in the article, and the MRI report template includes necessary information to determine the clear cell likelihood score, which is helpful for categorizing tumor histology and for management planning (5,19).

Surgery for Localized RCC

Renal CT or MRI results guide the decision process, including the choice of intervention and the specific surgical approach. Patient factors (age, health, and comorbidities) and tumor factors (size, location, and boundaries) are also important in surgical decision making. For most clinical T1 tumors (≤7 cm), partial nephrectomy offers an excellent chance of cure with often limited impact on renal function. When the perceived oncologic risk is low and the kidney has adequate function, partial nephrectomy is the preferred strategy, if technically feasible (6). Careful review of renal CT or MRI studies before surgery allows the surgeon to consider the operative approach, whether it be open or minimally invasive. The robotic-assisted laparoscopic approach has largely revolutionized the field and is used in the majority of cases in the United States. Whether performed open or by using a minimally invasive technique, other technical adjuncts may be used during partial nephrectomy. Intraoperatively, US can help identify the boundaries of the tumor before resection of the mass, particularly with endophytic tumors (Fig 6) (20). Indocyanine green with near-infrared fluorescence is another adjunct to partial nephrectomy that may assist in the identification of tumor margin and/or arterial supply for selective clamping. In clinical practice, indigo carmine or sodium fluorescein, which is excreted into the urinary collecting system, can be used to identify collecting system injury. Finally, most tumors have a pseudocapsule, and enucleative resection can be useful to peel the mass off the adjacent parenchyma facilitating renal preservation, as a margin is not feasible when tumors abut deep hilar structures (Fig 7).

Figure 6a.

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Figure 6b.

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Figure 6c.

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Figure 7a.

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Radical nephrectomy is the operative treatment of choice for large and/or complex tumors in patients when the oncologic risks outweigh renal preservation. Although the decision about what tumor is amenable to partial nephrectomy may be surgeon specific, certain characteristics of preoperative imaging findings should be judiciously reviewed before selection of an intervention. To this end, a RENAL nephrometry score can be calculated on the basis of the radius, exophytic or endophytic properties, and anterior or posterior location of the tumor and position relative to the polar line (5). The RENAL nephrometry score has not been shown to correlate with complications after partial nephrectomy but may predict the operative approach (21). In general, renal masses with a higher RENAL nephrometry score (eg, larger, endophytic, located in the interpolar region, and in close proximity to or invading the central sinus) are more difficult to resect by partial nephrectomy and may be directed to radical nephrectomy.

Radical nephrectomy is associated with shorter operative times and lower risk of postoperative complications than partial nephrectomy. Although nephron-sparing procedures have the benefit of preserving renal function, radical nephrectomy may be preferred when preoperative imaging shows central location and large size or when tumor location and anatomy preclude partial nephrectomy, such as with certain central and/or hilar tumors. Although renal CT is usually sufficient for tumor characterization and preoperative planning, MRI may offer additional information in complex cases, for detection of subtle enhancement or confirmation of invasion of an adjacent structure. Functional assessment of renal function with renal scintigraphy (technetium 99m [^99mTc]-mercaptoacetyltriglycine [MAG3]) may also be useful when considering nephrectomy to ensure adequate function of the unaffected kidney.

When preoperative imaging or intraoperative findings are suggestive of node-positive disease, a regional lymph node dissection (LND) may be included at the time of nephrectomy, generally for prognostication (6). LND may provide staging information but has not been shown to provide a survival benefit (22). While there is minimal additional morbidity, the additional operative time and lack of clear benefit leads many surgeons to omit LND in the absence of enlarged retroperitoneal lymph nodes at renal CT or MRI.

