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Renal-Cell Carcinoma

Article  in  New England Journal of Medicine · January 2006

DOI: 10.1056/NEJMra043172 · Source: PubMed

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 The new england journal of medicine

review article

medical progress

Renal-Cell Carcinoma
Herbert T. Cohen, M.D., and Francis J. McGovern, M.D.

i n the united states, renal cancer is the 7th leading malignant

condition among men and the 12th among women, accounting for 2.6 percent of
all cancers.1 About 2 percent of cases of renal cancer are associated with inherited
syndromes. In the United States, 36,160 new cases of renal cancer are predicted to oc-
cur in 2005, many of which are being discovered earlier because of the widespread
From the Renal and Hematology–Oncolo-
gy Sections, Departments of Medicine and
Pathology, Boston University School of
Medicine (H.T.C.); and the Department of
Urology, Massachusetts General Hospital
and Harvard Medical School (F.J.M.) —
all in Boston. Address reprint requests to
availability of radiographic testing. Nevertheless, 12,660 deaths from the disease are Dr. Cohen at the Department of Medicine,
predicted to occur in 2005.1 Renal-cell carcinomas arise from the renal epithelium and Renal Section, Boston University School of
account for about 85 percent of renal cancers. A quarter of the patients present with ad- Medicine, Evans Biomedical Research Cen-
ter, 650 Albany St., Rm. X-535, Boston, MA
vanced disease, including locally invasive or metastatic renal-cell carcinoma. More- 02118, or at htcohen@bu.edu.
over, a third of the patients who undergo resection of localized disease will have a re-
currence. Median survival for patients with metastatic disease is about 13 months. N Engl J Med 2005;353:2477-90.
Copyright © 2005 Massachusetts Medical Society.
Thus, there is a great need for more effective surgical and medical therapies.

overview
The classic presentation of renal-cell carcinoma includes the triad of flank pain, hema-
turia, and a palpable abdominal mass. Few patients now present in this manner.
Roughly half the cases are now detected because a renal mass is incidentally identified
on radiographic examination. Other common presenting features may be nonspecific,
such as fatigue, weight loss, or anemia. Risk factors for renal-cell carcinoma include
smoking, obesity, and hypertension,2 as well as acquired cystic kidney disease associ-
ated with end-stage renal disease. A 1.6:1.0 male predominance exists,1 and the peak
incidence is in the sixth and seventh decades. Gross or microscopic hematuria is an im-
portant clinical clue to the diagnosis of renal-cell carcinoma; thus, hematuria should
be evaluated promptly by a computed tomographic (CT) scan of the genitourinary tract
and, in patients older than 40 years of age, by cystoscopy to rule out bladder cancer.
Prognosis is closely related to the stage of disease (Fig. 1). The Heidelberg classifica-
tion of renal tumors was introduced in 19976 as a means of more completely correlat-
ing the histopathological features with the identified genetic defects (Table 1).

tumor types and molecular pathogenesis

conventional or clear-cell renal-cell carcinoma
Von Hippel–Lindau disease (number 193300 in Mendelian Inheritance in Man [MIM])
is a rare, autosomal dominant, familial cancer syndrome consisting chiefly of retinal
angiomas, hemangioblastomas of the central nervous system, pheochromocytomas,
and renal-cell carcinoma of the clear-cell type (Fig. 2). The von Hippel–Lindau tumor-
suppressor gene (VHL) was identified in 1993.7 In this disease, one VHL allele is inher-
ited with a mutation. Associated focal lesions, such as renal-cell carcinoma, arise from
the inactivation or silencing of the remaining normal (wild-type) VHL allele (Fig. 3). Re-
markably, defects in the VHL gene also appear to be responsible for about 60 percent of

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 The new england journal of medicine

Figure 1. Staging Overview and Five-Year Survival Rates for Renal Cancer.
Survival data3 are based on the 1997 tumor–node–metastasis (TNM) staging guidelines.4 More recent renal-cancer
staging is described elsewhere.5

