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1387

GENITOURINARY IMAGING
Role of Imaging in Renal Cell Carci-
noma: A Multidisciplinary Perspective

Asser M. Abou Elkassem, MD

Simon S. Lo, MD With the expansion in cross-sectional imaging over the past few
Andrew J. Gunn, MD decades, there has been an increase in the number of incidentally
Brian M. Shuch, MD detected renal masses and an increase in the incidence of renal cell
Molly E. Dewitt-Foy, MD carcinomas (RCCs). The complete characterization of an indeter-
Robert Abouassaly, MD, MSc minate renal mass on CT or MR images is challenging, and the
Sandeep S.Vaidya, MD authors provide a critical review of the best imaging methods and
Joseph I. Clark, MD essential, important, and optional reporting elements used to de-
Alexander V. Louie, MD, PhD scribe the indeterminate renal mass. While surgical staging remains
Shankar Siva, MD, PhD the standard of care for RCC, the role of renal mass CT or MRI
Anca-Ligia Grosu, MD
in staging RCC is reviewed, specifically with reference to areas
Andrew D. Smith, MD, PhD
that may be overlooked at imaging such as detection of invasion
through the renal capsule or perirenal (Gerota) fascia. Treatment
Abbreviations: AJCC = American Joint Com-
mission on Cancer, AS = active surveillance, options for localized RCC are expanding, and a multidisciplinary
AUA = American Urological Association, EAU = group of experts presents an overview of the role of advanced
European Association of Urology, PA = percuta-
neous ablation, PFS = progression-free survival,
medical imaging in surgery, percutaneous ablation, transarterial
RCC = renal cell carcinoma, RENAL = radius, embolization, active surveillance, and stereotactic body radiation
exophytic or endophytic, nearness to collecting therapy. Finally, the arsenal of treatments for advanced renal can-
system or sinus, anterior or posterior, and loca-
tion relative to polar lines, SBRT = stereotactic cer continues to grow to improve response to therapy while limit-
body radiation therapy, TAE = transarterial em- ing treatment side effects. Imaging findings are important in decid-
bolization, VTB = vascular tumor burden
ing the best treatment options and to monitor response to therapy.
RadioGraphics 2021; 41:1387–1407 However, evaluating response has increased in complexity. The
https://doi.org/10.1148/rg.2021200202 unique imaging findings associated with antiangiogenic targeted
Content Codes: therapy and immunotherapy are discussed.
From the Department of Radiology, University An invited commentary by Remer is available online.
of Alabama at Birmingham, 619 19th St S, JTN
452, Birmingham, AL 35249-6830 (A.M.A.E.,
Online supplemental material is available for this article.
A.J.G., A.D.S.); Department of Radiation On- ©
cology (S.S.L.) and Department of Radiology RSNA, 2021 • radiographics.rsna.org
(S.S.V.), University of Washington School of
Medicine, Seattle, Wash; Department of Urol-
ogy, UCLA Medical Center, Santa Monica, Ca-
lif (B.M.S.); Department of Urology, Cleveland
Clinic Foundation, Cleveland, Ohio (M.E.D.F., SA-CME LEARNING OBJECTIVES
R.A.); Division of Hematology/Oncology, De-
partment of Internal Medicine, Loyola Univer- After completing this journal-based SA-CME activity, participants will be able to:
sity Medical Center, Maywood, Ill (J.I.C.); De-
„ Describe essential, important, and optional reporting elements used to characterize
partment of Radiation Oncology, Sunnybrook
Health Science Centre, University of Toronto, an indeterminate renal mass.
Toronto, Ontario, Canada (A.V.L.); Division of „ Discuss the role of advanced medical imaging in surgery, PA, TAE, AS, and SBRT
Radiation Oncology, Peter MacCallum Cancer for the management of RCC.
Centre, University of Melbourne, Parkville, Vic-
toria, Australia (S.S.); and Department of Radia- „ Review imaging findings associated with treatment of advanced RCC with antian-
tion Oncology, University of Freiburg, Freiburg, giogenic therapy or immunotherapy.
Germany (A.L.G.). Presented as an education
exhibit at the 2019 RSNA Annual Meeting. See rsna.org/learning-center-rg.
Received October 9, 2020; revision requested
November 25 and received January 19, 2021;
accepted January 25. For this journal-based SA-
CME activity, the authors S.S.L., A.J.G, J.I.C.,
A.V.L., S.S., and A.D.S. have provided disclo- Introduction
sures (see end of article); all other authors, the Imaging has a crucial role in patients with renal cell carcinoma (RCC)
editor, and the reviewers have disclosed no rele-
vant relationships. Address correspondence to
for diagnosis, characterization, staging, treatment guidance, and post-
A.D.S. (e-mail: [email protected]). treatment evaluation. We provide a multidisciplinary overview of the
©
RSNA, 2021 role of imaging for surgery, percutaneous ablation (PA), transarterial
embolization (TAE), active surveillance (AS), stereotactic body radia-
An earlier incorrect version of this article ap- tion therapy (SBRT), and the evaluation of advanced RCC response
peared online. This article was corrected on after antiangiogenic target therapy or immunotherapy.
July 21, 2021.
1388 September-October 2021 radiographics.rsna.org

of renal mass CT or MRI is to characterize the

TEACHING POINTS renal mass and obtain information to assist with
„ In patients with normal renal function, the most appropriate
management. Up to 20% of indeterminate solid
imaging modality to fully characterize an indeterminate renal
mass is renal CT or MRI without and with intravenous contrast
renal masses are ultimately found to be benign,
material. with an increased incidence of benignity in small
„ There has been interspecialty consensus between radiologists (<4 cm) renal masses (1,2).
and urologists that the following imaging features are essen- Table 1 lists essential, important, and optional
tial reporting elements: tumor size, presence or absence of reporting elements used to describe the indeter-
macroscopic fat, tumor characterization as solid or cystic, and minate renal mass. There has been interspecialty
tumor enhancement.
consensus between radiologists and urologists
„ The main strengths of imaging for clinical staging are its non-
that the following imaging features are essential
invasive nature, the wide availability of CT and MRI, the ability
to measure tumor size, the detailed visualization of most of
reporting elements: tumor size, presence or ab-
the critical landmarks for T staging, and the ability to aid in sence of macroscopic fat, tumor characterization
the detection of pathologic lymph nodes, venous invasion, as solid or cystic, and tumor enhancement (4,8).
and distant metastases. The size of the mass should be reported in three
„ After renal mass ablation, the ablated area is often hypoat- orthogonal dimensions at initial imaging to pro-
tenuating on noncontrast CT images relative to the surround- vide information for tumor stage and direct man-
ing renal parenchyma, with areas of internal high attenuation
agement, and follow-up imaging should compare
from hemorrhage or proteinaceous debris that can be visu-
alized. However, there should be no central or nodular en- longest dimension length to that on the immedi-
hancement within the ablation cavity on postcontrast images. ate prior and oldest comparable examinations.
„ AS has become a great option for patients with small tumors The presence of macroscopic fat in a renal
(<3 cm) or slow-growing tumors (<5 mm per year) who are mass, particularly in the absence of calcifica-
older or have a life expectancy of less than 5 years, have high tion, is characteristic of an angiomyolipoma, a
comorbidities, have excessive perioperative risk, have poor benign renal mass. Macroscopic fat at CT is best
renal function, or who prefer to avoid the risks of other treat-
ments.
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
Image Evaluation of the mass that shows signal intensity loss after applica-
Indeterminate Renal Mass tion of fat suppression (not to be confused with
An indeterminate renal mass is any renal mass signal loss comparing opposed-phase to in-phase
that cannot be diagnosed as benign or malignant dual-echo T1-weighted images) or as linear or
at the time of discovery. In patients with normal curvilinear chemical shift artifact of the second
renal function, the most appropriate imaging kind causing India ink (etching) artifact within
modality to fully characterize an indeterminate or at the periphery of the mass, while the central
renal mass is renal CT or MRI, without and with portion of the mass matches the signal intensity
intravenous contrast material (1,2). The Society of subcutaneous or visceral fat (10). Conversely,
of Abdominal Radiology RCC Disease-Focused microscopic fat on MR images is characterized
Panel recommends that the renal CT image ac- by signal loss on the opposed-phase images com-
quisition protocol includes precontrast (obtained pared with the in-phase dual-echo T1-weighted
before the administration of contrast material) images and is not specific to fat-poor angiomyoli-
imaging and nephrographic phase imaging pomas and can be found in some RCC subtypes,
(100–120 seconds) at 3-mm section thickness most commonly clear cell RCC but occasionally
with weight-based dosing of intravenous iodin- papillary RCC (10,11).
ated contrast material, with optional imaging in Cystic renal masses, defined as a renal mass
the corticomedullary phase (40–70 seconds) and/ with greater than 75% nonenhancing compo-
or excretory phase (7–10 min) (3). The excretory nents, are less likely to be malignant than are
phase is recommended if the imaging is per- solid renal masses, and malignant cystic re-
formed for preprocedural planning (3). nal masses are less aggressive than malignant
The renal MRI acquisition protocol should solid renal masses (10,12). Cystic renal masses
include axial or coronal two-dimensional (2D) evaluated at renal CT or MRI without and with
T2-weighted images, axial 2D T1-weighted in- intravenous contrast material should be further
and out-of-phase images, axial and/or coronal categorized by the Bosniak classification system,
three-dimensional T1-weighted fat-saturated version 2019 to improve the clarity of radiology
pre- and postcontrast (obtained after the admin- reporting and stratify the risk of malignancy (10).
istration of contrast material) images, and axial The majority of urologists prefer quantitative
diffusion-weighted images for complete char- information on enhancement (eg, Hounsfield
acterization of a renal mass (4). The purpose unit measurements in the noncontrast and each
RG • Volume 41 Number 5 Abou Elkassem et al 1389