Imaging Surveillance after Surgery

Recommendations for imaging surveillance after surgery for low- and high-risk renal tumors are included in Table 4 and are based on the American Urological Association (AUA) guidelines (23). The American College of Radiology Appropriateness Criteria indicate that renal CT or MRI or CT with intravenous contrast material is usually appropriate after radical nephrectomy or partial nephrectomy. The Society of Abdominal Radiology RCC Disease-Focused Panel recommends that the renal CT image acquisition protocol after partial nephrectomy includes precontrast imaging and nephrographic phase imaging (100–120 seconds) at 3-mm section thickness, while routine portal venous phase imaging at 3–5-mm section thickness is sufficient after radical nephrectomy, although corticomedullary phase imaging can improve detection of clear cell RCC (3).

Table 4: Imaging Surveillance of a Renal Mass according to Management Approach

The European Association of Urology (EAU) guidelines suggest less-intensive image surveillance than the AUA guidelines, with US at 6 months postoperatively for low-risk patients, followed by alternating CT of the chest and abdomen and US annually until 3 years. For intermediate- or high-risk patients, CT of the chest and abdomen at 6 months and then annually is recommended. After 3 years, the EAU guidelines suggest that all patients are recommended to undergo CT every 2 years (24).

Since publication of the EAU 2017 guidelines, a multicenter database of 1612 cases of nonmetastatic RCC demonstrated no improvement in overall survival after recurrence in patients with follow-up imaging performed more often than suggested in the EAU 2017 guidelines. For example, after 5 years of follow-up by EAU guidelines, a high-risk patient should undergo six abdominal and six chest CT examinations. This analysis found no improvement in overall survival among patients undergoing 24 or more CT examinations compared with those who underwent eight or fewer examinations (24).

Imaging outside of routine follow-up is generally triggered by a change in symptoms or laboratory values. For example, bone scans and cross-sectional brain imaging should be reserved for patients with bone pain or elevation in alkaline phosphatase levels or new neurologic symptoms, respectively (Table 4) (23). Modification of routine CT acquisitions is occasionally needed to improve diagnostic accuracy. For example, renal CT with a corticomedullary phase can be performed to detect a pseudoaneurysm, and an excretory phase can be included to differentiate a postoperative urinoma from other postoperative fluid collections (eg, seroma, hematoma, or abscess).

Image-guided Interventions for RCC

Interventional radiology is an important partner for patients with RCC, as a variety of minimally invasive image-guided procedures can be used in both localized and advanced disease.

Percutaneous Ablation

PA is a potentially curative therapeutic option for patients with T1a tumors and should be considered as an alternative approach according to recommendations from the AUA and the National Comprehensive Cancer Network (6,26). In addition, patients with larger localized tumors (>4 cm) can be considered for PA with curative intent, according to a recent position statement from the Society of Interventional Radiology (SIR) (27). SIR cites multiple case series that demonstrate PA to be both safe and efficacious in the treatment of T1b tumors, although it should be noted that rates of local tumor progression can be 3%–39% in this cohort (27,28).

The decision to proceed with PA should be made in a multidisciplinary approach while taking into consideration the patient’s preference from available options. Generally, PA is favored for poor surgical candidates, in those with compromised renal function, in those with hereditary syndromes resulting in multiple RCCs, or for patients who wish to avoid traditional surgery. The primary technical success of PA is 94%–98% for T1a tumors and 80%–97% for T1b tumors (27). Clinical outcomes such as local recurrence and cancer-specific survival are nearly identical to those seen for partial nephrectomy in patients with T1a tumors. However, PA has the advantages of lower costs, fewer complications, shorter hospital stays, and less detriment to renal function (29,30). Contraindications to PA include an uncorrectable coagulopathy, active urinary tract infection, lack of percutaneous access to the tumor, and the inability to create a safe zone of ablation owing to adjacent structures (31). In practice, adjunctive techniques such as patient repositioning, hydrodissection, pneumodissection, and pyeloperfusion allow most ablations to be performed successfully (Fig 8).

Figure 8a.