the cases of sporadic clear-cell renal-cell carcino-
ma,8 which represents a major portion of all cases
of renal-cell carcinoma.
VHL protein, the product of the VHL gene, func-
tions as a tumor suppressor, inhibiting growth
when reintroduced into cultures of renal-cell carci-
noma.9,10 Hypoxia-inducible genes are normally in-
hibited by VHL protein,11 including several encod-
ing proteins involved in angiogenesis (e.g., vascular
endothelial growth factor [VEGF]), cell growth
(e.g., transforming growth factor a [TGF-a]), glu-
cose uptake (e.g., the GLUT-1 glucose transporter),
and acid–base balance (e.g., carbonic anhydrase IX
[CA9]). When VHL protein is lost, these proteins are
overexpressed, creating a microenvironment favor-
able for epithelial-cell proliferation (Fig. 4A). Thus,
cells deficient in VHL protein behave as if they are hy-
poxic, even in conditions of normoxia. VHL protein,
with elongin proteins C and B, binds cul2 protein (a
member of the cullin family of ubiquitin ligase pro-
teins), indicating that some VHL protein serves as
the receptor subunit of a ubiquitin ligase complex
that promotes the ubiquitination and destruction
of proteins (Fig. 4B).12,13 VHL protein binds the
transcriptional activators hypoxia-inducible factor
1a (HIF-1a) and 2a (HIF-2a) directly and destabiliz-
es them.14 Furthermore, VHL protein promotes the
ubiquitination and destruction of HIF-a.15-17 These
VHL-regulated pathways are being studied as po-
tential targets of therapies for clear-cell renal-cell
carcinoma.
HIF is the key regulator of the hypoxic response
in multicellular organisms. Thus, VHL protein has
a central role in oxygen sensing. For HIF-a to bind
VHL protein, a proline residue must undergo hy-
droxylation, which is an unusual protein modifi-
cation18,19 (Fig. 4B). A family of proline hydroxy-
lases operates on HIF-a in a graded fashion, so that
the extent of hydroxylation depends on oxygen ten-
sion.20,21 Hydroxylation of an asparagine residue
blocks the interaction of HIF-a with the transcrip-
tional coactivator p300.22 Thus, multiple hydroxyl-
ation steps cooperate to inhibit HIF-a activity.
To correlate the genotype with the disease phe-

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 medical progress

Table 1. Sporadic and Hereditary Renal-Cell Carcinomas and Genetic Defects According to Histologic Appearance.*

Sporadic Renal-Cell Carcinomas Renal-Cell Carcinomas in an Inherited Syndrome

Histologic Appearance Incidence Gene and Frequency Rare Syndrome† Gene
percent
Conventional 75 VHL, 60 VHL disease VHL
FCRC Chromosome 3p translocation
Hereditary paraganglioma SDHB
Papillary 12 MET, 13 HPRC MET
TFE3, <1 HLRCC FH
Chromophobe 4 Birt–Hogg–Dubé syndrome BHD
Oncocytoma 4 Birt–Hogg–Dubé syndrome BHD
Collecting duct <1
Unclassified 3–5

* VHL denotes von Hippel–Lindau, FCRC familial clear-cell renal cancer, SDHB succinate dehydrogenase B, HPRC hered-
itary papillary renal carcinoma, HLRCC hereditary leiomyomatosis and renal-cell cancer, and FH fumarate hydratase.
† Additional rare syndromes or infrequent associations are not included.

notype, naturally occurring VHL mutations have
been evaluated to determine their effect on HIF-a
ubiquitination. An intriguing finding is that the
VHL mutations that disrupt HIF-a processing are
the same as those associated with the vascular man-
ifestations of von Hippel–Lindau disease, such as
hemangioblastoma (Fig. 2).15,16,23,24 Since renal-
cell carcinoma develops in only a subgroup of pa-
tients with hemangioblastoma, the overexpression
of HIF-a appears to be necessary for, but not suf-
ficient to induce, renal tumorigenesis. Neverthe-
less, HIF-a is vitally important to the pathogenesis
of this disease. VHL-induced inhibition of HIF-a
is sufficient to suppress the growth of clear-cell
renal-cell carcinoma in preclinical models.25,26 The
cell-matrix protein fibronectin,27 chaperonin TRiC/
CCT,28 microtubules,29 and transcription factor
Jade-130-32 are all molecules that interact with VHL
protein in a manner that is dependent on VHL mu-
tation, suggesting that they may also contribute to
disease pathogenesis.
Distinct from von Hippel–Lindau disease, famil-
ial clear-cell renal cancer has been reported in pa-
tients with translocations of chromosome 3p at a
fragile site at 3p14.33 Loss of the translocated chro- illary renal-cell carcinoma38 with type 1 histologic
mosome 3p probably implicates VHL protein in
the development of these tumors. Additional trans-
locations of chromosome 3 have been associated
with clear-cell renal-cell carcinoma as well.
papillary renal-cell carcinoma
Sporadic papillary renal-cell carcinoma has a five- cinoma, the MET receptor tyrosine kinase domain
year survival rate approaching 90 percent and a strik- undergoes autoactivating amino-acid–substitu-
ing 5:1 male predominance. Localized papillary re-
nal-cell carcinoma metastasizes less frequently than
clear-cell renal-cell carcinoma.34 However, the sur-
vival rate for metastatic papillary renal-cell carci-
noma is probably worse than that for clear-cell
renal-cell carcinoma.35 The risk of both types is
particularly increased among patients with end-
stage renal disease. Chromosome 7, which harbors
the MET proto-oncogene, is duplicated in 75 percent
of sporadic papillary cases. There are two subtypes
of papillary renal-cell carcinoma.36 Type 1 tumors
are papillary lesions covered by small cells with pale
cytoplasm and small oval nuclei with indistinct
nucleoli, and type 2 tumors are papillary lesions
covered by large cells with abundant eosinophilic
cytoplasm. Type 2 cells are typified by pseudostratifi-
cation and large, spherical nuclei with distinct nu-
cleoli. Type 2 tumors are genetically more heteroge-
neous, have a poorer prognosis, and may arise from
type 1 tumors.37
Papillary renal-cell carcinoma occurs in several
familial syndromes (MIM number 605074). He-
reditary papillary renal carcinoma is an autosomal
dominant disorder associated with multifocal pap-
features (Fig. 3).39 The causative gene, mutations in
which are responsible for hereditary papillary re-
nal carcinoma, has been identified at chromo-
some 7 and encodes MET, a receptor tyrosine kinase
that is normally activated by hepatocyte growth
factor 40 (Fig. 4C). In hereditary papillary renal car-

