Renal Tumors: The Good, the Bad, and the Ugly...Renal Tumors: The Good, the Bad, and the Ugly Robert...

Renal Tumors: The Good, the Bad, and the

Ugly

Robert C. Flanigan, Anthony J. Polcari, Cory M. Hugen

Abstract- The term renal cell carcinoma

(RCC) is used to describe a

heterogeneous group of tumors which

vary histologically, genetically and

molecularly. Recently extensive

research has been conducted to identify

characteristics which predict outcomes

among patients with RCC. In addition to

histologic subtype, these include tumor

size, patient age, mode of presentation,

and various hematologic indices, among

others. Several groups have

incorporated these clinical and

pathologic features into nomograms

which help the clinician better define

individual patient prognosis and direct

the optimum therapeutic approach. In

this article we review these prognostic

variables and nomograms for RCC.

Keywords: renal, carcinoma, tumor,

prognosis, clear cell, papillary, predictor,

nomogram

I. Introduction

Renal cancer ranks fourteenth on the

list of most common malignancies

worldwide.1 Its incidence varies by

geographic region, with the highest rates

observed in Europe and North America.2

It occurs more commonly in the elderly,

with a rising incidence until about 75

years of age. 3 Men are affected more

commonly than women, although the

cancer-specific survival between the

groups is similar.4

In the United States, the incidence of

renal cancer has continued to increase by

approximately 3% each year over the

last three decades.5 Although the largest

rise has been observed among small

tumors, the incidence of large tumors

and the overall mortality has continued

to increase as well.5 Although a

significant downward stage migration

has occurred in recent years, up to 30%

of patients present with advanced

disease at diagnosis.6 In 2008 there

were fifty-seven thousand new diagnoses

of renal cancer and thirteen thousand

deaths, making renal cell carcinoma

(RCC) the most lethal of genitourinary

cancers.7

RCC is a heterogeneous disease with

tremendous variability observed

between, and even within, various tumor

subtypes. While many tumors behave in

a rather indolent manner, others progress

rapidly despite even the most aggressive

therapies. In recent years an

extraordinary amount of research has

focused on differentiating the good, bad,

and ugly tumors. In this paper we will

review various prognostic features that

are associated with RCC.

A. Size

Due to the widespread use of

abdominal imaging to evaluate

symptoms that are often unrelated to the

genitourinary tract, the incidental

detection of renal masses has become

commonplace.8 In fact, it is estimated

Proceedings of the World Medical Conference

39

that 50% of newly diagnosed renal

tumors are discovered in this fashion.9

Fortunately, this phenomenon has

resulted in a downward stage migration

and a more favorable prognosis for many

patients at diagnosis.10 Incidentally

discovered masses ultimately proven to

be RCC tend to be of lower grade and

stage, and are associated with an

improved 5-year survival rate compared

with their symptomatic counterparts.11, 12

Several authors have found that the

risk of malignancy is directly related to

tumor size. Frank et al. reviewed the

pathology of over 2,700 patients

undergoing surgery for renal tumors

between 1970 and 2000, and found that

46% of tumors <1 cm were benign

compared to only 6% of tumors >7 cm.

For each 1 cm increase in size the odds

of malignancy rose by 17%.13 A recent

study from Memorial Sloan-Kettering

Cancer Center found that among patients

with proven RCC, each 1cm increase in

tumor size increased the odds of having

a tumor of high grade by 25%.14 A

nomogram was developed by Lane et al.

to predict the likelihood that an

enhancing renal mass ≤ 7cm will be benign based on the age of the patient,

size of the lesion on computed

tomography (CT), presence or absence

of local symptoms, and history of

smoking.15

Recent data has helped to shed some

light on the natural history of the small

renal mass. A meta-analysis of 234

solid, untreated, observed renal masses

with a mean size of 2.6 cm found that

the average growth rate of all lesions

was 0.28 cm/year. Among those lesions

proven to be RCC by pathological

confirmation, the mean growth rate was

0.4cm/year. Interestingly, lesion size

was not predictive of growth rate, and

only 1% of patients in this series

developed progression to metastatic

disease.16

Tumor size is one of the most

important prognostic indicators among

patients with surgically treated renal cell

carcinoma.17-19 Russo analyzed the

survival rates of patients undergoing

resection of localized kidney cancers

between 1989 and 2004 and found

progression-free survival rates of 98%,

95%, 90%, and 70% for patients with

tumors <2 cm, 2-4 cm, 4-7 cm, and >7 cm, respectively.