Table 1: Reporting Elements for Indeterminate Renal Masses

Reporting Elements Guidance Importance

Basic Characteristics
Size Provide three orthogonal dimensions Essential
Mass type Describe solid vs cystic Essential
Macroscopic fat Describe present vs absent Essential
Enhancement Provide quantitative numbers Essential
Laterality Describe right vs left Important
Change in size over time Describe change in size from most recent and oldest examinations Important
Bosniak classification Provide specific category Important
Margins Describe >90% well-marginated vs infiltrative Important
Necrosis Provide estimated percentage Optional
MRI microscopic fat Describe present vs absent Optional
MRI signal characteristics Describe signal characteristics Optional
Location
Capsular location Describe endophytic, <50% exophytic, or >50% exophytic Important
Polar location Describe upper vs lower Important
Polar extent Describe 100% polar, >50% polar, or <50% polar Important
Axial location Describe anterior vs posterior Important
Distance to sinus fat Provide distance measurement Important
Detailed axial location Provide more detail for interventional planning Optional
Invasiveness
Collecting system Describe no invasion or invasion Important
Perirenal fat Describe no invasion or invasion Important
Perirenal fascia Describe no contact, contact, or invasion Important
Adjacent organs Describe no contact, contact, or invasion Important
Vascular
Venous thrombus Describe present vs absent; give detail on anatomic extent Important
Venous anatomy Describe major ipsilateral veins Optional
Arterial anatomy Describe major ipsilateral arteries and identify early branches Optional
Other
RENAL Nephrometry Score (5) Provide details and final score Optional
Clear cell likelihood score Provide T2-weighted imaging and enhancement characteristics Optional
Favored histology Provide likelihood of favored histology Optional
Follow-up recommendations Use AUA guidelines (6) Optional
Source.—Reference 7. Definitions of terms are described in more detail in reference 7.
Note.—AUA = American Urological Association, RENAL = radius, exophytic or endophytic, nearness to collect-
ing system or sinus, anterior or posterior, and location relative to polar lines.

contrast-enhanced phase) rather than simply change in signal intensity between pre- and
reporting the presence or absence of enhance- postcontrast T1-weighted images or subjective
ment (8). Enhancement at CT is classically definitive enhancement on subtraction images.
determined by an increase of 20 HU or more
between noncontrast and contrast-enhanced Staging of RCC
phases obtained at 120 kVp, with an increase of The staging system most commonly used for
10–19 HU considered indeterminate (9). The kidney cancer is the American Joint Commission
role of dual-energy and spectral CT and iodine on Cancer (AJCC) TNM system (Tables 2, 3)
quantification to characterize renal masses is (15). Clinical staging includes physical examina-
growing, although the need and best method tion, biopsy, and imaging findings, although the
for incorporation of dual-energy or spectral final stage is determined by surgical staging (also
CT techniques into a renal mass CT proto- referred to as pathologic staging).
col remain unclear (13,14). By comparison, The main strengths of imaging for clini-
MRI is more sensitive than CT for detection cal staging are its noninvasive nature, the wide
of enhancement, defined as a greater than 15% availability of CT and MRI, the ability to
1390 September-October 2021 radiographics.rsna.org

Table 2: AJCC TNM Staging System

Category Definition
Tumor
Tx Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Primary tumor is ≤7 cm in greatest dimension and confined within the renal capsule
T1a Primary tumor is ≤4 cm in greatest dimension and confined within the renal capsule
T1b Primary tumor is >4 but ≤7 cm in greatest dimension and confined within the renal capsule
T2 Primary tumor is >7 cm in greatest dimension and confined within the renal capsule
T2a Primary tumor is >7 cm but ≤10 cm in greatest dimension and confined within the renal capsule
T2b Primary tumor is >10 cm in greatest dimension and confined within the renal capsule
T3 Primary tumor extends into major veins or perinephric tissues but not into the ipsilateral adrenal
gland and not beyond the perirenal (Gerota) fascia
T3a Primary tumor extends into the renal vein, renal sinus fat, and renal capsule but not beyond the
perirenal (Gerota) fascia
T3b Primary tumor invades the IVC below the diaphragm
T3c Primary tumor invades the IVC above the diaphragm
T4 Primary tumor invades beyond the perirenal (Gerota) fascia or invades the ipsilateral adrenal gland
Lymph nodes
Nx Lymph nodes cannot be assessed
N0 No regional (retroperitoneal) lymph node metastasis
N1 Regional (retroperitoneal) lymph node metastasis
Distant metastasis
M0 No distant metastasis
M1 Distant lymph node or other metastasis, including noncontinuous adrenal involvement
Source.—Reference 15.
Note.—AJCC = American Joint Committee on Cancer, IVC = inferior vena cava.