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 The new england journal of medicine

Figure 2. Schematic Representation of the Clinical Spectrum of von Hippel–Lindau Disease and Potential Biologic Mechanisms.
The three major manifestations of von Hippel–Lindau (VHL) disease — central nervous system hemangioblastoma, pheochromocytoma,
and clear-cell renal-cell carcinoma — are represented as Venn diagrams. Affected families may not have all three conditions, depending large-
ly on the type of mutation in the VHL gene inherited. Circle sizes are not intended to reflect the numbers of patients in each group. Type 1 VHL
disease (Panel A) is most common; it comprises clear-cell renal-cell carcinoma with central nervous system hemangioblastoma and is due to
major disruptions in the VHL protein, such as those resulting from truncating mutations. Type 2 VHL disease (Panel A) includes pheochro-
mocytoma with one, both, or neither of the other features. Type 2B disease predisposes patients to all three conditions, whereas type 2A in-
cludes hemangioblastoma and pheochromocytoma and type 2C includes only pheochromocytoma. Type 2 is most often due to more subtle
VHL gene mutations, such as missense mutations that result in the substitution of a single amino acid. Besides classic von Hippel–Lindau
disease, sporadic cases of hemangioblastoma or pheochromocytoma have been shown to be due to germ-line VHL mutations. In addition,
familial Chuvash polycythemia, which does not include any of the features of von Hippel–Lindau disease, is an autosomal recessive disorder
caused by homozygosity for the specific VHL missense mutation R200W. In Panel B, the spectrum of manifestations of von Hippel–Lindau
disease, along with biochemical studies, suggests the involvement of specific biochemical pathways. For example, the mutations in VHL pro-
tein that disrupt the ubiquitination and destruction of hypoxia-inducible factor a (HIF-a) are the same as those that correlate with the lesions
of hemangioblastoma. Interestingly, von Hippel–Lindau disease type 2A mutations disrupt HIF-a processing and do not cause renal cancer,
suggesting that the HIF pathway plus additional, unknown VHL pathways (called X pathways) must be disrupted for clear-cell renal-cell car-
cinoma to develop. The probable involvement of additional pathways is supported by the multistep nature of renal tumorigenesis. Alterna-
tively, the unknown pathway or pathways may simply reflect a higher level of expression of HIF-a in this subgroup of patients. Pheochromocy-
tomas can arise from mutations in the gene for VHL protein that do not affect HIF-a processing, suggesting that they arise through the
disruption of other, unknown VHL pathways (called Y pathways). Thus, the overexpression of HIF-a correlates closely with the development
of hemangioblastoma; appears to be necessary for, but not sufficient to induce, renal tumorigenesis; and is not necessary for the develop-
ment of pheochromocytoma.

tion mutations, which promote cellular transforma-
tion.41 Subsequently, chromosome 7 harboring the
MET mutation is duplicated, increasing the gene
dose.42,43 Only a small percentage of the cases of
the sporadic papillary type have MET mutations.40
Thus, the pathogenesis of hereditary papillary re-
nal carcinoma is usually different from that of spo-
radic papillary renal-cell carcinoma.
Patients with the hereditary leiomyomatosis and
renal-cell cancer syndrome (MIM number 605839)
are at risk for cutaneous and uterine leiomyo-
mas and solitary papillary renal-cell carcinoma with
type 2 histologic features.44 Occasionally, cases of
collecting-duct or clear-cell renal-cell carcinoma
occur. These cases of papillary renal-cell carcino-
ma metastasize early and are the most aggressive
of the familial types.45 Intriguingly, FH, the gene that
causes this autosomal dominant syndrome, encodes
fumarate hydratase, a Krebs-cycle enzyme.46 As with
the loss of a tumor-suppressor gene, the wild-type
FH allele is lost in hereditary leiomyomatosis and
in lesions of renal-cell carcinoma.47 Along simi-
lar lines, cases of renal-cell carcinoma with solid
histologic features or cases of the clear-cell form

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 medical progress

Figure 3. Steps in the Development of Renal-Cell Carcinoma.

