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EDUCATION EXHIBIT
741
Papillary Renal Cell
Carcinoma: Radiologic-Pathologic Correlation and Spectrum
of Disease1
Online-Only
CME
See www.rsna
.org/education
/rg_cme.html
LEARNING
OBJECTIVES
After reading this
article and taking
the test, the reader
will be able to:
■■List
the imaging
features that help
distinguish papillary
renal cell carcinoma
from other subtypes.
■■Describe
the differences in histologic structure that
produce these imaging features.
■■Discuss
the staging of papillary renal
cell carcinoma and
the clinical significance of its staging.
Raghunandan Vikram, MBBS, MRCP, FRCR • Chaan S. Ng, MD
Pheroze Tamboli, MD • Nizar M. Tannir, MD • Eric Jonasch, MD • Surena
F. Matin, MD • Christopher G.Wood, MD • Carl M. Sandler, MD
Papillary renal cell carcinoma (pRCC) is the second most common
type of renal cell carcinoma (RCC). pRCC has unique imaging and
clinical features that may allow differentiation from clear cell RCC
(cRCC). There have been significant advances in our knowledge of the
natural history and treatment of pRCC, with data suggesting that it
may be best to manage pRCC differently from the other subtypes of
RCC. At contrast material–enhanced computed tomography, pRCC
enhances less than does cRCC in all phases of contrast-enhanced imaging. The difference in the degree of enhancement between pRCC
and cRCC is due to differences in their intratumoral vascularity.
In general, if a heterogeneous mass enhances to a degree similar to
that manifested by the renal cortex, it is likely to be a cRCC. A mass
that enhances to a lesser degree is likely to be a non–clear cell RCC.
It is common for metastatic lesions from pRCC to show enhancement characteristics similar to those of the primary tumor and be
hypovascular.
©
RSNA, 2009 • radiographics.rsnajnls.org
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POINTS
See last page
Abbreviations: cRCC = clear cell RCC, MVD = microvessel density, pRCC = papillary RCC, RCC = renal cell carcinoma
RadioGraphics 2009; 29:741–757 • Published online 10.1148/rg.293085190 • Content Codes:
From the Departments of Diagnostic Radiology (R.V., C.S.N., C.M.S.), Pathology (P.T.), Genitourinary Medical Oncology (N.M.T., E.J.), and
Urology (S.F.M., C.G.W.), University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030. Recipient of a Cum
Laude award for an education exhibit at the 2007 RSNA Annual Meeting. Received August 6, 2008; revision requested October 2 and received November 20; accepted December 17. N.M.T. is a consultant and member of the speakers bureau for Onyx Pharmaceuticals, Bayer, Wyeth, and Pfizer,
receives research support from Pfizer, Eli Lilly, and Hoffmann–La Roche, and has a spouse who is a stockholder in Merck; C.M.S. receives research
support from General Electric and has a spouse who is a stockholder in General Electric; all other authors have no financial relationships to disclose.
Address correspondence to R.V. (e-mail: [email protected]).
1
See the commentary by Yeh following this article.
©
RSNA, 2009
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742 May-June 2009
Introduction
Renal cell carcinoma (RCC) accounts for nearly
3% of all solid tumors. It is estimated that approximately 46,000 new cases of RCC were diagnosed in 2008 (1).
Most RCCs are incidentally diagnosed at imaging; the number of cases diagnosed by using
the classic triad of hematuria, flank pain, and a
mass in the abdomen continues to decline. The
incidence of RCC is gradually increasing, partly
due to increased use of imaging and partly due to
the increasing incidence of obesity in the general
population, a risk factor associated with increased
incidence of RCC (2). The majority of the solid
enhancing renal masses found at imaging tend to
be RCC, with other benign entities such as oncocytomas and lipid-poor angiomyolipomas being
less common.
It is now clear that RCC is not a single disease but an entity with different distinct genetic,
molecular, and histologic subtypes having varying clinical behavior and outcomes. The 2004
World Health Organization histologic classification of renal tumors acknowledges this concept
and defines a number of subtypes whose recognition has a bearing on treatment and outcome
(3). Table 1 shows the current histopathologic
classification of RCC.
Widespread use of nephron-sparing surgical
techniques for local disease makes accurate preoperative staging very important when staging
RCCs. Moreover, newer biologic and chemotherapeutic agents have been used for treatment
of metastatic RCC in the past few years; these
agents have generated considerable interest and
hold promise (4). There are now emerging data
indicating that papillary RCC (pRCC) responds
differently to the systemic therapy traditionally
used for metastatic RCC (5,6). Consequently,
radiologic diagnosis of the subtype may contribute to planning treatment. Although there is
overlap in the imaging appearances of the various
subtypes of RCC, there are usually differences in
the imaging appearances of pRCC and the more
common clear cell RCC (cRCC).
Table 1
2004 World Health Organization Classification of RCC
Clear cell (conventional) RCC
Multilocular clear cell RCC
Papillary RCC
Chromophobe RCC
Carcinoma of the collecting ducts of Bellini
Renal medullary carcinoma
Xp11 translocation carcinoma
Carcinoma associated with neuroblastoma
Mucinous tubular spindle cell carcinoma
Unclassified RCC
Source.—Reference 3.