measure tumor size, the detailed visualization of Table 3: Stage Groups for the AJCC TNM Stag-
most of the critical landmarks for T staging, and ing System
the ability to aid in the detection of pathologic
lymph nodes, venous invasion, and distant me- Stage Tumor Node Metastasis
tastases (Fig 1). The major limitation of imaging Stage 1 T1a or T1b N0 M0
for clinical staging of RCC is the limited ability Stage 2 T2a or T2b N2 M0
to aid in the detection of invasion of important Stage 3 T1a–3c N1 M0
landmarks, including the renal capsule or perire- T3a–3c Nx or N0 M0
nal (Gerota) fascia, and a minor limitation is the Stage 4 T4 Any N M0
requirement for the use of and risks of intrave- Any T Any N M1
nous contrast material. Source.—Reference 15.
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 exter- or push the perirenal fascia externally (T1-T3),
nally (T1a, T1b, or T2; Fig 2) or invade through especially large tumors (Fig 4), can be difficult to
the capsule (T3a; Fig 3), and the accuracy of CT differentiate from tumors that invade through the
for detecting invasion of the perirenal fat is poor perirenal fascia (T4), unless there is obvious inva-
at 32%–64% (16–18). Imaging findings associ- sion of other organs or structures (Fig 5). Mul-
ated with perirenal fat invasion include thickened tiplanar reformatted images can be helpful for
perirenal fascia, perinephric fat stranding, and detecting invasion through the perirenal fascia,
visualization of ill-defined margins between tumor but it is sometimes surprising when a large renal
tissue and the perinephric fat (16). mass displaces multiple structures and is ulti-
Perirenal fascia surrounds the perinephric fat mately found to be contained within the perirenal
and adrenal gland (Fig 1) and is commonly visu- fascia at surgical pathologic analysis (Fig 4).
alized on high-quality renal CT and MR images Appendices E1 and E2 and two structured
as a thin linear band. Renal tumors that contact report templates provide examples of standard-
RG • Volume 41 Number 5 Abou Elkassem et al 1391

Figure 1. Illustrations depict the AJCC TNM staging system for renal cell carcinoma (RCC) (orange areas). Ao = aorta, IVC = inferior
vena cava. T1a (≤4 cm) and T1b (>4 but ≤7 cm) tumors, A, and T2 (>7 cm) tumors, B, are confined within the renal capsule. T3a
tumors are defined by invasion of the renal sinus fat, C, invasion through the renal capsule into perirenal fat but not beyond perirenal
(Gerota) fascia, D, or invasion of the renal vein, E. T3b tumors invade the vena cava below the diaphragm, F. T3c tumors invade the
vena cava above the diaphragm, G, or the wall of the vena cava (not shown). T4 tumors invade beyond the perirenal (Gerota) fascia,
H, or invade the ipsilateral adrenal gland, I.

ized report templates designed for initial charac- nephrometry score, for surgical risk planning as
terization, staging, and management planning for described in more detail further in the article,
an indeterminate renal mass evaluated at renal and the MRI report template includes necessary
CT or MRI, respectively. The structured report information to determine the clear cell likelihood
templates for CT and MRI are available at score, which is helpful for categorizing tumor
https://radreport.org/home/RPT50857 and https:// histology and for management planning (5,19).
radreport.org/home/RPT50856, respectively. Both
the appendices and the structured report tem- Surgery for Localized RCC
plates include information to determine the Renal CT or MRI results guide the decision pro-
radius, exophytic or endophytic, nearness to cess, including the choice of intervention and the
collecting system or sinus, anterior or posterior, specific surgical approach. Patient factors (age,
and location relative to polar lines (RENAL) health, and comorbidities) and tumor factors
1392 September-October 2021 radiographics.rsna.org

Figure 2. Evaluation of capsular involve-

ment at renal CT in a 54-year-old man.
Axial (a) and coronal (b) images obtained
during the nephrographic phase show a
right-sided less than 50% exophytic 3.5-
cm clear cell RCC (categorized as T1a at
surgical pathologic analysis). The renal
capsule was intact at surgical pathologic
analysis but cannot be visualized on the
CT images. The smooth margins of the
tumor (arrow) suggest that the renal cap-
sule is intact.

Figure 3. Evaluation of perirenal fat invasion at renal CT in a 62-year-old woman. Axial (a)
and coronal (b) images obtained during the corticomedullary phase show a right-sided greater
than 50% exophytic 4.5-cm clear cell RCC (categorized as T3a at surgical pathologic analysis).
The tumor (*) has irregular margins, and there is thickening of the perirenal fascia (arrow).
Imaging findings associated with perirenal fat invasion include thickened perirenal fascia, peri-
nephric fat stranding, and visualization of ill-defined margins between tumor tissue and the
perinephric fat.

(size, location, and boundaries) are also impor- the identification of tumor margin and/or arterial
tant in surgical decision making. For most clinical supply for selective clamping. In clinical practice,
T1 tumors (≤7 cm), partial nephrectomy offers indigo carmine or sodium fluorescein, which
an excellent chance of cure with often limited is excreted into the urinary collecting system,
impact on renal function. When the perceived can be used to identify collecting system injury.
oncologic risk is low and the kidney has adequate Finally, most tumors have a pseudocapsule, and
function, partial nephrectomy is the preferred enucleative resection can be useful to peel the
strategy, if technically feasible (6). Careful review mass off the adjacent parenchyma facilitating re-
of renal CT or MRI studies before surgery allows nal preservation, as a margin is not feasible when
the surgeon to consider the operative approach, tumors abut deep hilar structures (Fig 7).
whether it be open or minimally invasive. The Radical nephrectomy is the operative treat-
robotic-assisted laparoscopic approach has ment of choice for large and/or complex tumors in
largely revolutionized the field and is used in the patients when the oncologic risks outweigh renal
majority of cases in the United States. Whether preservation. Although the decision about what
performed open or by using a minimally invasive tumor is amenable to partial nephrectomy may be
technique, other technical adjuncts may be used surgeon specific, certain characteristics of pre-
during partial nephrectomy. Intraoperatively, US operative imaging findings should be judiciously
can help identify the boundaries of the tumor reviewed before selection of an intervention. To
before resection of the mass, particularly with this end, a RENAL nephrometry score can be
endophytic tumors (Fig 6) (20). Indocyanine calculated on the basis of the radius, exophytic or
green with near-infrared fluorescence is another endophytic properties, and anterior or posterior
adjunct to partial nephrectomy that may assist in location of the tumor and position relative to the
RG • Volume 41 Number 5 Abou Elkassem et al 1393

Figure 4. Tumor invasion into

the perirenal fat and renal vein in
a 67-year-old man. Axial (a) and
coronal (b) renal CT images ob-
tained during the nephrographic
phase show a 10-cm partially calci-
fied left-sided clear cell RCC (cat-
egorized as T3a at surgical patho-
logic analysis) . The tumor invades
the perirenal fat and contacts but
does not invade through the peri-
renal (Gerota) fascia. The tumor
also invades the left renal vein (*
in a), a definitive sign of at least a
T3a tumor.

Figure 5. Tumor invasion into adjacent organs in a 57-year-old man. Axial (a) and coronal (b) renal CT
images obtained during the corticomedullary phase show a right-sided clear cell RCC that invades the
renal vein and subdiaphragmatic inferior vena cava, invades through the perirenal (Gerota) fascia into the
liver, and invades (obliterates) the ipsilateral adrenal gland (categorized as T4 at imaging). The invasion of
both the liver and the ipsilateral adrenal gland can be used to stage this tumor as T4.