In contrast to sporadic renal-cell carcinoma (Panels A and C), fewer steps are required for the development of renal-cell carcinoma in the in-
herited forms of the disease (Panels B and D), because all of the patient’s cells have a mutation that predisposes the patient to the disease.
As a result, the disease associated with the familial syndromes occurs earlier and is often multifocal. Each familial renal cancer syndrome is
autosomal dominant. In von Hippel–Lindau disease, a cellular recessive mechanism is involved, since both copies of the VHL gene are inac-
tivated (Panels A and B). VHL is a classic tumor-suppressor gene. In hereditary papillary renal carcinoma, one copy of the MET gene has an
activating mutation, which is inherited (Panel D). Chromosome 7, which includes the defective MET allele, becomes duplicated, increasing
the level of expression of the activated MET protein, which is a receptor tyrosine kinase for hepatocyte growth factor. Activated MET is a clas-
sic oncogene. A plus sign represents the wild-type allele; a minus sign represents a null allele. A plus sign in red type represents a mutated,
activated allele; two plus signs in red type represent duplication of that allele.

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 The new england journal
have been reported in patients with the hereditary
paraganglioma syndrome (MIM number 115310).
Certain forms of hereditary paraganglioma are as-
sociated with germ-line defects in the succinate de-
hydrogenase B gene.48 Succinate dehydrogenase B
protein is another mitochondrial, Krebs-cycle en-
zyme. Thus, an intriguing connection exists among
cellular ATP production, the hypoxic response, and
tumorigenesis in both neuronal and kidney tissue.
A number of sporadic cases of papillary renal-
cell carcinoma have chromosomal translocations in-
volving the TFE3 gene at chromosome Xp11.2.49-51
Children and young adults are affected without
predilection for sex, and the histologic features of
such cases have been variably described as papil-
lary renal-cell carcinoma, clear-cell renal-cell carci-
noma, or a unique type of pathology. The TFE3 gene
encodes a helix–loop–helix transcription factor
related to the proto-oncogene product c-myc. Key
TRE3 domains become fused with other gene prod-
ucts, and renal-cell carcinoma is probably due to
TFE3 overexpression.
oncocytoma and chromophobe renal-cell
carcinoma
Oncocytomas, which are benign, account for about
4 percent of nephrectomies performed because re-
nal-cell carcinoma is suspected. The chromophobe
variant of renal-cell carcinoma also accounts for
4 percent of all cases of renal-cell carcinoma52 and
may have a benign course after surgery, provided
that the tumor stage and grade are favorable.53 On-
cocytoma is thought to originate from type A in-
tercalated cells of the collecting duct, whereas
chromophobe renal-cell carcinoma is thought to
originate from type B intercalated cells.
The Birt–Hogg–Dubé syndrome (MIM number
135150) is a rare autosomal dominant disorder
characterized by hair-follicle hamartomas (fibro-
folliculomas) of the face and neck.54-57 About 15
percent of affected patients have multiple renal
tumors, most often chromophobe or mixed chro-
mophobe–oncocytomas. Occasionally, papillary or
clear-cell renal-cell carcinoma develops in patients
with the Birt–Hogg–Dubé syndrome. BHD, the gene
implicated in the syndrome, encodes the protein fol-
liculin,58 a suspected tumor suppressor. BHD mu-
tations occur only rarely in sporadic renal-cell car-
cinoma.59,60 The Birt–Hogg–Dubé renal phenotype
supports the existence of a close relationship be-
tween oncocytoma and chromophobe renal-cell
carcinoma.
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of medicine
Figure 4 (facing page). Molecular Mechanisms of the
Development of Renal-Cell Carcinoma.
Pathologic cooperativity between renal-cancer cells
of the clear-cell type and adjacent vasculature is shown
in Panel A. In clear-cell renal-cell carcinoma, hypoxia-
inducible factor a (HIF-a) transcription factor accumu-
lates, resulting in the overexpression of proteins that are
normally inducible with hypoxia, such as transforming
growth factor a and b (TGF-a and TGF-b, respectively),
vascular endothelial growth factor (VEGF), and platelet-
derived growth factor B chain (PDGF-B). The overex-
pressed VEGF, PDGF-B, and TGF-b act on neighboring
vascular cells to promote tumor angiogenesis. The aug-
mented tumor vasculature provides additional nutrients
and oxygen to promote the growth of tumor cells. TGF-a
acts in an autocrine manner on the tumor cells by signal-
ing through the epidermal growth factor receptor, which
promotes tumor-cell proliferation and survival. The role
of von Hippel–Lindau (VHL) protein in clear-cell renal-
cell carcinoma and in controlling the expression of the
HIF-a transcription factors is shown in Panel B. Under
normoxic conditions HIF-a is hydroxylated on two pro-
line residues by a proline hydroxylase and on an aspar-
agine residue by an asparagine hydroxylase.
Hydroxylation (OH) by proline hydroxylase permits bind-
ing of HIF-a to VHL protein, which promotes the ubiquit-
ination (Ub) and destruction of HIF-a by the proteasome
pathway. Hydroxylation by asparagine hydroxylase blocks
the interaction of HIF-a with transcriptional coactivator
p300. VHL protein, with elongin proteins C and B, binds
cul2 protein (a member of the cullin family of ubiquitin
ligase proteins). RING-box protein Rbx1 serves as the
ubiquitin transferase for the VHL skp-cullin-F-box pro-
tein (SCF) complex. In the absence of wild-type VHL
protein, hydroxylated HIF-a accumulates and is able
to heterodimerize with HIF-b and activate transcription
at hypoxia-response elements (HREs), which are found
in genes such as VEGF. In hypoxic conditions, HIF-a is
not hydroxylated and so cannot bind VHL protein. Panel
C shows the role of MET in papillary renal carcinoma.
MET is a receptor tyrosine kinase for hepatocyte growth
factor. In the absence of ligand, MET normally exists in
an autoinhibited state. MET homodimerizes in the pres-
ence of ligand hepatocyte growth factor and undergoes
reciprocal phosphorylation and activation. In hereditary
papillary renal carcinoma and in occasional sporadic
papillary renal-cell carcinoma, activating mutations of
MET disinhibit the receptor, even in the absence of
ligand. Furthermore, the mutated MET allele on chromo-
some 7 becomes duplicated, increasing the expression
of the activated MET protein.
collecting-duct renal-cell carcinoma
Collecting-duct renal-cell carcinoma accounts for
less than 1 percent of all cases of renal-cell carcino-
ma and is typically an aggressive tumor. Medullary
carcinoma of the kidney, which may be a variant of
the collecting-duct type, is associated with sickle
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 The new england journal of medicine