In this article, we illustrate and highlight
these differences in the imaging features of
pRCC and contrast them with those of cRCC.
We discuss the appearance of the primary tumor
and of metastases with a brief discussion of staging, prognostic factors, diagnostic pitfalls, and
treatment.
Background on pRCC
Papillary RCC is the second most frequent RCC
subtype, accounting for approximately 13%–15%
of all known RCC lesions (7). Patients present in
the third to eighth decades of life. As is true for
all other cell types, the majority of pRCCs are
discovered incidentally during work-up of unrelated conditions. The male-to-female ratio ranges
from 2:1 to 3.9:1. Although most pRCCs are unilateral, pRCC is the most common multifocal or
bilateral renal tumor (7).
Cytogenetic and molecular studies have revealed distinct findings in pRCC that allow differentiation from other renal epithelial tumors
(8,9). pRCCs are characterized by a papillary, tubular, or tubopapillary growth pattern. They are
composed of cells arranged on a delicate fibrovascular core. The cytoplasm may be basophilic,
eosinophilic, or sometimes partially clear.
In comparison with cRCC, pRCC at diagnosis
tends to have a smaller mean diameter and be
of lower stage. However, after correction for the
effects of stage, grade, size, sarcomatoid differentiation, and patient performance status, tumor
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Table 2
Familial Forms of pRCC
Syndrome
Hereditary papillary renal cell
cancer
Hereditary leiomyomatosis
and RCC
Birt-Hogg-Dubé
Chromosome
7q31
1q42-43
17p11.2
Renal Lesions
Other Features
Multiple bilateral type 1
pRCCs
Type 2 pRCC
...
Skin nodules (leiomyomas),
uterine leiomyomas and
leiomyosarcomas
Multiple chromophobe RCCs, Facial fibrofolliculomas, lung
cRCCs, oncocytomas,
cysts, spontaneous pneupRCCs
mothorax
Source.—Reference 3.
histologic type (pRCC vs cRCC) was not found
to be an independent predictor of cancer-specific
mortality (10,11).
Delahunt et al (12) described two morphologic types of pRCC with different clinical behavior. Type 1 tumors have papillae covered by
a single layer of cuboidal or low columnar cells
with scanty cytoplasm and low-grade nuclei. Type
2 tumors are of a higher nuclear grade and contain more than one layer of cells with abundant
eosinophilic cytoplasm. Type 2 tumors generally
carry a worse prognosis than do type 1 tumors.
Sarcomatoid dedifferentiation is seen in approximately 5% of pRCCs; it has been associated with
both type 1 and type 2 tumors and is associated
with a worse prognosis (3).
Most pRCCs are sporadic. However, there
are a few familial forms. The majority of sporadic pRCCs are characterized by trisomy
of chromosomes 7 and 17, as well as loss of
chromosome Y in males (7,8,13). Hereditary
papillary renal cell cancer syndrome, hereditary
leiomyomatosis and RCC syndrome, and occasionally Birt-Hogg-Dubé syndrome are associated with papillary renal cell cancers (Table 2).
However, Birt-Hogg-Dubé syndrome is more
commonly associated with chromophobe RCC
and oncocytomas (3). This is in contrast to the
loss of genetic material from chromosome 3 and
mutations in the von Hippel–Lindau gene found
in cRCC. Inactivation of the von Hippel–Lindau
gene is thought to activate a hypoxic response,
including an increase in angiogenic factors,
which might explain the hypervascularity of
cRCC in contrast to the typical hypovascular
appearance of pRCC.
pRCC shares its histologic characteristics
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with a benign entity called papillary adenoma.
Point
Like most pRCCs, papillary adenoma shows
trisomies of chromosomes 7 and 17 and loss of
chromosome Y. There is general consensus that
the term papillary adenoma is appropriate for tumors 5 mm or smaller (3,14) and of a low grade.
Owing to their common histologic and genetic
makeup, an adenoma-carcinoma sequence akin
to that of colorectal polyps and colorectal carcinoma has been proposed (15,16). Papillary
adenomas are common and their prevalence increases during adulthood, from 10% in patients
younger than 40 years to over 40% in patients
older than 70 years (3).
Imaging Features of pRCC
Computed Tomography
pRCC was known to be less vascular than cRCC
even before the advent of computed tomography
(CT) (17,18). It was subsequently reported in
several CT studies that pRCC typically enhances
to a lesser degree than cRCC (19–23) (Fig 1).
The difference in the degree of enhancement between pRCC and cRCC is due to differences in
the intratumoral vascularity, measured in terms
of microvessel density (MVD) (24,25). Wang et
al (24) showed that the degree of enhancement
of RCC was directly proportional to the MVD of
the tumor.