20 Tumor size is an

important component of the 2002 TNM

staging system for renal cancer, which

stratifies organ confined tumors into

stage T1 or T2 based on a size cutoff of

7cm. Although other investigators have

proposed different cutoff points for

distinguishing T1 from T2 tumors18, 21, 22

,23 the is little debate that size remains

among the most important prognostic

factors. In fact, one study from New

Zealand demonstrated that the risk of

death increases as a continuous variable

with increasing tumor size.24

Partial nephrectomy (PN) has become

a well-established treatment for RCC,

and size has been used to select patients

for this modality. Hafez reviewed the

Cleveland Clinic experience with PN

and found that patients with tumors of

size ≤ 4 cm had significantly more favorable 5-year cancer specific survival

and recurrence rates than those with

tumors greater than 4 cm.25 Another

series of selected patients demonstrated

that the outcomes for patients with

tumors between 4 and 7cm were similar

whether partial or radical nephrectomy

(RN) was performed.26 Recently a

multicenter international series of over

fourteen hundred patients also found that

there was no difference in the rate of

cancer-specific death for patients with

stage T1b tumors undergoing partial


40

versus radical nephrectomy (6% vs. 9%,

p=0.6).27

Other benefits of renal preservation

among those undergoing treatment of

small renal masses have also become

more apparent in recent years. Huang et

al. retrospectively reviewed a cohort of

662 patients with normal serum

creatinine concentrations and two

healthy kidneys who underwent either

radical or partial nephrectomy for

solitary renal cortical tumors ≤ 4 cm. Those undergoing RN as compared with

PN were 3.8 and 11.8 times more likely

to develop chronic kidney disease as

defined by glomerular filtration rate

(GFR) < 60 and < 45 ml/min per 1.73 m2, respectively.

28 Chronic kidney

disease has been independently

associated with death, cardiovascular

disease, and hospitalization.29

Furthermore, another study by Huang

found that after a median follow-up of 4

years, patients with tumors < 4 cm who received RN as compared with PN had

an almost 40% increased risk of

cardiovascular events after surgery and

all cause mortality.30 These data in

combination with the excellent

oncologic outcomes for partial

nephrectomy have led to the

development of the American Urological

Association Guidelines on the

management of clinical stage T1 renal

masses.31

B. Histology

RCC represents a group of

heterogenous tumors with unique

histogenic origin, cytogenetic

characteristics, and biologic behavior.

According to the 1997 American Joint

Committee on Cancer (AJCC) and

International Union Against Cancer

(UICC) classification, there are four

major histological subtypes of RCC:

clear cell, papillary, chromophobe, and

collecting duct carcinomas. The modern

concept of origin of renal cancers

suggests that clear cell and papillary

cancers arise from the proximal tubules,

whereas chromophobe tumors,

oncocytomas and collecting duct

carcinomas arise from the distal

convoluted tubules and collecting ducts.