cell trait or disease. The collecting-duct form may ing. Organizations such as the VHL Family Alli-
be most similar to transitional-cell carcinoma of the ance (www.vhl.org) are a vital resource for patients,
urothelium. families, physicians, and researchers.

management of sporadic prognosis

and hereditary renal-cell
carcinoma
An enhancing renal mass on a CT scan obtained
after the administration of contrast material is a
strong clue that renal cancer is present. A staging
workup should be performed before treatment is
initiated. Multiple enhancing lesions, or a family his-
tory of renal-cell carcinoma, particularly in persons
younger than 50 years of age, suggests a hereditary
predisposition to the disease. Von Hippel–Lindau
disease, hereditary leiomyomatosis and renal-cell
cancer, and the Birt–Hogg–Dubé syndrome all have
extrarenal manifestations, whereas familial clear-
cell renal cancer and hereditary papillary renal carci-
noma do not. Thus, a careful physical examination
including ophthalmologic, neurologic, and derma-
tologic evaluation may be helpful. CT scanning or
magnetic resonance imaging (MRI) of the abdomen
and pelvis may reveal uterine tumors in patients
with hereditary leiomyomatosis and renal-cell can-
cer or renal cysts or pancreatic or adrenal involve-
ment in patients with von Hippel–Lindau disease.
Patients with hereditary renal-cell carcinoma
should be closely monitored. CT before and after
the administration of contrast material is the best
test for detection and assessment of renal masses,
with gadolinium-enhanced MRI as an alternative.
Such studies can be performed at intervals ranging
from every three to six months to every two to three
years, depending on the size of the lesions and the
type of syndrome. Larger masses require more fre-
quent evaluation. Because small masses are usually
of low grade, they can be observed until they reach
3 cm, at which time they should be removed.61,62
However, tumors caused by hereditary leiomyoma-
tosis and renal-cell cancer should be excised im-
mediately because of their aggressive nature. Pa-
tients with von Hippel–Lindau disease should
undergo MRI studies of the brain and spinal cord
to screen for hemangioblastoma. A family pedigree
should be generated, and family members at risk
should be encouraged to seek medical attention.
Testing is available for the VHL, MET, FH, and BHD
genes. One goal of such testing is to free unaffect-
ed family members from continued cancer screen-
Defining the prognosis of renal-cell carcinoma is
important for both therapeutic decision-making
and counseling patients. For metastatic renal-cell
carcinoma, poor prognostic factors include a low
Karnofsky performance-status score (a standard
way of measuring functional impairment in pa-
tients with cancer), a high level of serum lactate de-
hydrogenase, a low hemoglobin level, and a high
corrected level of serum calcium.63,64 The Univer-
sity of California, Los Angeles, Integrated Staging
System was developed to evaluate the prognosis at
diagnosis and in the presence of metastatic dis-
ease; it includes tumor–node–metastasis (TNM)
staging, the patient’s score on the Eastern Cooper-
ative Oncology Group performance-status scale (an-
other measure of functional impairment in patients
with cancer), and the Fuhrman nuclear grade, which
assesses histologic features of the tumor.65 This sys-
tem has been used successfully in more than 4000
patients at eight international centers.66
surgical treatment
radical nephrectomy
Surgical excision is the primary treatment for re-
nal-cell carcinoma. Radical nephrectomy, which
includes removal of the kidney en bloc with Gero-
ta’s fascia, the ipsilateral adrenal gland, and re-
gional lymph nodes, has been the standard thera-
py, although more limited approaches are being
explored. The surgical approach is determined by
the size and location of the tumor within the kid-
ney, the TNM stage, and any special anatomical
considerations.
Staging and evaluation for the presence of me-
tastases, including a careful history-taking and
physical examination, should be completed before
surgery. Routine laboratory studies should include
measurement of the hematocrit and serum levels
of creatinine, calcium, and alkaline phosphatase and
a urinalysis for proteinuria. Imaging studies, such as
radiographs of the chest, CT of the abdomen and
pelvis, and in some cases, MRI evaluation of the re-
nal vein and inferior vena cava, CT of the chest or
head, or bone scanning may be needed. The fre-