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Figure 1. Enhancement of RCC. Unenhanced (left), corticomedullary phase (middle), and
excretory phase (right) CT scans show pRCC (a), cRCC (b), and chromophobe RCC (c).
pRCC is relatively hypovascular in comparison with cRCC. Typically, cRCC shows intense
enhancement in the corticomedullary phase. Chromophobe RCC and pRCC are difficult to
differentiate because both enhance to a similar degree; their vascular densities measured in
terms of MVD are similar.
Jinzaki et al (25) further studied the MVD
of various RCC subtypes and reported that the
MVD of pRCC was less than that of cRCC. They
counted the number of microscopic vessels in
a high-power field of a light microscope (×400;
0.1771 mm2 per field). cRCC had the highest
MVD at 653.6/mm2 ± 161.5, compared with
only 110.7/mm2 ± 21 for pRCC (Fig 2). This dif-
ference explains the differences in the degree of
enhancement between pRCC and cRCC. Furthermore, the difficulty often reported in prior
studies of differentiating between pRCC and
chromophobe RCC (19,21) is better explained
by their finding of lack of a significant difference
in the MVD of pRCC (110.7/mm2 ± 21) and
chromophobe RCC (124.2/mm2 ± 11) (Fig 1).
At nonenhanced CT, calcification is seen
slightly more often in pRCC than in cRCC.
However, the presence or absence of calcification
is not of value in making this differentiation (21).
pRCC enhances to a lesser degree than does
cRCC in all phases of postcontrast imaging. Kim
et al (21) report that these differences in enhance-
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Figure 2. Histologic analysis of pRCC and cRCC. (a) Photomicrograph (original magnification, ×100; hematoxylin-eosin stain) of a pRCC shows eosinophilic cytoplasm and sparse capillaries (arrows). (b) Photomicrograph
(original magnification, ×100; hematoxylin-eosin stain) of a cRCC shows abundant clear cytoplasm and abundant
capillaries (arrows). The differences in enhancement patterns between pRCC and cRCC can be explained by the
relative abundance of vascularity in cRCC.
Figure 3. Heterogeneous pRCC in a 58-year-old
man. Contrast-enhanced CT scan shows a 6.5-cm
mass in the left kidney. The heterogeneous appearance
of the mass is due to necrosis.
ment peak in the corticomedullary phase. They
found that cRCC enhanced to a mean of 149 HU
± 46, whereas pRCC enhanced to a mean of 91
HU ± 12. The difference was less marked in the
excretory phase, with cRCC enhancing to a mean
of 95 HU ± 17 and pRCC enhancing to 71 HU ±
10 (Fig 1).
When assessing the enhancement of the tumor, it is important to be aware that several extrinsic and intrinsic factors influence perfusion
of a tissue. The extrinsic factors are determined
by the CT protocol used, including the type of
contrast material, the quantity, and the rate and
duration of injection. The variability introduced
by these extrinsic factors can be controlled by the
CT protocol used. However, the intrinsic factors
such as the patient’s weight, cardiac function,
state of hydration, and renal function are more
difficult to correct. Herts et al (20) describe a
method to calculate the ratios of enhancement of
the tumor to those of the aorta and the normal
renal parenchyma to correct for these intrinsic
factors. Ruppert-Kohlmayr and colleagues (26)
describe another method of correcting for these
factors by multiplying the measured attenuation
value by a standardizing factor.
In practice, we have found that if a heterogeneous mass enhances to a degree similar to that
manifested by the renal cortex, it is likely to be a
cRCC. A mass that enhances to a lesser degree
is likely to represent a pRCC or a chromophobe
RCC.
In general, pRCCs can be classified on the
basis of their CT appearance as solid or cystic
masses. Solid tumors can appear homogeneous
and uniform or heterogeneous with areas of necrosis (Figs 3–6). At CT, pRCC is more likely to
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Figures 4, 5. (4) Homogeneous pRCC in a 48-year-old man. (a) Unenhanced (left), corticomedullary phase
(middle), and excretory phase (right) CT scans show a 2.5-cm solid hypovascular mass in the upper pole of the
right kidney. (b) Photograph of the cut surface of the specimen from partial nephrectomy shows that the tumor has
a homogeneous texture, with no evidence of necrosis or hemorrhage. (5) pRCC in a 54-year-old man. Unenhanced
(left), corticomedullary phase (middle), and excretory phase (right) CT scans show a 6.5-cm solid tumor (arrow) in
the right kidney.
Figure 6. pRCC in a 77-year-old man. Unenhanced (left), corticomedullary phase (middle), and nephrographic
phase (right) CT scans show a 2.7-cm solid tumor (arrow) in a horseshoe kidney. A large simple cyst (*) is seen adjacent to the tumor.
be homogeneous in comparison with cRCC (20),
particularly in cases of smaller tumors (<3 cm in
diameter). pRCCs larger than 3 cm in diameter
may be heterogeneous with areas of necrosis and
hemorrhage (20,21) (Fig 3); this may be a useful
finding, particularly in differentiating between
pRCC and chromophobe RCC at CT, since
chromophobe RCCs tend to be homogeneous
even when large (21). Small tumors (<3 cm in
diameter) are better identified on nephrographic
phase images than on corticomedullary phase images (27) (Fig 7).