Clear cell RCC is the most common

renal cancer subtype, accounting for 60-

70% of all cases in the United States. 32

Alterations in chromosome 3p have been

detected in the vast majority of sporadic

clear cell RCCs, many of which involve

the Von Hippel-Lindau (VHL) tumor

suppressor gene. 33 Whether clear cell

histology portends a worse outcome than

other histologic subtypes has been

controversial, although there is mounting

evidence that clear cell carcinomas are

more aggressive.34-36 In a recent study

from the Mayo Clinic, clear cell

carcinoma subtype was an independent

predictor of metastasis and cancer

specific death as compared to papillary

and chromophobe tumors, even after

adjusting for other clinicopathologic

features.37

One newly recognized subset of clear

cell RCCs, cystic renal cell carcinoma,

deserves mention. Several small series

have described the low malignant

potential of these tumors and have

recommended nephron-sparing surgery

whenever feasible. Among a total of 89

patients with cystic renal cell carcinomas

across 3 series, only 1 developed a

recurrence and none died of renal

cancer.38-40

Webster et al. recently

reviewed the outcomes of 85 patients

with this tumor type. The estimated 5-

year cancer specific survival for the

group was 100%, which was

significantly more favorable than


41

patients with pT1N0 noncystic clear cell

RCC. 41

Papillary renal cell carcinoma

(PRCC) accounts for 10-15% of RCCs

and occurs in two distinct subtypes with

quite different prognoses.37, 42, 43 ,44

These two subtypes of papillary RCC

(Type I and II) have been described

based on differences in histology 44 and

molecular and cytogenetic profiles.45, 46

Type I papillary tumors (genetic basis an

abnormality of the MET proto-oncogene

with trisomy of chromosome 7) are

generally felt to have a better prognosis

than clear cell tumors, whereas Type II

papillary tumors (most commonly

associated with the fumarate hydratase

gene) have been associated with higher

stage and grade and a worse prognosis

than Type I tumors.46, 47

Chromophobe tumors account for

approximately 5% of RCCs. Multiple

studies have described a more favorable

prognosis for chromophobe than for

clear cell tumors 35, 43, 48, 49

.

Histologically it is often difficult to

differentiate between variants of

chromophobe RCC and oncocytoma.

Recently, hybrid lesions between

oncocytoma and chromophobe RCC

have been identified, leading some

authors to hypothesize that chromophobe

tumors represent a progression from

oncocytoma.50

Collecting duct carcinoma is a rare

subtype of RCC with an aggressive

clinical course. Fortunately it accounts

for less than 1% of all RCCs.

Metastases are identified upon

presentation in up to two-thirds of

patients, and most die within 2 years of

diagnosis.51, 52

Renal medullary

carcinoma is another rare but highly

aggressive type of RCC. It arises from

the renal medulla and occurs almost

exclusively in young black males with

sickle cell trait or disease.51 In a series

of 6 patients with median age of 24.5

years, the mean time from diagnosis to

death was 3 months (range 1-7

months).53

Translocation tumors are a recently

recognized subset of RCCs involving

chromosomal translocations of the TFE3

gene on chromosome Xp11. They have

distinct histological features consisting

of both clear cells and papillary

architecture, and tend to occur in young

patients. Translocation tumors

occurring in adults tend to be highly

aggressive, often present with widely

metastatic disease, and carry a poor

prognosis. Interestingly, affected

children who present with nodal but not

systemic metastases seem to have a more

favorable outcome than anticipated.

Thus, it appears that TFE3 translocation

tumors occurring in children behave in a

more indolent fashion than in adults.

Larger series with more patients are

needed to further characterize the

clinical course of these rare tumors.54

C. Grade and Other Histologic Features

The Fuhrman system is the most

commonly used grading scheme for

RCC. It distinguishes grades 1 to 4

based on nuclear size and morphology

and as well as nucleolar prominence.50

Nuclear grade has been shown to

correlate with tumor size, stage, and the

presence of metastasis.48, 51 Although

the prognostic value of the Fuhrman

grading system for papillary and

chromophobe tumors has been

debated,32, 55-57

its independent

predictive value for clear cell tumors has

been demonstrated in multiple studies. 32,

58, 59 In a nationwide study of over six

hundred patients from Iceland, nuclear

grade was an independent predictor of


42

survival among patients with

pathologically confirmed RCC.32, 58

One of the main difficulties in assigning

nuclear grade has been poor inter-

observer reproducibility.51, 60, 61

Several other histologic features have

demonstrated prognostic importance.

Sarcomatoid RCC, initially considered a

distinct subtype, is now recognized as a

high-grade transformation that can arise

in any subtype of RCC.62 This rare

growth pattern, which is present in less

than 5% of RCC cases, is characterized

by spindled elements and automatically

classifies the tumor as nuclear grade 4.48

One study compared 101 patients with

sarcomatoid differentiation to a cohort of

851 lacking this pathologic feature.