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 medical progress

quency of follow-up after surgery depends on the adjacent structures. Because identification of the
stage of the tumor. type of renal-cell carcinoma is important, a core bi-
opsy of the renal mass should be performed as part
surgery for metastatic disease of the procedure. Ideal candidates for minimally
Nephrectomy may be warranted, even in the pres- invasive percutaneous ablative therapy are patients
ence of metastatic disease. The combination of in- with tumors less than 3 cm in diameter who have
terferon alfa and nephrectomy is superior to inter- serious coexisting conditions and for whom stan-
feron alfa alone, offering a survival advantage of dard approaches would pose substantial risks. Pa-
3 to 10 months.67,68 Surgical excision of a solitary tients with multifocal tumors may also benefit from
metastasis in patients with advanced renal-cell car- minimally invasive percutaneous procedures. High-
cinoma is recommended in many cases, but this frequency focused ultrasound applied externally to
approach has not yet been proved to be effective in the body is being studied as another potential min-
prolonging survival. imally invasive therapy.

nephron-sparing partial nephrectomy medical treatment

Nephron-sparing partial nephrectomy has gained
acceptance for treating tumors less than 4 cm in di- Medical therapies are generally offered for locally
ameter. Other indications for partial nephrectomy advanced or metastatic renal-cell carcinoma (Ta-
may include a solitary kidney, bilateral renal masses, ble 2), and much of the clinical experience with
or renal insufficiency, as well as the presence of hy- this approach is in patients with the clear-cell type.
pertension, diabetes, or hereditary renal-cell carci- Because response rates are low, the need to identify
noma syndromes. Results achieved with nephron- new therapeutic agents is great.74
sparing surgery are similar to those with radical
nephrectomy, but a disadvantage is a rate of local chemotherapy
recurrence of 3 to 6 percent.69 Rates of response to chemotherapy alone are low
(roughly 4 to 6 percent).75 Drug resistance may be
laparoscopic nephrectomy related to the expression of the multidrug resis-
First reported in 1991,70 laparoscopic nephrecto- tance transporter in proximal-tubule cells — the
my has accelerated the evolution toward minimally cells from which clear-cell and papillary renal-cell
invasive surgical management of renal-cell carci- carcinoma may originate. Chemotherapy may be
noma. The benefits of the laparoscopic approach more efficacious for advanced non–clear-cell re-
include decreased postoperative pain, a shorter hos- nal-cell carcinoma, particularly the collecting-duct
pitalization, and a quicker recovery. The laparo- type.76-78 A phase 2 trial of carboplatin and pacli-
scopic approach has been used for both radical taxel for the collecting-duct form of the disease is
nephrectomy and partial nephrectomy. The laparo- under way.
scopic partial nephrectomy, however, is a technically
demanding procedure with the potential for in- immunomodulatory therapies
creased perioperative complications.71 The value of immunomodulatory therapy for clear-
cell renal-cell carcinoma is supported by reports of
percutaneous ablative approaches occasional spontaneous tumor regression, infre-
The most recent evolution in the surgical manage- quent complete regression of metastatic disease
ment of small tumors has been percutaneous ther- with cytokine therapies, and promising early results
mal ablative techniques that use radiofrequency with allogeneic stem-cell transplantation and tumor
heat ablation72 or cryoablation73 to destroy tumor vaccines. The goal of immunomodulatory therapy
cells. A needle probe is advanced through the skin is to boost either tumor antigenicity or host surveil-
and directed into the tumor under image guid- lance. Unique tumor antigens may also be induc-
ance. Although early results of radiofrequency ab- ible in renal-cell carcinoma.79
lation and cryoablation are encouraging, larger tri-
als with long-term follow-up are needed. The rates Interferon Alfa
of complications appear to be low, but reported ad- About 14 percent of cases of metastatic clear-cell
verse events include intraoperative and postopera- renal carcinoma respond to interferon alfa alone.
tive hemorrhage, urinary leakage, and injury to Various doses and routes have been used.80 The me-

