RCC, which accounts for 2% to 3% of all adult malignant neoplasms, is the most lethal of the common urologic cancers.

Five-year relative survival rates for patients diagnosed in 2002 to 2008 were 71% for kidney cancer, 78% for bladder
cancer (excluding carcinoma in situ), and 99% for prostate cancer Approximately 65,000 new diagnoses of RCC are made
each year in the United States, and 13,000 patients die of disease. Overall, approximately 12 new cases are diagnosed
per 100,000 population per year, with a male-to-female predominance of 3 : 2 . This is primarily a disease of
older adults, with typical presentation between 50 and 70 years of age. However, diagnosis of renal cancer has
increased more rapidly in those less than 40 years of age than any other age group. Incidence rates are 10% to 20%
higher and 5-year survival rates 5% lower in African-Americans for unknown reasons. The majority of cases of
RCC are believed to be sporadic; only 2% to 3% are proven to be familial . The incidence of RCC has increased
since the 1970s by an average of 3% to 4% per year, largely related to the more prevalent use of ultrasonography
and CT for the evaluation of a variety of abdominal complaints . This trend has correlated with an increased
proportion of incidentally discovered and localized tumors and with improved 5-year survival rates for patients with this
stage of disease. However, other factors must also be at play because a steadily increasing mortality rate from RCC per
unit population has been observed in all ethnic groups and both genders since the 1980s. This rising mortality rate is
particularly troubling because the proportion of advanced tumors has actually decreased.
This suggests that a deleterious change in tumor biology may have occurred during the past several decades, perhaps
related to tobacco use, dietary factors, or exposure to other carcinogens
RCC in childhood is uncommon, representing only 2.3% to 6.6% of all renal tumors in children. Mean age at
presentation in children is 8 to 9 years, and the incidence is similar in boys and in girls. Although Wilms tumor is much
more common in younger children, RCC is as common as Wilms tumor during the second decade of life. RCC in
children and young adults is more likely to be symptomatic, locally advanced, high grade, and of unfavorable histologic
subtypes.
TFE3 protein overexpression, which correlates with the presence of ASPL-TFE3 and PRCC-TFE3 gene translocation events
involving the X and first chromosomes, is relatively common in children and young adults with RCC and is unique to this
population. The clinical significance of TFE3 protein overexpression is not well defined, although preliminary data
suggest that these tumors may show differential sensitivity to certain chemotherapeutic agents. A distinct pathologic
subtype has been described in patients with TFE3 overexpression that exhibits both clear cell and papillary features .
Most studies suggest that stage for stage, children and young adults with RCC may respond better to surgical
therapy, and a number of longterm survivors have been reported after RN and lymphadenectomy for lymph node–
positive disease.An aggressive surgical approach with formal lymphadenectomy has thus been recommended
at the time of RN when RCC is suspected in children or young adults

RCCs were traditionally thought to arise primarily from the proximal convoluted tubules, and this is probably
true for the clear cell and papillary variants. However, we now know that other histologic subtypes of RCC, such
as chromophobe RCC and collecting duct carcinoma, are derived from the more distal components of the nephro).
The most generally accepted environmental risk factor for RCC is tobacco exposure, although the relative
ssociated risks have been modest, ranging from 1.4 to 2.5 compared with controls. All forms of tobacco use have
been implicated, and risk increases with cumulative dose or pack-years. Relative risk is directly related to duration of
smoking and begins to fall after cessation, further supporting a cause-andeffect relationship Tobacco use accounts for
20% to 30% of cases of RCC in men and 10% to 20% in women.
Obesity is now accepted as another major risk factor for RCC, with an increased relative risk of 1.07 for each
additional unit of body mass index . The increased prevalence of obesity likely contributes to the increased incidence of
RCC in Western countries, and it has been estimated that more than 40% of cases of RCC in the United States may be
causally linked to obesity . Potential mechanisms linking obesity to RCC include increased insulin-like growth factor-1
expression, increased circulating estrogen levels, and increased arteriolar nephrosclerosis and local inflammation
Hypertension appears to be the third major etiologic factor for RCC. Diuretics and other antihypertensive
medications have also been implicated, but the weight of the epidemiologic evidence suggests that it is the underlying
disorder, hypertension, rather than the treatment, that increases the risk of RCC. The proposed mechanisms are
hypertensioninduced renal injury and inflammation or metabolic or functional changes in the renal tubules that may
increase susceptibility to carcinogens.