The imaging features of type 1 and type 2
pRCC are very similar; to our knowledge, there
are no large studies that show any specific features that help differentiate between type 1 and
type 2 pRCC. Type 2 pRCCs tend to be of a
more advanced stage. In a small series of 19 pa-
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Figure 7. pRCC in a 54-year-old woman. Unenhanced (far left), corticomedullary phase (left middle), nephrographic phase (right middle), and excretory phase (far right) CT scans show a 1-cm low-attenuation mass (arrow)
in the right renal cortex. The tumor is not clearly visible on the unenhanced and corticomedullary phase images; it is
better demonstrated on the nephrographic and excretory phase images.
Figure 8. Nonenhancing pRCC in a 65-year-old
man. (a) Unenhanced (left) and contrast-enhanced
(right) CT scans show a cystic lesion in the left kidney
with rim calcification but without significant enhancement. The imaging features are suggestive of a complex
cyst. (b) Image shows hepatic metastases (arrows)
from the renal lesion, which was a papillary renal cell
tumor.
tients, Yamada and colleagues (28) reported that
type 2 pRCCs tend to have indistinct margins
and were more commonly heterogeneous with
areas of necrosis than type 1 lesions. Larger studies may be required to validate these findings.
The relative hypovascularity of pRCC can
cause it to be mistaken for a simple renal cyst.
Simple cysts do not enhance by more than 10
HU from precontrast to postcontrast imaging
(29). Enhancement of 10–20 HU is considered
suspicious and should alert the radiologist to
look for other suspicious signs of malignancy,
such as a solid nodule or enhancing septa. In
some exceptional cases, a solid pRCC fails to
show a difference in enhancement greater than
10 HU (Fig 8).
In the absence of precontrast images, the presence of de-enhancement or contrast material
washout at delayed phase imaging, such as during
the excretory phase, is equally useful information
and an indicator of vascularity (30).
Conversely, the pseudoenhancement of renal
cysts seen on postcontrast images may mimic
low-level enhancement and hence be mistaken
for pRCC or other hypovascular lesions. The
phenomenon of pseudoenhancement is found
to be more common in the modern multidetector CT scanners (31). Use of ultrasonography
(US) may be helpful in such cases to distinguish
solid hypovascular lesions from cysts. Alternatively, magnetic resonance (MR) imaging may
be of value.
pRCCs can occasionally manifest as cystic
masses. Their cystic nature may be due to their
inherent architecture (Fig 9) or secondary to
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748 May-June 2009
Figures 9, 10. (9) pRCC in a 66-year-old woman who had a cystic renal neoplasm with an intramural nodule. (a) CT scan shows a unilocular cystic neoplasm with an enhancing intramural nodule (arrow). (b) US scan
shows the echogenic nodule (arrow) in the cystic neoplasm. Unilocular cystic neoplasms tend to be of the papillary
subtype. (10) pRCC in a 59-year-old man. (a) Maximum intensity projection image from contrast-enhanced thinsection CT shows a large exophytic cystic pRCC with extensive necrotic areas, calcification, and peripheral enhancement. (b) Photograph of the cut surface of the specimen from radical nephrectomy shows the heterogeneous tumor
with a large cystic component secondary to necrosis.
cystic degeneration and extensive necrosis (Fig
10). Although cystic RCCs may belong to any
subtype, a unilocular cystic RCC tends to be
of the papillary subtype. It is characterized by
a single cyst with a nodule within it or tumor
growth filling part of the cyst (Fig 9).
Cystic degeneration is almost as likely to occur in pRCC as in cRCC (32). Analysis of the
enhancement characteristics of the solid components may sometimes help differentiate one from
the other.
MR Imaging
Magnetic resonance (MR) imaging is occasionally used in characterizing renal lesions. It is
generally used in patients who are allergic to iodinated contrast material. However, owing to the
superior tissue contrast provided by MR imaging,
it may also be used in differentiating solid from
cystic lesions.
At MR imaging, pRCC frequently shows a
pseudocapsule and frequently has low signal
intensity on both T1- and T2-weighted images,
whereas cRCC has higher signal intensity on T2weighted images (33). As in contrast-enhanced
CT, enhancement at MR imaging is less intense
in pRCC than in cRCC. The ability to subtract
post- and precontrast images obtained with
three-dimensional gradient-echo acquisitions can
help detect subtle enhancement.
Unlike in CT, where attenuation values are
measurable and reproducible, enhancement at
MR imaging takes the form of arbitrary values
based on signal intensity and is unique to each
examination. Moreover, when determining enhancement at MR imaging, care should be taken
that the pre- and postcontrast acquisitions are
performed in a single examination with no calibration changes between acquisitions.