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Copyright © 2005 Massachusetts Medical Society. All rights reserved.
 The new england journal
Table 2. Medical Therapies for Advanced Renal Cancer.*
FDA-approved regimen
High-dose interleukin-2 (aldesleukin, immunomodula-
tory cytokine)
Commonly used agents
Low-dose interleukin-2
Interferon alfa (immunomodulatory cytokine)
Experimental therapies
Bevacizumab (humanized VEGF-neutralizing antibody)
Sunitinib malate (VEGF receptor and multitargeted kinase
inhibitor)
Sorafenib tosylate (VEGF receptor and multitargeted ki-
nase inhibitor)
Panitumumab (human EGFR-neutralizing antibody)
Gefitinib (EGFR tyrosine kinase inhibitor)
Erlotinib (EGFR tyrosine kinase inhibitor)
Temsirolimus (inhibitor of the mammalian target of
rapamycin)
Tumor vaccines
Allogeneic stem-cell transplantation
* FDA denotes Food and Drug Administration, VEGF vas-
cular endothelial growth factor, and EGFR epidermal
growth factor receptor. The trade name for interleukin-2
is Proleukin; for bevacizumab, Avastin; for sunitinib
malate, Sutent; for sorafenib tosylate, Nexavar; for gefi-
tinib, Iressa; for erlotinib, Tarceva.
dian duration of response is six months and rarely
exceeds two years. Because the side effects of the
drug are not onerous, it appears to be a good choice
to use in combination with other agents in experi-
mental approaches.
Interleukin-2
High-dose interleukin-2 is the standard therapy for
advanced renal-cell carcinoma and is the only regi-
men for this disease approved by the Food and
Drug Administration. However, many patients with
metastatic disease cannot take high-dose interleu-
kin-2, because it causes a capillary leak syndrome
or because it is not available in all treatment cen-
ters. High-dose interleukin-2 induces responses in
21 percent of patients, as compared with only 13
percent of patients who receive low-dose interleu-
kin-2.81 The median duration of response has been
reported to be 54 months overall, and for those
with a complete response, the median duration of a
response is yet to be reached.82 Interleukin-2 has
also been used in combination with other drugs,
but it is unclear whether combined therapy achieves
better results than interleukin-2 alone. Thus, inter-
leukin-2 is a highly effective therapy for a subgroup
2486 n engl j med 353;23 www.nejm.org
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Copyright © 2005 Massachusetts Medical Society. All rights reserved.
of medicine
of patients with metastatic disease. Identifying fea-
tures predictive of a response to interleukin-2 would
represent a further advance, and efforts are being
made to identify patients with clear-cell renal carci-
noma who would be likely to have a response to in-
terleukin-2 therapy on the basis of pathological
characteristics and expression of CA9.
adjuvant therapy
Given the high rate of recurrence of renal-cell car-
cinoma after nephrectomy, a follow-up adjuvant
approach would be desirable, especially for pa-
tients with high-risk, locally advanced disease.
However, conventional chemotherapy, interferon
alfa, or even interleukin-283 has not proved effec-
tive as an adjuvant therapy. Approaches currently
being tested include tumor vaccines and a mono-
clonal antibody directed against CA9.
evolving therapies
stem-cell transplantation
Allogeneic stem-cell transplantation performed af-
ter the administration of a non–marrow ablative
regimen elicits a potent graft-versus-tumor effect
and appears promising for treating clear-cell renal-
cell carcinoma.84 Protocols developed at the Nation-
al Institutes of Health have used myelosuppress-
ive pretreatment, followed by an infusion of donor
CD34+ cells and T cells from an HLA-identical sib-
ling.84 A course of immunosuppressive agents,
such as cyclosporine, is used to limit graft-versus-
host disease and is rapidly tapered. Twenty of the
first 45 patients with metastatic renal-cell carcino-
ma who underwent stem-cell transplantation had a
response (44 percent).85 However, results in some
other centers have been less promising. The re-
sponses have correlated well with the development
of graft-versus-host disease and with the conver-
sion of T-cell chimerism to full donor origin. One
goal is to identify the tumor epitopes that are initi-
ating the graft-versus-tumor response to improve
treatment specificity. The two drawbacks to stem-
cell transplantation have been severe graft-versus-
host disease, which can be life-threatening, and
the need for a haplotype-matched sibling donor.
Prognosis is also an important guide to patient se-
lection, since responses take several months. The
next generation of strategies for stem-cell transplan-
tation may include the use of tumor vaccines after
transplantation as well as the use of cytokine thera-
py to boost recipient or even donor immunity.
december 8, 2005
 medical progress