Figure 6. Intraoperative US to guide surgical decisions in a 46-year-old man with a 4.5-cm endophytic left-sided papillary RCC (cat-
egorized as T1b at surgical pathologic analysis). (a) Axial contrast-enhanced CT image shows the predominantly endophytic nature
of a hypoenhancing mass (*), which was used to guide the decision to proceed with a partial nephrectomy. (b) Intraoperative US
image shows an intact renal capsule (arrow). (c) Intraoperative photograph shows scoring of the renal capsule at a safe location that
avoids violating the tumor.

polar line (5). The RENAL nephrometry score has tive approach (21). In general, renal masses with
not been shown to correlate with complications af- a higher RENAL nephrometry score (eg, larger,
ter partial nephrectomy but may predict the opera- endophytic, located in the interpolar region, and
1394 September-October 2021 radiographics.rsna.org

Figure 7. Partial nephrectomy for a renal mass (categorized as T3a) in a 58-year-old woman with a 4.2-cm right-sided papillary
RCC. (a) Axial contrast-enhanced CT image shows the tumor (T) invading the sinus fat and contacting a hilar artery (categorized as
T3a at imaging and surgical pathologic analysis). (b) Intraoperative photograph shows the tumor (T) abutting the clamped renal
artery (RA) and the renal vein (RV). (c) Explant photograph of the dissected and cleaned tumor shows an intact pseudocapsule.

in close proximity to or invading the central sinus) (23). The American College of Radiology Ap-
are more difficult to resect by partial nephrectomy propriateness Criteria indicate that renal CT or
and may be directed to radical nephrectomy. MRI or CT with intravenous contrast material
Radical nephrectomy is associated with shorter is usually appropriate after radical nephrectomy
operative times and lower risk of postoperative or partial nephrectomy. The Society of Abdomi-
complications than partial nephrectomy. Although nal Radiology RCC Disease-Focused Panel
nephron-sparing procedures have the benefit of recommends that the renal CT image acquisi-
preserving renal function, radical nephrectomy tion protocol after partial nephrectomy includes
may be preferred when preoperative imaging precontrast imaging and nephrographic phase
shows central location and large size or when imaging (100–120 seconds) at 3-mm section
tumor location and anatomy preclude partial thickness, while routine portal venous phase im-
nephrectomy, such as with certain central and/or aging at 3–5-mm section thickness is sufficient
hilar tumors. Although renal CT is usually suf- after radical nephrectomy, although corticome-
ficient for tumor characterization and preoperative dullary phase imaging can improve detection of
planning, MRI may offer additional information clear cell RCC (3).
in complex cases, for detection of subtle enhance- The European Association of Urology (EAU)
ment or confirmation of invasion of an adjacent guidelines suggest less-intensive image surveil-
structure. Functional assessment of renal function lance than the AUA guidelines, with US at 6
with renal scintigraphy (technetium 99m [99mTc]- months postoperatively for low-risk patients,
mercaptoacetyltriglycine [MAG3]) may also be followed by alternating CT of the chest and
useful when considering nephrectomy to ensure abdomen and US annually until 3 years. For in-
adequate function of the unaffected kidney. termediate- or high-risk patients, CT of the chest
When preoperative imaging or intraoperative and abdomen at 6 months and then annually is
findings are suggestive of node-positive disease, recommended. After 3 years, the EAU guidelines
a regional lymph node dissection (LND) may suggest that all patients are recommended to
be included at the time of nephrectomy, gener- undergo CT every 2 years (24).
ally for prognostication (6). LND may provide Since publication of the EAU 2017 guidelines,
staging information but has not been shown to a multicenter database of 1612 cases of nonmeta-
provide a survival benefit (22). While there is static RCC demonstrated no improvement in
minimal additional morbidity, the additional op- overall survival after recurrence in patients with
erative time and lack of clear benefit leads many follow-up imaging performed more often than
surgeons to omit LND in the absence of enlarged suggested in the EAU 2017 guidelines. For exam-
retroperitoneal lymph nodes at renal CT or MRI. ple, after 5 years of follow-up by EAU guidelines,
a high-risk patient should undergo six abdominal
Imaging Surveillance after Surgery and six chest CT examinations. This analysis
Recommendations for imaging surveillance after found no improvement in overall survival among
surgery for low- and high-risk renal tumors are patients undergoing 24 or more CT examinations
included in Table 4 and are based on the Ameri- compared with those who underwent eight or
can Urological Association (AUA) guidelines fewer examinations (24).
RG • Volume 41 Number 5 Abou Elkassem et al 1395

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

Management (Risk
Group and Stage) Recommendations
Any management Brain imaging: acute neurologic signs and symptoms should prompt brain MRI* or CT;
(any stage) optional brain MRI* or CT if asymptomatic with widespread stage IV disease
Spine imaging: acute neurologic signs and symptoms should prompt spine MRI* or spine
CT, without and with intravenous contrast material
Bone imaging: elevated serum alkaline phosphatase levels and clinical signs and symp-
toms suggestive of bone metastasis or positive findings at other imaging examinations
should prompt bone scan
Partial nephrectomy Chest imaging: annual chest radiography for 3 years; continue annual chest radiography
(low risk; T1a or on the basis of patient risk factors
T1b) Abdominal imaging: baseline renal CT or MRI between 3 and 12 months after surgery;
if baseline imaging is negative, annual surveillance with renal US, CT, or MRI may be
performed for 3 years on the basis of patient risk factors
Radical nephrectomy Chest imaging: annual chest radiography for 3 years; continue annual chest radiography
(low risk; T1a or on the basis of patient risk factors
T1b) Abdominal imaging: baseline renal CT or MRI between 3 and 12 months after surgery; if
the baseline imaging examination is negative, annual surveillance with renal US, CT, or
MRI may be performed on the basis of patient risk factors
Surgery (high risk; ≥ Chest imaging: baseline chest CT between 3 and 6 months after surgery; continued
T2 or node-posi- surveillance with chest radiography or chest CT every 6 months for 3 years and then
tive disease) annually thereafter to year 5; perform annual chest radiography or chest CT after 5
years on the basis of patient risk factors
Abdominal imaging: baseline renal CT or MRI between 3 and 6 months after surgery;
continued surveillance with renal US, CT, or MRI every 6 months for 3 years and then
annually thereafter to year 5; perform annual renal US, CT, or MRI after 5 years on the
basis of patient risk factors
Renal mass ablation Biopsy: pre- or intraprocedural biopsy is recommended; repeat biopsy with signs of
(low risk; T1a) recurrence
Chest imaging: no chest imaging is needed with pathologic analysis confirmation of
benign disease and confirmation of treatment success without complications; annual
chest radiography for 5 years for biopsy-proven low-risk RCC, oncocytoma, tumor
with oncocytic features, and nondiagnostic biopsy results; perform chest radiography
or chest CT after 5 years on the basis of patient risk factors
Abdominal imaging: baseline renal CT or MRI at 3 and 6 months after ablation and
continue annually thereafter for 5 years; perform renal CT or MRI after 5 years on
the basis of patient risk factors
Active surveillance Biopsy: consider biopsy before active surveillance; consider biopsy for rapidly growing
(AS) (low risk; renal masses
T1a) Chest imaging: annual chest radiography for biopsy-proven RCC or a tumor with onco-
cytic features
Abdominal imaging: baseline renal CT or MRI within 6 months of AS initiation; contin-
ued surveillance with renal US, CT, or MRI at least annually thereafter
Stereotactic body Chest imaging: annual chest radiography for 5 years; continue annual chest radiography
radiation therapy on the basis of patient risk factors
(SBRT) (low risk; Abdominal imaging: baseline renal CT or MRI between 6 and 12 months of SBRT and
T1a or T1b) continued annually thereafter for 5 years; perform renal CT or MRI after 5 years on
the basis of patient risk factors
Systemic therapy Chest imaging: baseline CT and follow-up every 6–16 weeks on the basis of the patient’s
(highest risk; stage clinical status; imaging adjusted on the basis of the rate of disease change
IV) Abdominal imaging: baseline CT or MRI and follow-up recommended concurrently with
chest CT imaging on the basis of the patient’s clinical status; imaging adjusted on the
basis of rate of disease change
Pelvic imaging: baseline CT and optionally continued concurrently with abdominal
imaging thereafter if there are positive imaging findings at baseline examination or if
symptomatic

*MRI is preferred over CT for brain and spine imaging.