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There are a variety of ablation technologies that can be used, including radiofrequency ablation, microwave ablation, cryoablation, and irreversible electroporation, each with its own advantages and disadvantages. No convincing survival benefit exists to favor one modality over another in RCC (32). Major complications occur in 3%–6% of patients with T1a tumors after PA, with hemorrhage, hematuria, urine leak, ureteral injury, bowel injury, nerve injury, infection and/or abscess, and pneumothorax being the most frequently encountered (27). Finally, limited case series have described using PA to palliate symptoms of RCC such as pain and hematuria (33).

Imaging Surveillance after Percutaneous Ablation.—At the authors’ institution, the majority of patients are discharged the same day the procedure is performed, with an assessment in approximately 2–3 weeks in the interventional radiology ambulatory clinic. Recommendations for imaging surveillance after PA are included in Table 4 and are based on the AUA guidelines, with initial abdominal imaging at 3 and 6 months after ablation and continued annually for 5 years (23). Some interventionalists prefer to assess for complication and technical success by imaging between 1 day and 6 weeks after the procedure. Regarding imaging modalities, multiphase CT, MRI, and contrast-enhanced US can all be used to monitor the treatment area with excellent sensitivity and specificity (34). The Society of Abdominal Radiology RCC Disease-Focused Panel recommends that the renal CT image acquisition protocol for postablative indications includes precontrast imaging and nephrographic phase imaging (100–120 seconds) at 3-mm section thickness, with weight-based dosing of intravenous iodinated contrast material, although corticomedullary phase imaging can help improve detection of clear cell RCC (3,35).

After renal mass ablation, the ablated area is often hypoattenuating on noncontrast CT images relative to the surrounding renal parenchyma, with areas of internal high attenuation from hemorrhage or proteinaceous debris that can be visualized. However, there should be no central or nodular enhancement within the ablation cavity on postcontrast images

(36). Blood products or proteinaceous materials may have hyperintensity on T1- and T2-weighted images before contrast material administration (37). MRI has an added advantage of obtaining postcontrast subtracted images for better assessment of internal enhancement.

After contrast material administration, a treated RCC will not demonstrate enhancement, although many treated tumors will have an area of soft-tissue attenuation in the perinephric fat, which is thought to represent peripheral inflammation and scarring. Residual or locally recurrent tumor most often appears as an area of nodular enhancement along the periphery of the ablation zone (Fig 9). Small areas of residual or locally recurrent disease can usually be successfully treated with repeat PA. Follow-up imaging should also be carefully scrutinized for any evidence of postprocedural complications such as hemorrhage, pseudoaneurysms, ureteral injury, abscess formation, or urinary leak.

Figure 9a.

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Transarterial Embolization

Clear cell RCC, the most common histologic variant, is characterized as a hypervascular tumor at contrast-enhanced imaging. Consequently, TAE of the vessels supplying the tumor could be used as an adjunctive technique or stand-alone therapy. As an adjunctive technique before partial nephrectomy, one study compared patients that underwent TAE to a group of matched patients who did not undergo TAE, reporting survival benefits at both 5 and 10 years in the TAE cohort (38). On the other hand, a later propensity score–matching analysis failed to show any benefits of preoperative TAE in overall survival, cancer-specific survival, complications, or intraoperative blood loss (39). Similarly, investigations into the role of TAE before PA have shown mixed results (Fig 10). One study found a reduction in hemorrhagic complications after renal cryoablation in tumors larger than 5 cm for patients who underwent preprocedural TAE (40). Yet, a subsequent propensity score–matching analysis that included patients with any tumor size failed to demonstrate any significant improvements in technical success, complications, blood loss, or local recurrence (41). Certainly, further work is needed to investigate TAE as an adjunctive technique in RCC to identify objective outcome improvements and assist in patient selection.

Figure 10a.