tumor vaccines vided a key “proof of principle” of the efficacy of

Tumor vaccines represent a potential means of en- anti-angiogenic therapy and may offer additional
hancing host immunity. A promising approach to benefit when given in combination with other
the treatment of advanced clear-cell renal carcinoma drugs. Inhibitors of VEGF receptor tyrosine kinase
uses autologous or donor dendritic cells, which are being developed and tested. Indeed, the multi-
initiate a primary immune response by presenting targeted kinase inhibitors sunitinib and sorafenib
antigen in the context of costimulatory molecules. have shown great promise in phase 2 and phase 3
Dendritic cells can be pulsed with tumor protein,86 trials, with at least stabilization of disease in as many
DNA, or RNA87; they can even be fused with tumor as 70 percent of patients with cytokine-refractory
cells88,89 to present tumor antigens in a context fa- disease.
vorable for therapy. Such vaccines are generally
well tolerated, but they will require further optimi- TGF-a–Pathway Components as Molecular Targets
zation. Concomitant administration of cytokines TGF-a is a potent growth factor for epithelial cells
may improve the response to vaccines. that acts through the epidermal growth factor re-
ceptor (EGFR), which is a receptor tyrosine kinase.
target antigens TGF-a is overexpressed in the epithelium in clear-
A goal of stem-cell or vaccine therapies is to char- cell renal carcinoma and is a VHL target.95 Over-
acterize the tumor antigens involved in the immune expression of TGF-a is an early event in the patho-
response. One potential target is the G250 renal can- genesis of this disease.96 Furthermore, growth
cer antigen, which has been identified as CA9. The of renal cancer cells in culture is dependent on
CA9 gene is a target of HIF and so is overexpressed TGF-a.97 Thus, the TGF-a pathway is a logical
in VHL-related clear-cell renal carcinoma, even in the choice for therapeutic intervention.
earliest lesions of von Hippel–Lindau disease.90 Antibodies against EGFR are thought to bind
Thus, in cases of renal-cell carcinoma, a high pro- EGFR and promote its down-regulation from
portion of CA9-positive cells may be associated with the cell surface. A fully human monoclonal anti-
a more favorable prognosis.91 As a transmembrane body against human EGFR, called panitumumab
protein, CA9 may also be a therapeutically useful tu- (ABX-EGF), has been evaluated in a phase 2 trial
mor antigen.92,93 It will be important to identify involving 88 patients with metastatic renal-cell car-
additional target antigens. cinoma.98 Only one patient had a complete re-
sponse, and two had partial responses — a disap-
therapies targeting vegf and tgf-a pointing result. Small-molecule inhibitors of the
pathways EGFR tyrosine kinase are also being developed.99
Originally identified as regulated by VHL, VEGF The quinazolines gefitinib and erlotinib are now in
and TGF-a are now promising therapeutic targets phase 2 trials. In a phase 1 trial of erlotinib, just
in clear-cell renal carcinoma. The manner in which one patient with metastatic disease had a com-
these molecules interact with the cancer epitheli- plete response.100 Erlotinib is also being tested in
um and surrounding vascular endothelium leads to combination with bevacizumab, although encour-
tumor progression (Fig. 4A). A combination of ther- aging initial results could not be confirmed in a
apies based on rational targets such as these may randomized phase 2 trial.
therefore be a powerful approach to advanced renal-
cell carcinoma. Other Approaches
Temsirolimus (CCI-779), a selective inhibitor of
VEGF-Pathway Components as Molecular Targets the mammalian target of rapamycin, has shown
VEGF is overexpressed throughout clear-cell renal- efficacy in a phase 2 trial of metastatic renal-cell
cell carcinoma tissue and may be the most impor- carcinoma.101 Temsirolimus may inhibit HIF as
tant tumor angiogenic factor. A randomized phase well. Partial responses were noted in 7 percent of
2 trial involving patients with metastatic renal-cell patients, and minor responses in 26 percent. The
carcinoma investigated the efficacy of bevacizu- median survival rate was 15 months. The notable
mab, a humanized VEGF-neutralizing antibody.94 activity of the drug in patients with poor prognos-
This agent extended the interval before tumor pro- tic features prompted a phase 3 trial. Other op-
gression to 4.8 months, as compared with 2.5 tions are being pursued, including agents target-
months for placebo. Bevacizumab therefore pro- ing HIF.

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Copyright © 2005 Massachusetts Medical Society. All rights reserved.
 The new england journal of medicine

The mutated, activated hepatocyte growth factor

summary and prospects
for the future
The poor prognosis of advanced renal-cell carci-
noma demands an aggressive search for new ther-
apeutic agents and strategies. Leads will probably
come from both a careful elucidation of the biology
of each type of the disease and broader approach-
es, such as gene-expression–array and proteome
analyses. Much has been accomplished since the
identification of the VHL gene in 1993. Already,
VHL protein pathways, such as those involving
VEGF and TGF-a, are being exploited therapeuti-
cally, and agents affecting these pathways might be
more effective when used in combination. Identi-
fication of the MET gene was another key advance.
receptor MET could be targeted in the papillary
form of the disease.102,103 The immune respon-
siveness of renal-cell carcinoma provides an op-
portunity for the development and optimization of
vaccines and other immune therapies. Preserva-
tion of as much renal function as possible and re-
duced rates of complications are two goals of new
minimally invasive approaches to renal-cell carci-
noma; other goals are to identify early markers of
disease, prognosis, or responsiveness to therapy.
Supported in part by grants (RO1 CA79830 and RO1 DK67569, to
Dr. Cohen) from the National Institutes of Health.
We are indebted to Drs. Michael B. Atkins, William G. Kaelin, Jr.,
Matthew R. Smith, Walter M. Stadler, and Berton Zbar for careful re-
view of the manuscript.

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