Ultrasonography
To our knowledge, there is no known technique
that has been validated for differentiating different RCC subtypes by using US. As a diagnostic
and staging tool for renal masses, US has mostly
been replaced by CT and MR imaging. However,
US is useful in differentiating cystic from solid
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Table 3
American Joint Committee on Cancer TNM Staging System for RCC
Stage
T
T1
T1a
T1b
T2
T3
T3a
T3b
T3c
T4
N
N0
N1
N2
M
M0
M1
Description
Primary tumor
Tumor 7 cm or less in greatest dimension, limited to the kidney
Tumor 4 cm or less in greatest dimension, limited to the kidney
Tumor more than 4 cm but not more than 7 cm in greatest dimension, limited to the kidney
Tumor more than 7 cm in greatest dimension, limited to the kidney
Tumor extends into the major veins or invades the adrenal gland or perinephric tissues but not
beyond the Gerota fascia
Tumor directly invades the adrenal gland or perirenal and/or renal sinus fat but not beyond the
Gerota fascia
Tumor grossly extends into the renal vein or its segmental branches or the vena cava below the
diaphragm
Tumor grossly extends into the vena cava above the diaphragm or invades the wall of the vena cava
Tumor invades beyond the Gerota fascia
Regional lymph nodes*
No regional lymph node metastases
Metastasis in a single regional lymph node
Metastases in more than one regional lymph node
Distant metastasis
No distant metastasis
Distant metastasis
Source.—Reference 37.
*The regional lymph nodes are the renal hilar, paracaval, aortic (paraaortic, periaortic, lateral aortic), and retroperitoneal nodes. Laterality does not affect the N classification.
At US, RCCs may appear hypo-, iso-, or hyperechoic relative to the surrounding renal parenchyma. Twenty percent to 50% of small RCCs
(<3 cm in diameter) are found to be hyperechoic,
thus sharing sonographic characteristics with the
more common angiomyolipoma (34–36). Therefore, noncalcified hyperechoic lesions are best
characterized with CT or MR imaging (34).
Staging
Figure 11. T staging according to the American
Joint Committee on Cancer TNM staging system for
RCC. Tumors confined to the kidney are staged as T1
when smaller than 7 cm and as T2 when larger than 7
cm. Tumors invading the renal sinus fat, adrenal gland,
or perinephric fat are staged as T3a (Table 3).
masses, particularly for lesions that show borderline enhancement at CT and for high-attenuation
lesions that show little or no enhancement at CT.
Clinically, pRCC is staged according to the TNM
staging system (Table 3, Fig 11). This system of
staging is common to all subtypes of RCC and
is perhaps the most important prognostic factor.
The predominance of cRCC and the relatively
small numbers of pRCC mean that the utility of
this staging system has been validated in cRCC
but not necessarily in other subtypes.
In a recent study of 245 patients with pRCC
and 1912 patients with cRCC, Margulis et al
(11) found some discriminating differences in
the natural history of cRCC and pRCC. Unlike
in other reported series, they found that although
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pRCC was associated with a low stage, low grade,
and smaller tumor size, papillary histologic type
was not an independent prognostic predictor.
Tumor extension into the inferior vena cava,
the renal vein, or its branches (stage T3b and
T3c) (Fig 12) is relatively less common in pRCC
(8.2% of cases) than in cRCC (23.6%). However,
venous extension is associated with a drastic decrease in survival compared with that of similarly
staged cRCC cases (5-year cancer-specific survival, 35% for pRCC vs 66% for cRCC) (11).
pRCC is associated with an increased prevalence of nodal involvement (13%) (Fig 13) than
occurs in cRCC (8.6%). However, unlike in
cRCC, where nodal involvement carries a poorer
prognosis, pRCC with regional nodal metastases
is not necessarily associated with a poorer prognosis. Patients with pRCC and nodal metastases
show significantly improved survival compared
with that of a similar cohort of cRCC patients
(11). Once replaced by tumor cells, lymph nodes
show enhancement characteristics similar to
those of the primary tumor. Metastatic pRCC
nodes enhance to a lesser degree than do metastatic cRCC nodes.
Spread to mediastinal lymph nodes and supraclavicular lymph nodes is not unusual (Fig 14).
However, such spread is considered to represent
distant metastases and is classified as M1 disease.
pRCC has been noted to metastasize less frequently than cRCC. The prevalence of visceral
metastases is 5.7%–11% in pRCC and 11.9%–
26.9% in cRCC (11,38). Beck and colleagues
(38) report that the lung is the commonest site of
metastases in patients with pRCC, a result similar
to that in cRCC. Bone and the brain were other
common sites of metastases. It has been reported
that pRCC tends to recur locoregionally, whereas
cRCC often manifests with distant metastases.
There is possibly a difference in the common
sites of metastases for different RCC subtypes.
However, studies specifically examining this point
are small in numbers and are poorly powered for
drawing realistic conclusions (39,40).
Patients with pRCC and visceral metastases
have a dismal prognosis. Such patients have a
significantly lower median survival (9.1 months)
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Figure 12. Venous tumor extension in a
61-year-old man with pRCC of the right kidney.
Coronal unenhanced T1-weighted MR image
shows a malignant thrombus extending into the
inferior vena cava (arrow) below the diaphragm
(primary tumor not shown).