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TAE may also have a role in patients with advanced RCC. For example, one study reported that 13% of patients with metastatic RCC experienced a regression of metastatic lesions after TAE of the primary mass, suggesting an abscopal effect (42). A more recent analysis compared the overall survival of patients with metastatic RCC who underwent TAE of the primary renal mass to that of matched patients who did not receive TAE (43). After TAE, patients had a longer mean overall survival (229 vs 116 days) and higher rates of overall survival at 1 (29% vs 13%), 2 (15% vs 7%), and 3 (10% vs 3%) years (42). Apart from any oncologic benefits, TAE has been shown to improve symptoms in patients with advanced RCC, including pain and hematuria. One case series (n = 73) demonstrated an elimination of hematuria and pain in 100% and 72% of patients with advanced RCC, respectively, after TAE of the primary mass (44). Moreover, a smaller series of patients with inoperable RCC (n = 25) found that 68% of patients reported a reduction in pain and/or hematuria after TAE of the primary mass (45). Finally, two early reports have described the intra-arterial delivery of either chemotherapy or yttrium-90 (⁹⁰Y) as a stand-alone therapy for RCC, although the data are too early to integrate into routine clinical practice (46,47).

Imaging surveillance after TAE is variable and is dependent on the main purpose. For example, if TAE precedes PA, then imaging surveillance would follow recommendations for PA (Table 4). Conversely, if TAE is used in the management of advanced cancer, then imaging surveillance would follow recommendations for systemic therapy (Table 4).

Active Surveillance of Small Renal Masses

The majority of small renal masses will ultimately be found to be benign or have fairly indolent potential (48).

AS has become a great option for patients with small tumors (<3 cm) or slow-growing tumors (<5 mm per year) who are older or have a life expectancy of less than 5 years, have high comorbidities, have excessive perioperative risk, have poor renal function, or who prefer to avoid the risks of other treatments

The risk of requiring delayed intervention is low and the rate of metastases remains low for lesions smaller than 4 cm (49). Imaging recommendations for patients undergoing AS are included in Table 4 and are based on the AUA guidelines (23). Baseline contrast-enhanced renal CT or MRI is essential and must completely evaluate the tumor itself and identify regional or distant metastasis. For all patients undergoing AS, repeating imaging within the first 6 months is recommended with renal CT, MRI, or contrast-enhanced US to assess any interval growth (6,16,23). The Society of Abdominal Radiology RCC Disease-Focused Panel recommends that the renal CT image acquisition protocol for AS includes precontrast imaging and nephrographic phase imaging (100–120 seconds) at 3-mm section thickness (3). Follow-up imaging should be performed with the same modality to minimize issues with measurement. After this initial period, the AUA recommends that renal CT, MRI, or contrast-enhanced US be repeated annually, although the interval of examinations may decrease as long as the lesion is growing at an acceptable rate (<5 mm per year) (6).

Most renal lesions will grow over time, although there is wide variability in tumor growth rates, and the rate of growth may not accurately predict adverse pathology or metastatic potential (16,50,51). However, in the absence of better surrogates, prompts to initiate an invasive treatment in a patient undergoing AS include tumor size (3 or 4 cm, depending on the treatment center preference), progression of stage, rapid growth (>5 mm per year), or patient anxiety and/or preference (6). Renal mass biopsy is not required for safe AS but can be performed before an AS program or can be offered after growth if the results will affect decision making (6). Patients with renal tumors that are larger than those observed with AS can consider this management strategy if the treatment risks outweigh the benefit or if the patient is willing to accept the associated risks. Of note, large lesions grow at a more rapid growth than their smaller counterparts (52). Patients at high risk who are undergoing AS may need increased monitoring to evaluate for dissemination or local invasion.

SBRT for RCC

RCC has traditionally been regarded as having a radioresistant histology. With the advent of advanced technology and the experience with SBRT, also called stereotactic ablative radiation therapy, for primary and metastatic tumors in the lung, liver, and spine, there is emerging use of SBRT for primary and metastatic RCC. SBRT is a noninvasive technique characterized by high-precision delivery of ablative therapeutic radiation, either delivered in a single or a few outpatient treatment sessions, with single fraction associated with better progression-free and cancer-free survival (53). SBRT is typically recommended for patients who are poor surgical candidates and tumors that are not suitable for ablation (54). The practical aspects of performing SBRT for primary RCC are described in the International Radiosurgery Oncology Consortium for Kidney consensus statement (55).