Although a number of other potential etiologic factors have been identified in animal models, including viruses,
lead compounds, and more than 100 chemicals such as aromatic hydrocarbons, no specific agent has been
definitively established as causative in human RCC. The potential role of trichloroethylene exposure has been actively
investigated; some studies showed relative risks ranging from twofold to sixfold, but others have argued that inherent
biases likely account for these results. Slightly increased relative risks for RCC have been reported for workers in the
metal, chemical, rubber, and printing industries and those exposed to asbestos or cadmium, but the data are not
particularly convincing. Case-control studies have shown that RCC is more common among individuals with low
socioeconomic status and urban background, although the causative factors have not been defined.
The typical modern Western diet (high in fat and protein), increased intake of dairy products, and increased consumption
of coffee or tea have been associated with RCC, but the relative risks have been modest, and conflicting data are available
in most instances. A family history of RCC may also be a factor; one study showed a relative risk of 2.9 for individuals
with a first- or second-degree relative with RCC. Other potential iatrogenic causes include regular usage of nonsteroidal
anti-inflammatory drugs, which was associated with a relative risk of 1.51, while aspirin and acetaminophen were not
associated with any increased risk. Retroperitoneal radiation therapy, typically administered for Wilms tumor or
testicular cancer, appears to be a risk factor for RCC, although the relative risks are low. An increased incidence of RCC is
also observed in patients with end-stage renal disease and certain familial syndromes such as tuberous sclerosis, as
discussed later.

Most RCCs are round to ovoid and circumscribed by a pseudocapsule

of compressed parenchyma and fibrous tissue rather
than a true histologic capsule. Unlike upper tract urothelial carcinomas,
most RCCs are not grossly infiltrative, with the notable
exception of collecting duct carcinoma and sarcomatoid variants.
Tumor size has averaged between 4 and 8 cm in most series but can
vary from a few millimeters to large enough to fill the entire
abdomen. Tumors smaller than 3 cm were previously classified as
benign adenomas, but some small tumors have been associated
with metastases (Nguyen and Gill, 2009), and most pathologists
agree that, with the exception of oncocytomas and some small
(<5-mm) low-grade papillary adenomas, there are no reliable
histologic or ultrastructural criteria to differentiate benign from
malignant renal epithelial tumors (see Chapter 56). When they
are bivalved, RCCs consist of yellow, tan, or brown tumor interspersed
with fibrotic, necrotic, or hemorrhagic areas; few are
uniform in gross appearance. Cystic degeneration is found in 10%
to 25% of RCCs and appears to be associated with a better prognosis
compared with purely solid RCC (Webster et al, 2007; Jhaveri
et al, 2013). Calcification can be stippled or plaquelike and is found
in 10% to 20% of RCCs.
Nuclear features can be highly variable. Grading has been
based primarily on nuclear size and shape and the presence or
absence of prominent nucleoli. Fuhrman’s system (Table 57-6) is
an independent prognostic factor for RCC generally and for clear
cell RCC in particular (Fuhrman et al, 1982). Recent evidence suggests
that Fuhrman grade is also a significant predictor of outcome
for papillary RCC (Klatte et al, 2010a; Sukov et al, 2012), but features
other than nuclear characteristics may form the basis of a
preferred scheme for chromophobe RCC (Delahunt et al, 2007;
Finley et al, 2011; Cheville et al, 2012).
Aggressive local behavior is not uncommon with RCC and can
be expressed in a variety of ways. Frank invasion and perforation
of the renal capsule, renal sinus, or collecting system are found
in approximately 20% of cases, although displacement of these
structures is a more common finding. Further spread to involve
adjacent organs or the abdominal wall is often precluded by the
Gerota fascia, although some high-grade RCCs are able to overcome
this natural barrier. One unique feature of RCC is its
predilection for involvement of the venous system, which is
found in 10% of RCCs, more often than in any other tumor
type (Skinner et al, 1972; Schefft et al, 1978). This is most commonly
manifested in the form of a contiguous tumor thrombus
that can extend into the inferior vena cava (IVC) as high as the
right atrium. Many such tumor thrombi are highly vascularized
by arterial blood flow (Novick et al, 1990), and some directly
invade the wall of the renal vein or vena cava, which correlates
with compromised prognosis (Skinner et al, 1972; Schefft et al,
1978; Zini et al, 2008).