1396 September-October 2021 radiographics.rsna.org

Imaging outside of routine follow-up is (SIR) (27). SIR cites multiple case series that
generally triggered by a change in symptoms demonstrate PA to be both safe and efficacious in
or laboratory values. For example, bone scans the treatment of T1b tumors, although it should
and cross-sectional brain imaging should be be noted that rates of local tumor progression can
reserved for patients with bone pain or elevation be 3%–39% in this cohort (27,28).
in alkaline phosphatase levels or new neurologic The decision to proceed with PA should be
symptoms, respectively (Table 4) (23). Modifi- made in a multidisciplinary approach while
cation of routine CT acquisitions is occasion- taking into consideration the patient’s prefer-
ally needed to improve diagnostic accuracy. ence from available options. Generally, PA is
For example, renal CT with a corticomedullary favored for poor surgical candidates, in those
phase can be performed to detect a pseudoan- with compromised renal function, in those with
eurysm, and an excretory phase can be included hereditary syndromes resulting in multiple
to differentiate a postoperative urinoma from RCCs, or for patients who wish to avoid tradi-
other postoperative fluid collections (eg, seroma, tional surgery. The primary technical success of
hematoma, or abscess). PA is 94%–98% for T1a tumors and 80%–97%
for T1b tumors (27). Clinical outcomes such
Image-guided Interventions as local recurrence and cancer-specific survival
for RCC are nearly identical to those seen for partial
Interventional radiology is an important partner nephrectomy in patients with T1a tumors.
for patients with RCC, as a variety of minimally However, PA has the advantages of lower costs,
invasive image-guided procedures can be used in fewer complications, shorter hospital stays, and
both localized and advanced disease. less detriment to renal function (29,30). Con-
traindications to PA include an uncorrectable
Renal Mass Biopsy coagulopathy, active urinary tract infection, lack
Renal biopsy has been validated as a safe, ac- of percutaneous access to the tumor, and the
curate, reliable, and reproducible method to inability to create a safe zone of ablation owing
diagnose malignancy. Image-guided renal mass to adjacent structures (31). In practice, adjunc-
biopsy should be considered when a mass is tive techniques such as patient repositioning,
suspected to be hematologic or metastatic or sus- hydrodissection, pneumodissection, and pyelo-
picious for a benign entity, such as a lipid-poor perfusion allow most ablations to be performed
angiomyolipoma (6). As 20% of small solid renal successfully (Fig 8).
neoplasms (≤4 cm) are benign, the results of a There are a variety of ablation technolo-
renal mass biopsy can help determine the need gies that can be used, including radiofrequency
for an invasive management approach. The diag- ablation, microwave ablation, cryoablation, and
nostic yield of a renal mass biopsy exceeds 90% irreversible electroporation, each with its own
and has high concordance with nephrectomy, advantages and disadvantages. No convincing
although renal mass biopsy results frequently fail survival benefit exists to favor one modality over
to identify sarcomatoid RCC and have dimin- another in RCC (32). Major complications occur
ished accuracy for tumor grade, with up to 20% in 3%–6% of patients with T1a tumors after PA,
of low-grade tumors on renal mass biopsy results with hemorrhage, hematuria, urine leak, ureteral
being upgraded to high-grade tumors after sur- injury, bowel injury, nerve injury, infection and/
gery. A core-needle renal mass biopsy is recom- or abscess, and pneumothorax being the most
mended by the AUA before PA to guide postpro- frequently encountered (27). Finally, limited case
cedural imaging surveillance and to evaluate for series have described using PA to palliate symp-
suspected recurrence after ablation. A renal mass toms of RCC such as pain and hematuria (33).
biopsy is considered optional when AS is the
planned management option (6,25). Imaging Surveillance after Percutaneous Abla-
tion.—At the authors’ institution, the majority of
Percutaneous Ablation patients are discharged the same day the proce-
PA is a potentially curative therapeutic option dure is performed, with an assessment in approx-
for patients with T1a tumors and should be imately 2–3 weeks in the interventional radiology
considered as an alternative approach accord- ambulatory clinic. Recommendations for imaging
ing to recommendations from the AUA and the surveillance after PA are included in Table 4 and
National Comprehensive Cancer Network (6,26). are based on the AUA guidelines, with initial ab-
In addition, patients with larger localized tumors dominal imaging at 3 and 6 months after ablation
(>4 cm) can be considered for PA with curative and continued annually for 5 years (23). Some
intent, according to a recent position statement interventionalists prefer to assess for complica-
from the Society of Interventional Radiology tion and technical success by imaging between 1
RG • Volume 41 Number 5 Abou Elkassem et al 1397

Figure 8. Hydrodissection before cryoablation to develop a safe ablation zone in an 82-year-old woman
with a 2.2-cm mass in the right kidney (categorized as T1a at imaging). Percutaneous biopsy results
confirmed clear cell RCC. (a) Axial contrast-enhanced CT image shows that the renal mass (arrow) hy-
perenhances and is partially exophytic. The patient was a poor surgical candidate and elected to un-
dergo cryoablation. (b) Axial CT image obtained during cryoablation shows one of two ablation probes.
However, the colon is adjacent to the ablation zone (*), putting it at risk for injury. (c) Axial CT image
obtained during cryoablation shows hydrodissection using saline and diluted iodinated contrast material
performed through a 22-gauge needle to create space between the mass and kidney and adjacent colon
(*). (d) Axial contrast-enhanced CT image obtained 3 months after ablation shows a complete response
to treatment (arrow), with absence of tumor enhancement and without colonic injury.

day and 6 weeks after the procedure. Regarding debris that can be visualized. However, there
imaging modalities, multiphase CT, MRI, and should be no central or nodular enhancement
contrast-enhanced US can all be used to monitor within the ablation cavity on postcontrast images
the treatment area with excellent sensitivity and (36). Blood products or proteinaceous materials
specificity (34). The Society of Abdominal Radi- may have hyperintensity on T1- and T2-weighted
ology RCC Disease-Focused Panel recommends images before contrast material administration
that the renal CT image acquisition protocol (37). MRI has an added advantage of obtaining
for postablative indications includes precon- postcontrast subtracted images for better assess-
trast imaging and nephrographic phase imaging ment of internal enhancement.
(100–120 seconds) at 3-mm section thickness, After contrast material administration, a
with weight-based dosing of intravenous iodin- treated RCC will not demonstrate enhancement,
ated contrast material, although corticomedul- although many treated tumors will have an area
lary phase imaging can help improve detection of of soft-tissue attenuation in the perinephric fat,
clear cell RCC (3,35). After renal mass ablation, which is thought to represent peripheral inflam-
the ablated area is often hypoattenuating on mation and scarring. Residual or locally recur-
noncontrast CT images relative to the surround- rent tumor most often appears as an area of
ing renal parenchyma, with areas of internal high nodular enhancement along the periphery of the
attenuation from hemorrhage or proteinaceous ablation zone (Fig 9). Small areas of residual or
1398 September-October 2021 radiographics.rsna.org

Figure 9. Imaging findings suggestive of recurrence after cryoablation in a 64-year-old woman with a
3.2-cm mass in the left kidney (categorized as T1a at imaging) who was referred for interventional radiol-
ogy owing to patient preference. Percutaneous biopsy results confirmed clear cell RCC. (a) Axial contrast-
enhanced CT image shows the partially exophytic renal mass (arrow). (b) Axial CT image obtained dur-
ing cryoablation shows one of three probes and the ice ball (*). There is a narrow slice of tissue along the
medial margin that is outside of the ablation zone (arrow) and was not identified during the procedure.
(c) Axial noncontrast CT image obtained 3 months after ablation shows the treated area (arrow) before
intravenous contrast material administration (~30 HU). (d) Axial contrast-enhanced CT image shows a
rim of hyperenhancing tissue (arrow; ~150 HU) along the medial margin, consistent with residual disease.