Figure 13. Nodal involvement in a 59-year-old man
with pRCC. Contrast-enhanced CT scan shows a large
cystic papillary renal cancer of the right kidney. There
are several enlarged retroperitoneal lymph nodes. The
tumor was staged as N2 owing to involvement of multiple nodes. Laterality does not affect N staging.
than do patients with metastatic cRCC (22
months) (11).
It is common for metastatic lesions from
pRCC to show enhancement characteristics
similar to those of the primary tumor and
be hypovascular (Figs 14–17). In contrast,
metastatic lesions from cRCC are generally
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Figure 14. Distant metastases from RCC. (a) Contrast-enhanced CT scans of a 58-year-old
woman show metastatic pRCC in the left supraclavicular (top arrow) and superior mediastinal
(bottom arrows) lymph nodes. (b) Contrast-enhanced CT scan of a 63-year-old woman shows
metastatic cRCC in a pretracheal lymph node (arrow). At contrast-enhanced CT, metastatic
lymph nodes from pRCC usually have lower attenuation than do those from cRCC. Thus, the enhancement characteristics of metastases parallel those of the primary tumor.
Figure 15. Metastatic lesion in a 65-year-old man with pRCC. Arterial phase (left), venous
phase (middle), and delayed phase (right) CT scans show a pleural metastasis, which does not
demonstrate avid enhancement during any of these phases.
Figure 16. Metastatic pRCC versus metastatic cRCC. (a) Contrast-enhanced CT scan of an 82-year-old
man with metastatic pRCC shows a metastatic lesion (large arrow), which is hypovascular. There is also a
hypervascular lesion (small arrow), which represents a hemangioma. (b) Contrast-enhanced CT scan of a
69-year-old woman with metastatic cRCC shows a metastatic lesion (arrow), which is hypervascular.
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Figure 17. Metastatic lesion in a 56-year-old man with pRCC. Left: Contrast-enhanced
CT scan shows a cystic pRCC of the right kidney. Right: Contrast-enhanced CT scan obtained 3 months later shows a contralateral renal metastasis (arrow).
hypervascular (Figs 14, 16). However, it is important to recognize that metastatic cRCC treated
with the newer antiangiogenic chemotherapeutic
agents may become hypovascular (Fig 18).
Treatment of pRCC
Radical nephrectomy or the more recently developed nephron-sparing procedures such as partial
nephrectomy or thermal tumor ablation remain
the only effective method of cure for all subtypes
of localized RCC (41–44). However, there have
been several recent advances in systemic therapy
for metastatic RCCs.
First-line therapy for metastatic pRCC is generally similar to that of metastatic cRCC. Antiangiogenesis agents such as bevacizumab, sunitinib,
and sorafenib have been shown to increase progression-free survival in patients with both clear
cell and non–clear cell RCC (4,45). However, patients with cRCC tend to have a better response
to these antiangiogenic agents (6).
Other chemotherapy regimens including
gemcitabine and capecitabine are reported to
have activity in patients with cRCC but do not
appear to be effective in pRCC (46). However,
the investigational agent temsirolimus, which
targets the mammalian target of rapamycin
(mTOR) receptor pathway, appears to improve
Figure 18. Metastatic lesion in a 62-year-old man
with cRCC. Contrast-enhanced CT scans obtained
before (left) and after (right) treatment with sunitinib
show a metastatic anterior mediastinal lymph node
(arrow), which is hypervascular before treatment but
hypovascular afterward. Lesions such as metastatic
cRCC can be rendered hypovascular with the newer
antiangiogenic treatments used and may have overlapping imaging features with those of metastatic pRCC.
overall survival in patients with metastastic
pRCC compared with that in patients with metastatic cRCC (47).
Conclusions
The pattern and degree of enhancement appear
to be the key in differentiating primary cRCC
from pRCC. The relative hypovascularity of these
tumors poses specific diagnostic pitfalls and challenges. There is also a great degree of overlap in
the imaging appearances of non–clear cell RCCs.
RG ■ Volume 29 • Number 3
There are discriminating differences in the
natural history of pRCC and cRCC based on the
commonly used TNM staging criteria. Knowledge of the differences in prognostic significance
unique to different subtypes while staging helps
us recognize “tipping points” that may impact
clinical management.
Our increasing knowledge of the differences
in clinical behavior of different RCC subtypes is
being translated into treatment approaches tailored specifically to each individual patient. These
changes in clinical management place a similar
expectation on our interpretation of the results of
imaging and staging studies.
Acknowledgment: The authors would like to thank
David L. Bier for providing the illustrations.
References
1.American Cancer Society. Cancer facts & figures
2008. Atlanta, Ga: American Cancer Society, 2008.
2.Hu J, Mao Y, White K; Canadian Cancer Registries
Epidemiology Research Group. Overweight and
obesity in adults and risk of renal cell carcinoma in
Canada. Soz Praventivmed 2003;48:178–185.
3.Eble JN, Sauter G, Epstein JI, Sesterhenn IA.
WHO classification of tumours: pathology and genetics of tumours of the urinary system and male
genital organs. Paris, France: International Agency
for Research on Cancer, 2004.