Phase I trials have demonstrated safety with SBRT for primary RCC (56,57). A subsequent pooled analysis study of 223 patients treated with SBRT for RCC showed an excellent local control rate of over 95%, with minimal toxic effects (53). In a pooled analysis, patients with primary RCC in a solitary kidney appeared to have similar outcomes compared with patients with RCC with bilateral kidneys (58).

A select group of patients with limited metastases or oligometastases may also benefit from metastasis-directed SBRT. A recent randomized phase II trial (SABR-COMET [The Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastases]) comparing standard therapy and SBRT for patients with one to five metastases from a variety of histologies showed that SBRT improved progression-free and overall survival (59). SBRT has been applied to patients with oligometastatic RCC with promising outcomes in terms of local control and toxic effects. A meta-analysis of 28 studies of oligometastatic RCC showed promising results, but further research can better define the role of SBRT in the setting of RCC (60).

Imaging after SBRT

The optimal method of imaging response assessment after SBRT for treatment of primary RCC has not been established, although renal CT or MRI studies without and with intravenous contrast material are probably the best options. While local control is currently determined with CT and size-based criteria such as Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, size-based tumor assessments have significant limitations. Tumor growth and local failure are rare after SBRT, and the determinants of treatment success, such as tumor shrinkage, may require years to observe (53).

Progressive tumor shrinkage over the course of years after delivery of SBRT has been consistently observed across studies (56,57). Therefore, persistent renal masses are a normal finding after SBRT, and RECIST 1.1 complete response is a rare occurrence (Fig 11). A further issue with size-based response assessment is the phenomenon of early pseudoprogression after SBRT. A repeatedly observed phenomenon in RCC is initial size increase that may be misinterpreted as disease progression but may actually be due to treatment-induced inflammation (Fig 12) (61). This typically plateaus and subsequently gives way to tumor shrinkage. To account for this, some prospective clinical trials, such as the TransTasman Radiation Oncology Group FASTRACK (Focal Ablative STereotactic Radiosurgery for Cancers of the Kidney) II study, do not perform CT-based tumor size assessment until after 6 months after SBRT (62).

Figure 11a.

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Figure 12a.

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Assessment of CT-based contrast enhancement characteristics is also not indicative of treatment success in SBRT kidney. Decreased contrast enhancement is not always seen with SBRT, and thus ongoing enhancement, even increased enhancement in some cases, can be misinterpreted as persistent or recurrent disease, although no correlation with local failure has been observed (63). This is likely attributable to the differences in mechanisms of action. SBRT sterilizes tumors by DNA damage and invokes tumor cell killing that progressively and slowly destroys the tumor, as compared with the immediate physical destruction of tumor and vascular architecture through ablative technologies. Thus, there is a pressing clinical need for a more effective imaging biomarker of treatment response than conventional CT after SBRT for primary RCC.

Currently novel imaging methods such as dynamic contrast enhancement (DCE) at MRI and prostate-specific membrane antigen (PSMA)–based PET are under investigation for treatment response assessment. Some DCE parameters appear to correlate with long-term tumor shrinkage at conventional imaging (64). New evidence also exists for the use of PSMA-based PET in metastatic RCC (65). PSMA is highly expressed in RCC neovasculature, and thus, PSMA-targeted radiotracers are effective for identifying RCC metastases and assessing response after SBRT, although this property may be confounded by the intrinsic activity in normal renal parenchyma where the tracer is excreted. While both of these imaging modalities are promising, more data are required before these approaches can be used routinely in clinical practice.

Systemic Therapy for Advanced RCC

The 5-year survival rate among patients with kidney cancer has increased steadily over the past 30 years, attributable to early detection of low-stage tumors and more effective systemic therapy for advanced-stage disease. One-third of patients with kidney cancer are diagnosed with regional or distant metastases, and approximately one-fourth of patients with localized RCC treated surgically with curative intent will relapse with distant metastases (66).