locally recurrent disease can usually be success- (38). On the other hand, a later propensity score–
fully treated with repeat PA. Follow-up imag- matching analysis failed to show any benefits
ing should also be carefully scrutinized for any of preoperative TAE in overall survival, cancer-
evidence of postprocedural complications such as specific survival, complications, or intraoperative
hemorrhage, pseudoaneurysms, ureteral injury, blood loss (39). Similarly, investigations into the
abscess formation, or urinary leak. role of TAE before PA have shown mixed results
(Fig 10). One study found a reduction in hemor-
Transarterial Embolization rhagic complications after renal cryoablation in
Clear cell RCC, the most common histologic tumors larger than 5 cm for patients who under-
variant, is characterized as a hypervascular tumor went preprocedural TAE (40). Yet, a subsequent
at contrast-enhanced imaging. Consequently, propensity score–matching analysis that included
TAE of the vessels supplying the tumor could be patients with any tumor size failed to demon-
used as an adjunctive technique or stand-alone strate any significant improvements in technical
therapy. As an adjunctive technique before partial success, complications, blood loss, or local recur-
nephrectomy, one study compared patients that rence (41). Certainly, further work is needed to
underwent TAE to a group of matched patients investigate TAE as an adjunctive technique in
who did not undergo TAE, reporting survival RCC to identify objective outcome improvements
benefits at both 5 and 10 years in the TAE cohort and assist in patient selection.
RG • Volume 41 Number 5 Abou Elkassem et al 1399

Figure 10. Transarterial chemoembolization as an adjunctive technique before percutaneous ablation

(PA) in a 73-year-old man with a 6.7-cm left renal mass (categorized as T1b at imaging) who was referred
to interventional radiology owing to chronic kidney disease. Percutaneous biopsy results confirmed clear
cell RCC. (a) Axial contrast-enhanced CT image shows that the exophytic mass (arrows) enhances and
is well marginated. (b) Anteroposterior projection of a digital subtraction angiographic image of the left
renal artery shows a hypervascular mass in the left upper pole (arrows). (c) Anteroposterior projection of
a digital subtraction angiographic image obtained following particle embolization of the mass from the
left renal artery shows reduced vascularity of the mass. (d) Axial prone position CT image obtained during
the subsequent cryoablation shows two of eight probes used and adequate coverage of the tumor by the
ice ball (arrows). Follow-up contrast-enhanced US (not shown) showed no residual disease.

TAE may also have a role in patients with respectively, after TAE of the primary mass (44).
advanced RCC. For example, one study reported Moreover, a smaller series of patients with inoper-
that 13% of patients with metastatic RCC experi- able RCC (n = 25) found that 68% of patients
enced a regression of metastatic lesions after TAE reported a reduction in pain and/or hematuria
of the primary mass, suggesting an abscopal effect after TAE of the primary mass (45). Finally, two
(42). A more recent analysis compared the overall early reports have described the intra-arterial de-
survival of patients with metastatic RCC who livery of either chemotherapy or yttrium-90 (90Y)
underwent TAE of the primary renal mass to that as a stand-alone therapy for RCC, although the
of matched patients who did not receive TAE (43). data are too early to integrate into routine clinical
After TAE, patients had a longer mean overall sur- practice (46,47).
vival (229 vs 116 days) and higher rates of overall Imaging surveillance after TAE is variable and
survival at 1 (29% vs 13%), 2 (15% vs 7%), and 3 is dependent on the main purpose. For example,
(10% vs 3%) years (42). Apart from any oncologic if TAE precedes PA, then imaging surveillance
benefits, TAE has been shown to improve symp- would follow recommendations for PA (Table 4).
toms in patients with advanced RCC, including Conversely, if TAE is used in the management
pain and hematuria. One case series (n = 73) dem- of advanced cancer, then imaging surveillance
onstrated an elimination of hematuria and pain in would follow recommendations for systemic
100% and 72% of patients with advanced RCC, therapy (Table 4).
1400 September-October 2021 radiographics.rsna.org

Active Surveillance of Small Renal large lesions grow at a more rapid growth than
Masses their smaller counterparts (52). Patients at high
The majority of small renal masses will ulti- risk who are undergoing AS may need increased
mately be found to be benign or have fairly monitoring to evaluate for dissemination or lo-
indolent potential (48). AS has become a great cal invasion.
option for patients with small tumors (<3 cm)
or slow-growing tumors (<5 mm per year) who SBRT for RCC
are older or have a life expectancy of less than RCC has traditionally been regarded as having
5 years, have high comorbidities, have excessive a radioresistant histology. With the advent of
perioperative risk, have poor renal function, or advanced technology and the experience with
who prefer to avoid the risks of other treatments SBRT, also called stereotactic ablative radia-
(6). In short, AS may be an appropriate choice tion therapy, for primary and metastatic tumors
when the benefits of treatment are not likely to in the lung, liver, and spine, there is emerging
outweigh the potential risks (6). use of SBRT for primary and metastatic RCC.
The risk of requiring delayed intervention is SBRT is a noninvasive technique characterized
low and the rate of metastases remains low for by high-precision delivery of ablative therapeu-
lesions smaller than 4 cm (49). Imaging rec- tic radiation, either delivered in a single or a
ommendations for patients undergoing AS are few outpatient treatment sessions, with single
included in Table 4 and are based on the AUA fraction associated with better progression-free
guidelines (23). Baseline contrast-enhanced re- and cancer-free survival (53). SBRT is typically
nal CT or MRI is essential and must completely recommended for patients who are poor surgical
evaluate the tumor itself and identify regional or candidates and tumors that are not suitable for
distant metastasis. For all patients undergoing ablation (54). The practical aspects of perform-
AS, repeating imaging within the first 6 months ing SBRT for primary RCC are described in the
is recommended with renal CT, MRI, or con- International Radiosurgery Oncology Consor-
trast-enhanced US to assess any interval growth tium for Kidney consensus statement (55).
(6,16,23). The Society of Abdominal Radiology Phase I trials have demonstrated safety with
RCC Disease-Focused Panel recommends that SBRT for primary RCC (56,57). A subsequent
the renal CT image acquisition protocol for pooled analysis study of 223 patients treated
AS includes precontrast imaging and nephro- with SBRT for RCC showed an excellent local
graphic phase imaging (100–120 seconds) at control rate of over 95%, with minimal toxic
3-mm section thickness (3). Follow-up imaging effects (53). In a pooled analysis, patients with
should be performed with the same modality to primary RCC in a solitary kidney appeared to
minimize issues with measurement. After this have similar outcomes compared with patients
initial period, the AUA recommends that renal with RCC with bilateral kidneys (58).
CT, MRI, or contrast-enhanced US be repeated A select group of patients with limited metas-
annually, although the interval of examinations tases or oligometastases may also benefit from
may decrease as long as the lesion is growing at metastasis-directed SBRT. A recent randomized
an acceptable rate (<5 mm per year) (6). phase II trial (SABR-COMET [The Stereotactic
Most renal lesions will grow over time, Ablative Radiotherapy for the Comprehensive
although there is wide variability in tumor Treatment of Oligometastases]) comparing stan-
growth rates, and the rate of growth may not dard therapy and SBRT for patients with one
accurately predict adverse pathology or meta- to five metastases from a variety of histologies
static potential (16,50,51). However, in the showed that SBRT improved progression-free
absence of better surrogates, prompts to initiate and overall survival (59). SBRT has been ap-
an invasive treatment in a patient undergoing plied to patients with oligometastatic RCC with
AS include tumor size (3 or 4 cm, depending promising outcomes in terms of local control
on the treatment center preference), progres- and toxic effects. A meta-analysis of 28 studies
sion of stage, rapid growth (>5 mm per year), of oligometastatic RCC showed promising re-
or patient anxiety and/or preference (6). Renal sults, but further research can better define the
mass biopsy is not required for safe AS but can role of SBRT in the setting of RCC (60).
be performed before an AS program or can be
offered after growth if the results will affect Imaging after SBRT
decision making (6). Patients with renal tumors The optimal method of imaging response assess-
that are larger than those observed with AS can ment after SBRT for treatment of primary RCC
consider this management strategy if the treat- has not been established, although renal CT
ment risks outweigh the benefit or if the patient or MRI studies without and with intravenous
is willing to accept the associated risks. Of note, contrast material are probably the best options.
RG • Volume 41 Number 5 Abou Elkassem et al 1401