4.Motzer RJ, Basch E. Targeted drugs for metastatic
renal cell carcinoma. Lancet 2007;370:2071–2073.
5.Schrader AJ, Olbert PJ, Hegele A, Varga Z, Hofmann R. Metastatic non-clear cell renal cell carcinoma: current therapeutic options. BJU Int 2008;
101:1343–1345.
6.Choueiri TK, Plantade A, Elson P, et al. Efficacy of
sunitinib and sorafenib in metastatic papillary and
chromophobe renal cell carcinoma. J Clin Oncol
2008;26:127–131.
7.Reuter VE. The pathology of renal epithelial neoplasms. Semin Oncol 2006;33:534–543.
8.Presti JC Jr, Rao PH, Chen Q, et al. Histopathological, cytogenetic, and molecular characterization of renal cortical tumors. Cancer Res 1991;51:
1544–1552.
9.Yoshida MA, Ohyashiki K, Ochi H, et al. Cytogenetic studies of tumor tissue from patients with
nonfamilial renal cell carcinoma. Cancer Res 1986;
46:2139–2147.
10.Patard JJ, Leray E, Rioux-Leclercq N, et al. Prognostic value of histologic subtypes in renal cell
Vikram et al 753
carcinoma: a multicenter experience. J Clin Oncol
2005;23:2763–2771.
11.Margulis V, Tamboli P, Matin SF, Swanson DA,
Wood CG. Analysis of clinicopathologic predictors
of oncologic outcome provides insight into the natural history of surgically managed papillary renal
cell carcinoma. Cancer 2008;112:1480–1488.
12.Delahunt B, Eble JN, McCredie MR, Bethwaite
PB, Stewart JH, Bilous AM. Morphologic typing
of papillary renal cell carcinoma: comparison of
growth kinetics and patient survival in 66 cases.
Hum Pathol 2001;32:590–595.
13.Kovacs G, Wilkens L, Papp T, de Riese W. Differentiation between papillary and nonpapillary renal
cell carcinomas by DNA analysis. J Natl Cancer
Inst 1989;81:527–530.
14.Kovacs G, Akhtar M, Beckwith BJ, et al. The
Heidelberg classification of renal cell tumours. J
Pathol 1997;183:131–133.
15.Van Poppel H, Nilsson S, Algaba F, et al. Precancerous lesions in the kidney. Scand J Urol Nephrol
Suppl 2000;205:136–165.
16.Kiyoshima K, Oda Y, Nakamura T, et al. Multicentric papillary renal cell carcinoma associated
with renal adenomatosis. Pathol Int 2004;54:266–
272.
17.Weiss RM, Becker JA, Davidson AJ, Lytton B. Angiographic appearance of renal papillary-tubular
adenocarcinomas. J Urol 1969;102:661–664.
18.Blath RA, Mancilla-Jimenez R, Stanley RJ. Clinical
comparison between vascular and avascular renal
cell carcinoma. J Urol 1976;115:514–519.
19.Wildberger JE, Adam G, Boeckmann W, et al.
Computed tomography characterization of renal
cell tumors in correlation with histopathology. Invest Radiol 1997;32:596–601.
20.Herts BR, Coll DM, Novick AC, et al. Enhancement characteristics of papillary renal neoplasms
revealed on triphasic helical CT of the kidneys.
AJR Am J Roentgenol 2002;178:367–372.
21.Kim JK, Kim TK, Ahn HJ, Kim CS, Kim KR, Cho
KS. Differentiation of subtypes of renal cell carcinoma on helical CT scans. AJR Am J Roentgenol
2002;178:1499–1506.
22.Fujimoto H, Wakao F, Moriyama N, Tobisu K,
Sakamoto M, Kakizoe T. Alveolar architecture of
clear cell renal carcinomas (< or = 5.0 cm) show
high attenuation on dynamic CT scanning. Jpn J
Clin Oncol 1999;29:198–203.
23.Zhang J, Lefkowitz RA, Ishill NM, et al. Solid renal
cortical tumors: differentiation with CT. Radiology
2007;244:494–504.
754 May-June 2009
24.Wang JH, Min PQ, Wang PJ, et al. Dynamic CT
evaluation of tumor vascularity in renal cell carcinoma. AJR Am J Roentgenol 2006;186:1423–1430.
25.Jinzaki M, Tanimoto A, Mukai M, et al. Doublephase helical CT of small renal parenchymal
neoplasms: correlation with pathologic findings
and tumor angiogenesis. J Comput Assist Tomogr
2000;24:835–842.
26.Ruppert-Kohlmayr AJ, Uggowitzer M, Meissnitzer
T, Ruppert G. Differentiation of renal clear cell
carcinoma and renal papillary carcinoma using
quantitative CT enhancement parameters. AJR Am
J Roentgenol 2004;183:1387–1391.
27.Szolar DH, Kammerhuber F, Altziebler S, et al.
Multiphasic helical CT of the kidney: increased
conspicuity for detection and characterization of
small (<3-cm) renal masses. Radiology 1997;202:
211–217.