Systemic therapy for advanced RCC has expanded tremendously over the past 15 years (Table E1). All target agents (antiangiogenic, mechanistic target of rapamycin inhibitors, and immunotherapy agents) approved for metastatic kidney cancer have been shown to improve progression-free survival (PFS) or overall survival (67). Each class of drugs, from cytokines to targeted agents to checkpoint inhibitors, have unique toxic effects that may be detected at imaging (Table 5) and that require close monitoring by treating physicians, often resulting in dose adjustments or discontinuation of therapy (68–70). Common complications from targeted agents used to treat advanced RCC that can be identified on images include pleural effusion, pneumonitis, pulmonary fibrosis, thromboembolic events, ascites, enteritis, colitis, and pneumatosis.

Table 5: Common and Uncommon Toxic Effects of Targeted and Immunotherapy Agents for Advanced RCC, with Radiologic Implications

Ongoing trials are evaluating newer combinations of approved agents and newer agents in the treatment in advanced RCC. The challenge facing treating physicians is identifying which agent or agents to use in which setting for their patients with metastatic RCC. Ongoing research evaluating biomarkers as predictors of response should allow more refined treatment choices (71,72).

Imaging Biomarkers for Predicting Advanced RCC Response

The introduction of targeted agents and immunotherapy to the management of metastatic RCC has offered significant benefits in overall survival and prognosis. However, not all patients respond equally to targeted agents and immunotherapy, and several imaging biomarkers and response evaluation criteria have been proposed to predict response, or efficacy.

The RECIST 1.1 criteria, which are based on tumor size changes, are the most commonly used response evaluation method within RCC clinical trials, despite known limitations in the context of novel systemic agents and locally ablative treatment modalities. These limitations have resulted in the suggestion of lower thresholds of either a 10% or 20% change in measured long-axis diameter as a more sensitive method for response evaluation, and recent studies have shown that incorporating tumor attenuation and morphologic features can improve the predictive accuracy of response evaluation in patients with metastatic RCC treated with antiangiogenic therapy. For example, Morphology, Attenuation, Size, and Structure (MASS) Criteria objective response categories incorporate changes in tumor size, tumor attenuation (enhancement), and tumor necrosis and are predictive of PFS in patients with metastatic RCC treated with antiangiogenic therapy (74).

Vascular tumor burden (VTB) is an example of a quantitative CT biomarker to monitor response of metastatic RCC to antiangiogenic agents. VTB is defined as the amount of vascularized tumor within a two-dimensional region of interest on axial CT images and is designed to quantify tumor devascularization in patients who underwent treatment with antiangiogenic therapy (71). By using images and data from a multinational phase III clinical trial, changes in VTB at initial CT performed after therapy were highly predictive of PFS and overall survival in patients with RCC treated with sunitinib antiangiogenic therapy (Fig 13) and were a better predictor of PFS than RECIST 1.1, 10% Tumor Diameter criteria, Choi criteria, modified Choi criteria, and MASS criteria (74). The generalizability of VTB criteria to other targeted agents is under investigation.

Figure 13a.

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The ideal imaging biomarker would capture the main effect of a therapy, be predictive of PFS, and be widely available, widely applicable, amenable to high throughput, inexpensive, and highly reproducible across multiple institutions and readers (72,74). Multiple additional predictive imaging biomarkers have been evaluated in the context of small single-center patient cohorts, but none are ideal biomarkers and most lack multi-institutional validation.

Conclusion

The treatment options for localized and advanced RCC continue to expand and improve patient care, and the radiologist’s understanding of the role of imaging in helping select the best treatment options and evaluating response have increased in complexity. This article provides a multidisciplinary overview of the role of advanced medical imaging in the characterization of the indeterminate renal mass, RCC staging, and management of localized RCC by surgery, PA, TAE, AS, and SBRT, as well as the role of imaging in evaluation of advanced RCC response to targeted therapy and immunotherapy.