Most sporadic RCCs are unilateral and unifocal. Bilateral
involvement can be synchronous or asynchronous and is found
in 2% to 4% of sporadic RCCs, although it is considerably more
common in patients with familial forms of RCC, such as von
Hippel-Lindau disease. Multicentricity, which is found in 10% to
20% of cases, is more common in association with papillary
histology and familial RCC (Mukamel et al, 1988; Cheng et al,
1991; Krambeck et al, 2008). Satellite lesions are often small and difficult to identify by preoperative imaging,
intraoperative ultrasonography,
or visual inspection; they appear to be the main factor
contributing to local recurrence after partial nephrectomy (Mukamel
et al, 1988). Microsatellite analysis suggests a clonal origin for
most multifocal RCC within the same kidney (Junker et al, 2002),
but tumor in the contralateral kidney is likely to be an independent
growth if it is synchronous or a metastasis if it is asynchronous
(Kito et al, 2002). Molecular analyses, such as gene expression
profiling, may help to determine whether an asynchronous tumor
is a second primary tumor or a metastasis (Lane et al, 2009a). Most
recently, comprehensive sequencing of multiple biopsy specimens
obtained from primary and metastatic tumors in the same patient
has revealed significant intratumor heterogeneity (Gerlinger et al,
2012). These studies suggest that analysis of single biopsy samples
may underestimate this inherent heterogeneity and prevent discernment
of “driver” mutations from “passenger” mutations, presenting
significant challenges to personalized medicine and biomarker
development.
All RCCs are, by definition, adenocarcinomas, derived from
renal tubular epithelial cells (Zhou, 2009) (Table 57-7). Most
RCCs share ultrastructural features, such as surface microvilli
and complex intracellular junctions, with normal proximal
tubular cells and are believed to be derived from this region of
the nephron (Kim and Kim, 2002; Axelson and Johansson, 2013).
Two aggressive subtypes of RCC, renal medullary carcinoma and
collecting duct carcinoma, appear to be derived from more distal
elements of the nephron Since the early 1990s the histologic classification of RCC has
undergone several major revisions (see Table 57-7) (Zambrano
et al, 1999; Zhou, 2009; Algaba et al, 2011). Traditionally, RCC was
divided into four histologic subtypes: clear cell, granular cell, tubulopapillary,
and sarcomatoid. On the basis of advances in the
molecular genetics of RCC and a more discerning interpretation of
histologic and ultrastructural features, a newer classification scheme
was proposed by Kovacs (1993). This classification system was
approved by an international consensus workshop of clinicians and
researchers in the field (Weiss et al, 1995; Störkel et al, 1997; Zambrano
et al, 1999). In this system, granular cell tumors were reclassified
into other categories based on distinct histopathologic
features, chromophobe RCC was recognized as a new RCC subtype,
and sarcomatoid features were categorized as variants of other histologic
subtypes rather than a distinct tumor type. Current practice
is to identify the primary histologic subtype and comment on
the presence and extent of sarcomatoid differentiation rather
than to separate these tumors into a distinct category, although
the prognostic implications have not changed (Cheville et al,
2004; Algaba et al, 2011). Depending on well-defined histologic
and ultrastructural criteria, granular cell tumors were reclassified as
papillary RCC or as eosinophilic variants of chromophobe RCC or
combined with clear cell RCC. Another important development was
the identification of renal medullary carcinoma that is common in
young African-Americans with sickle cell trait (Davis et al, 1995;
Abern et al, 2012). With additional advances in ancillary pathologic
studies, including electron microscopy, immunohistochemistry,
molecular genetics, and cytogenetics, several additional unique subtypes
of RCC have been identified since implementation of the
1993 classification system. Based on these findings, an updated
classification of malignant epithelial tumors of the kidney was presented by the World Health Organization in 2004 and
remains
current at this time (see Table 57-7) (Eble et al, 2004).
The World Health Organization classification reflects current
understanding of RCC not as a single malignant neoplasm but
rather as a group comprising several different tumor subtypes,
each with a distinct genetic basis and unique clinical features.
Important changes include the addition of several RCC subtypes
with distinct pathologic and clinical features that were previously
grouped within “conventional” or unclassified RCC. One example
of this is RCC associated with XP11.2 translocations/TFE3 gene
fusions, which has microscopic features of both clear cell and papillary
RCC and occurs primarily in children and young adults (Argani
et al, 2001; Camparo et al, 2008; Geller et al, 2008). Another is
mucinous tubular and spindle cell carcinoma, which is indolent in
almost all instances (Hes et al, 2002; Ferlicot et al, 2005; Fine et al,
2006). Sophisticated gene expression profiling and proteomic analyses
support the individuality of each of these tumor subtypes and
hold great promise for differentiating additional subtypes in the
future (Yang et al, 2006; Jonasch et al, 2012). This is clearly a field
in evolution, with changes stimulated by basic science advances and
astute clinical observation.