28.Yamada T, Endo M, Tsuboi M, et al. Differentiation of pathologic subtypes of papillary renal cell
carcinoma on CT. AJR Am J Roentgenol 2008;191:
1559–1563.
29.Chung EP, Herts BR, Linnell G, et al. Analysis of
changes in attenuation of proven renal cysts on
different scanning phases of triphasic MDCT. AJR
Am J Roentgenol 2004;182:405–410.
30.Macari M, Bosniak MA. Delayed CT to evaluate
renal masses incidentally discovered at contrastenhanced CT: demonstration of vascularity with
deenhancement. Radiology 1999;213:674–680.
31.Wang ZJ, Coakley FV, Fu Y, et al. Renal cyst pseudoenhancement at multidetector CT: what are the
effects of number of detectors and peak tube voltage? Radiology 2008;248:910–916.
32.Brinker DA, Amin MB, de Peralta-Venturina M,
Reuter V, Chan DY, Epstein JI. Extensively necrotic
cystic renal cell carcinoma: a clinicopathologic
study with comparison to other cystic and necrotic
renal cancers. Am J Surg Pathol 2000;24:988–995.
33.Roy C, Sauer B, Lindner V, Lang H, Saussine C,
Jacqmin D. MR imaging of papillary renal neoplasms: potential application for characterization of
small renal masses. Eur Radiol 2007;17:193–200.
34.Farrelly C, Delaney H, McDermott R, Malone D.
Do all non-calcified echogenic renal lesions found
radiographics.rsnajnls.org
on ultrasound need further evaluation with CT?
Abdom Imaging 2008;33:44–47.
35.Yamashita Y, Ueno S, Makita O, et al. Hyperechoic
renal tumors: anechoic rim and intratumoral cysts
in US differentiation of renal cell carcinoma from
angiomyolipoma. Radiology 1993;188:179–182.
36.Siegel CL, Middleton WD, Teefey SA, McClennan
BL. Angiomyolipoma and renal cell carcinoma: US
differentiation. Radiology 1996;198:789–793.
37.Greene FL, Page DL, Fleming ID, et al. AJCC
cancer staging handbook. 6th ed. New York, NY:
Springer, 2002.
38.Beck SD, Patel MI, Snyder ME, et al. Effect of
papillary and chromophobe cell type on diseasefree survival after nephrectomy for renal cell carcinoma. Ann Surg Oncol 2004;11:71–77.
39.Mai KT, Landry DC, Robertson SJ, et al. A comparative study of metastatic renal cell carcinoma
with correlation to subtype and primary tumor.
Pathol Res Pract 2001;197:671–675.
40.Renshaw AA, Richie JP. Subtypes of renal cell carcinoma: different onset and sites of metastatic disease. Am J Clin Pathol 1999;111:539–543.
41.Russo P. Renal cell carcinoma: presentation, staging, and surgical treatment. Semin Oncol 2000;27:
160–176.
42.Marshall FF, Stewart AK, Menck HR. The National Cancer Data Base: report on kidney cancers.
The American College of Surgeons Commission
on Cancer and the American Cancer Society. Cancer 1997;80:2167–2174.
43.Novick AC. Advances in the management of localized renal cell cancer. Can J Urol 2000;7:960–966.
44.Ng CS, Wood CG, Silverman PM, Tannir NM,
Tamboli P, Sandler CM. Renal cell carcinoma: diagnosis, staging, and surveillance. AJR Am J Roentgenol 2008;191:1220–1232.
45.Escudier B, Eisen T, Stadler WM, et al. Sorafenib
in advanced clear-cell renal-cell carcinoma. N Engl
J Med 2007;356:125–134.
46.Tannir NM, Thall PF, Ng CS, et al. A phase II trial
of gemcitabine plus capecitabine for metastatic
renal cell cancer previously treated with immunotherapy and targeted agents. J Urol 2008;180:867–
872; discussion 872.
47.Jean-Jacques P. New treatment options for renal
cell cancer: critical evaluation. Eur Urol Suppl
2008;7:443–446.
This article meets the criteria for 1.0 AMA PRA Category 1 Credit TM. To obtain credit, see www.rsna.org/education
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RG
Volume 29 • Number 3 • May-June 2009
Vikram et al
Papillary Renal Cell Carcinoma: Radiologic-Pathologic
Correlation and Spectrum of Disease
Raghunandan Vikram, MBBS, MRCP, FRCR, et al
RadioGraphics 2009; 29:741–757 • Published online 10.1148/rg.293085190 • Content Codes:
Page 742
Papillary RCC is the second most frequent RCC subtype, accounting for approximately 13%–15% of
all known RCC lesions (7).
Page 743
pRCC shares its histologic characteristics with a benign entity called papillary adenoma.
Pages 743
The difference in the degree of enhancement between pRCC and cRCC is due to differences in the
intratumoral vascularity, measured in terms of microvessel density (MVD) (24,25).
Page 744
pRCC enhances to a lesser degree than does cRCC in all phases of postcontrast imaging.
Page 745
A mass that enhances to a lesser degree is likely to represent a pRCC or a chromophobe RCC.