Figure 11. Residual mass after SBRT in a

76-year-old man with a 3.3-cm right-sided
clear cell RCC (categorized as T1a at imaging).
(a) Axial contrast-enhanced CT image shows
that the mass hyperenhances and is partially
exophytic. (b) Axial dose-distribution CT image
shows isodose lines (colored lines). The SBRT
dose prescription was 26 Gy in 1 fraction to the
estimated glomerular filtration rate. (c) Axial
contrast-enhanced CT image obtained 6 years
after SBRT shows that the treated tumor has de-
creased in size and enhancement, and there is
a circular thin rim of soft tissue in the adjacent
perirenal fat, the latter of which is similar in ap-
pearance to that visualized with PA procedures.

While local control is currently determined with study, do not perform CT-based tumor size as-
CT and size-based criteria such as Response sessment until after 6 months after SBRT (62).
Evaluation Criteria in Solid Tumors (RECIST) Assessment of CT-based contrast enhance-
1.1, size-based tumor assessments have signifi- ment characteristics is also not indicative of treat-
cant limitations. Tumor growth and local failure ment success in SBRT kidney. Decreased con-
are rare after SBRT, and the determinants of trast enhancement is not always seen with SBRT,
treatment success, such as tumor shrinkage, may and thus ongoing enhancement, even increased
require years to observe (53). enhancement in some cases, can be misinter-
Progressive tumor shrinkage over the course preted as persistent or recurrent disease, although
of years after delivery of SBRT has been con- no correlation with local failure has been ob-
sistently observed across studies (56,57). served (63). This is likely attributable to the dif-
Therefore, persistent renal masses are a normal ferences in mechanisms of action. SBRT sterilizes
finding after SBRT, and RECIST 1.1 complete tumors by DNA damage and invokes tumor cell
response is a rare occurrence (Fig 11). A further killing that progressively and slowly destroys the
issue with size-based response assessment is tumor, as compared with the immediate physical
the phenomenon of early pseudoprogression destruction of tumor and vascular architecture
after SBRT. A repeatedly observed phenom- through ablative technologies. Thus, there is a
enon in RCC is initial size increase that may be pressing clinical need for a more effective imag-
misinterpreted as disease progression but may ing biomarker of treatment response than con-
actually be due to treatment-induced inflamma- ventional CT after SBRT for primary RCC.
tion (Fig 12) (61). This typically plateaus and Currently novel imaging methods such as dy-
subsequently gives way to tumor shrinkage. To namic contrast enhancement (DCE) at MRI and
account for this, some prospective clinical trials, prostate-specific membrane antigen (PSMA)–
such as the TransTasman Radiation Oncology based PET are under investigation for treatment
Group FASTRACK (Focal Ablative STereotac- response assessment. Some DCE parameters ap-
tic Radiosurgery for Cancers of the Kidney) II pear to correlate with long-term tumor shrinkage
1402 September-October 2021 radiographics.rsna.org

Figure 12. Changes in tumor size and en-

hancement after SBRT in a 76-year-old woman
with a 3.9-cm left-sided inoperable RCC (catego-
rized as T1a at imaging). Percutaneous biopsy
results confirmed clear cell RCC. (a) Coronal
contrast-enhanced CT image shows that the
mass hyperenhances and is partially exophytic.
(b) Coronal dose-distribution CT image shows
isodose lines (colored lines). SBRT dose prescrip-
tion was 26 Gy in 1 fraction to the estimated
glomerular filtration rate. (c) Coronal contrast-
enhanced CT image obtained 5 years after SBRT
shows that the treated tumor has decreased in
size and enhancement, and there are posttreat-
ment changes in the adjacent perirenal fat.

at conventional imaging (64). New evidence also (Table E1). All target agents (antiangiogenic,
exists for the use of PSMA-based PET in meta- mechanistic target of rapamycin inhibitors, and
static RCC (65). PSMA is highly expressed in immunotherapy agents) approved for metastatic
RCC neovasculature, and thus, PSMA-targeted kidney cancer have been shown to improve
radiotracers are effective for identifying RCC progression-free survival (PFS) or overall sur-
metastases and assessing response after SBRT, vival (67). Each class of drugs, from cytokines
although this property may be confounded by to targeted agents to checkpoint inhibitors, have
the intrinsic activity in normal renal parenchyma unique toxic effects that may be detected at
where the tracer is excreted. While both of these imaging (Table 5) and that require close moni-
imaging modalities are promising, more data are toring by treating physicians, often resulting in
required before these approaches can be used dose adjustments or discontinuation of therapy
routinely in clinical practice. (68–70). Common complications from targeted
agents used to treat advanced RCC that can be
Systemic Therapy for Advanced RCC identified on images include pleural effusion,
The 5-year survival rate among patients with pneumonitis, pulmonary fibrosis, thrombo-
kidney cancer has increased steadily over the past embolic events, ascites, enteritis, colitis, and
30 years, attributable to early detection of low- pneumatosis.
stage tumors and more effective systemic therapy Ongoing trials are evaluating newer combina-
for advanced-stage disease. One-third of patients tions of approved agents and newer agents in
with kidney cancer are diagnosed with regional or the treatment in advanced RCC. The challenge
distant metastases, and approximately one-fourth facing treating physicians is identifying which
of patients with localized RCC treated surgi- agent or agents to use in which setting for their
cally with curative intent will relapse with distant patients with metastatic RCC. Ongoing re-
metastases (66). search evaluating biomarkers as predictors of
Systemic therapy for advanced RCC has response should allow more refined treatment
expanded tremendously over the past 15 years choices (71,72).
RG • Volume 41 Number 5 Abou Elkassem et al 1403

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

Drug Class Agents Toxic Effects with Imaging Findings

Tyrosine kinase Axitinib, cabozantinib, Posterior reversible encephalopathy syndrome, pleural effu-
inhibitors lenvatinib, pazopanib, sion, gastrointestinal bleeding, bowel perforation, enteroco-
sorafenib, sunitinib litis, pneumatosis, ascites, cholecystitis, pancreatitis, delayed
wound healing, thromboembolic events
Target of rapamycin Everolimus, temsiroli- Pneumonitis, pulmonary fibrosis, pleural effusion, enterocolitis,
inhibitors mus pneumatosis
VEGF-ligand anti- Bevacizumab Hypophysitis, enterocolitis, bowel perforation, thromboembolic
body events
Immune-checkpoint Ipilimumab, nivolumab, Hypophysitis, pneumonitis, sarcoidlike lymphadenopathy, hepa-
inhibitor pembrolizumab titis, colitis, bowel perforation, pancreatitis
PD-L1 antibody Avelumab Pneumonitis, hepatitis, colitis
Cytokine High-dose interleukin 2 Capillary leak syndrome, pulmonary edema, acute kidney injury
Note.—PD-L1 = programmed cell death ligand 1, VEGF = vascular endothelial growth factor.

Imaging after Systemic Therapy for overall survival and thereby are signs of a favor-
Advanced RCC able response to therapy (73,74).
Patients receiving systemic therapy for metastatic In response to immunotherapy, immune cells
RCC undergo an office visit with a history and can infiltrate macroscopic and microscopic meta-
physical examination every 6–16 weeks or more static tumors and result in a transient increase in
frequently as clinically indicated and adjusted for tumor size or visualization of new lesions, respec-
the type of systemic therapy they are receiving tively, followed by tumor shrinkage as the immune
(26). The Society of Abdominal Radiology RCC reaction subsides and the tumors undergo cell
Disease-Focused Panel recommends CT in the death, which is a phenomenon known as pseudo-
portal venous phase (60–90 seconds) at 3–5-mm progression. Pseudoprogression can occur at any
section thickness, with optional imaging of the time during therapy. Of course, immunotherapy
abdomen in the late arterial phase (40–50 sec- may eventually fail resulting in tumor growth and
onds) to help improve detection of hypervascular the development of new lesions, which are features
metastases in the liver and pancreas (3). No sin- of progressive disease that overlap with features of
gle follow-up plan is appropriate for all patients. pseudoprogression. It can therefore be difficult to
Follow-up should be individualized on the basis differentiate pseudoprogression from progressive
of treatment schedules, side effects, comorbidi- disease by using size-based criteria. In patients
ties, and symptoms. Recommended imaging at with metastatic RCC treated with immunotherapy,
baseline and follow-up in patients with advanced an increase in size or the presence of new lesions
RCC is outlined in Table 4 (26). should prompt repeat imaging in 4–6 weeks to dif-
Measurement of advanced RCC tumor size ferentiate pseudoprogression from true progressive
has been the traditional method to determine disease, whereby tumors with pseudoprogression
tumor response. However, in the era of targeted will stabilize or decrease in size and tumors that
antiangiogenic agents and immune checkpoint progress can be identified as further increasing in
inhibitors, changes in tumor size are insufficient size or number (75).
to evaluate response.
Targeted antiangiogenic agents act mainly as Imaging Biomarkers for Predicting
cytostatic agents rather than cytotoxic agents Advanced RCC Response
and often induce tumor stabilization and/or The introduction of targeted agents and immu-
cause tumor devascularization (72). In patients notherapy to the management of metastatic RCC
with metastatic RCC who receive antiangiogenic has offered significant benefits in overall survival
targeted agents and undergo portal venous phase and prognosis. However, not all patients respond
contrast-enhanced CT, a greater than or equal equally to targeted agents and immunotherapy,
to 20% decrease in the sum of target lesions, and several imaging biomarkers and response
marked central necrosis (with >50% of the mass evaluation criteria have been proposed to predict
becoming necrotic), and marked decreased tumor response, or efficacy.
attenuation (defined as a decrease in attenuation The RECIST 1.1 criteria, which are based on
of ≥40 HU) are predictors of prolonged PFS and tumor size changes, are the most commonly used
1404 September-October 2021 radiographics.rsna.org

Figure 13. Vascular tumor burden (VTB) to monitor treatment response in a 63-year-old woman with
metastatic clear cell RCC. (a) Baseline axial contrast-enhanced CT image shows hyperenhancing liver me-
tastases (arrow). (b) Axial contrast-enhanced CT image obtained 7 weeks after the first cycle of sunitinib
antiangiogenic therapy shows a slight decrease in size of the lesions (arrow) but marked central necrosis.
(c, d) Axial contrast-enhanced CT images with free-form regions of interest around the liver metastases
show the VTB (red area) at baseline (c) and 7 weeks after the first cycle of sunitinib therapy (d). The per-
centage change in the sum of the longest dimensions is 14%, compared with a 36% change in the sum of
the VTB. A greater than or equal to 30% decrease in the VTB is a predictor of prolonged progression-free
survival (PFS) and overall survival. This patient had PFS at 2.6 years and overall survival of 4.2 years.

response evaluation method within RCC clinical response of metastatic RCC to antiangiogenic
trials, despite known limitations in the context of agents. VTB is defined as the amount of vascular-
novel systemic agents and locally ablative treat- ized tumor within a two-dimensional region of
ment modalities. These limitations have resulted in interest on axial CT images and is designed to
the suggestion of lower thresholds of either a 10% quantify tumor devascularization in patients who
or 20% change in measured long-axis diameter as underwent treatment with antiangiogenic therapy
a more sensitive method for response evaluation, (71). By using images and data from a multina-
and recent studies have shown that incorporating tional phase III clinical trial, changes in VTB at
tumor attenuation and morphologic features can initial CT performed after therapy were highly
improve the predictive accuracy of response evalu- predictive of PFS and overall survival in patients
ation in patients with metastatic RCC treated with with RCC treated with sunitinib antiangiogenic
antiangiogenic therapy. For example, Morphology, therapy (Fig 13) and were a better predictor of
Attenuation, Size, and Structure (MASS) Criteria PFS than RECIST 1.1, 10% Tumor Diameter
objective response categories incorporate changes criteria, Choi criteria, modified Choi criteria,
in tumor size, tumor attenuation (enhancement), and MASS criteria (74). The generalizability of
and tumor necrosis and are predictive of PFS in VTB criteria to other targeted agents is under
patients with metastatic RCC treated with antian- investigation.
giogenic therapy (74). The ideal imaging biomarker would capture
Vascular tumor burden (VTB) is an example the main effect of a therapy, be predictive of PFS,
of a quantitative CT biomarker to monitor and be widely available, widely applicable, ame-
RG • Volume 41 Number 5 Abou Elkassem et al 1405

nable to high throughput, inexpensive, and highly diology.org/wp-content/uploads/2020/11/RCC.MRIproto-

colfinal-7-15-17.pdf. Accessed February 1, 2021.
reproducible across multiple institutions and 5. Kutikov A, Uzzo RG. The R.E.N.A.L. nephrometry score:
readers (72,74). Multiple additional predictive a comprehensive standardized system for quantitating renal
imaging biomarkers have been evaluated in the tumor size, location and depth. J Urol 2009;182(3):844–853.
6. Campbell S, Uzzo RG, Allaf ME, et al. Renal Mass
context of small single-center patient cohorts, but and Localized Renal Cancer: AUA Guideline. J Urol
none are ideal biomarkers and most lack multi- 2017;198(3):520–529.
institutional validation. 7. Shinagare AB, Davenport MS, Park H, et al. Lexicon for
renal mass terms at CT and MRI: a consensus of the soci-
ety of abdominal radiology disease-focused panel on renal
Conclusion cell carcinoma. Abdom Radiol (NY) 2020. doi:10.1007/
The treatment options for localized and ad- s00261-020-02644-x. Published online August 18, 2020.
Accessed February 1, 2021.
vanced RCC continue to expand and improve 8. Davenport MS, Hu EM, Smith AD, et al. Reporting
patient care, and the radiologist’s understanding standards for the imaging-based diagnosis of renal masses
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Varian Industries, Merck-Sharp-Dohme, Bayer Pharmaceuti- surgery in a prospective study with 76 patients: compari-
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Electric; payment for lectures from Canon Medical and Algo­ 19. Steinberg RL, Rasmussen RG, Johnson BA, et al. Prospective
Medica; multiple patents on image processing algorithms; travel performance of clear cell likelihood scores (ccLS) in renal
accommodations/meeting expenses paid from Canon Medical; masses evaluated with multiparametric magnetic resonance
owner and CEO of AI Metrics and Radiostics. Other activities: imaging. Eur Radiol 2021;31(1):314–324.
disclosed no relevant relationships. 20. Liu B, Zhan Y, Chen X, Xie Q, Wu B. Laparoscopic ultra-
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TM
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