Those with sarcomatoid change

presented at a higher stage and had a

worse prognosis. The 5-year disease

specific survival of those with and

without sarcomatoid change was 22%

and 79%, respectively.62

Tumor necrosis is another

histological feature that affects

prognosis. Lam reviewed 310 patients

with localized and metastatic RCC and

found that the presence and extent of

histologic necrosis was an independent

predictor of survival among those with

localized disease.63 Another important

study from the Mayo Clinic examined

the importance of tumor necrosis among

various histologic RCC subtypes. They

found that tumor necrosis was present in

28% of clear, 47% of papillary, and 20%

of chromophobe RCCs. Even after

adjusting for tumor stage, size, and

grade, the presence of necrosis was

associated with a 4 to 5 fold increased

risk of death among patients with clear

cell and chromophobe but not papillary

RCC. 64

D. Age

The incidence of renal cell carcinoma

increases with age, and only 5% of

tumors occur in patients younger than 40

years. Several studies have found that

younger patients with pathologically-

proven RCC have a better prognosis than

older patients, which may be related to a

lower grade and stage at diagnosis.

Eggener et al. performed a multi-

institutional review of all patients under

the age of 45 undergoing surgical

resection of a solid or complex cystic

renal mass. 56% presented with

symptoms and 7% had a family history

of VHL. Overall, 20% of lesions were

benign, and young females were much

more likely than males to have benign

pathology (36% vs. 9%, p<0.01).

Among the 80% of malignant lesions,

almost all of which were RCC, 76%

were grade ≤2 and 89% were organ-confined. Despite a symptomatic

presentation, younger patients with RCC

appeared to have a more favorable

prognosis.65 Siemer and colleagues also

noted a higher incidence of benign

tumors (40%) in women under the age of

40.66

In a study of over one thousand

patients which included 70 “young

patients” (defined as age under 45),

young patients were more likely to have

lower stage and grade tumors and had a

higher 5-year cancer-specific survival

than older patients.67 Jung also found

that young age was associated with

lower grade and stage and was an

independent predictor of survival among

patients with low stage clear cell RCC.68

Interestingly, another study from the

Memorial Sloan Kettering Cancer Center

found that despite more unfavorable

histopathological characteristics and a

higher incidence of lymph node

metastases, younger patients had an

improved disease-specific and


43

recurrence-free survival on multivariable

analysis.69

Mode of Presentation

Despite the increase in incidentally

discovered renal tumors as previously

mentioned, a significant proportion of

patients still present symptomatically

with flank pain, an abdominal mass,

hematuria, or with constitutional

symptoms. Investigators from the

University of Michigan found in a 2002

study that 57% of RCCs were

incidentally discovered while 42% were

found upon workup of tumor-related

symptoms. A symptomatic presentation

correlated with aggressive histology,

advanced disease, and in multivariate

analysis was a predictor of worse

disease-free and disease-specific

survival.70 Schips reviewed 683 patients

treated for RCC and found that those

presenting symptomatically had a 1.8

fold increased risk of dying from cancer

compared to those who were

asymptomatic.71

In contrast, other studies examining

the mode of presentation suggest that

incidentally discovered tumors may be

of lower stage and grade than

symptomatic ones, but the mere presence

or absence of symptoms may not be an

independent predictor of prognosis.11

Thus, the significance of various

presenting symptoms has been examined

in more detail. Kim performed a

multivariable analysis which included

grade, stage, and Eastern Cooperative

Oncology Group performance status

(ECOG PS) on a group of over one

thousand patients with RCC and found

that 4 findings, namely

hypoalbuminemia, weight loss, anorexia,

and malaise, were independent

predictors of disease specific survival.

These specific symptoms were termed

“cachexia related findings,” and the

presence of just one was associated with

a worse disease specific survival in

patients with both localized and

metastatic RCC.72 ,73

Patard et al. from France have also

created a symptom based classification,

termed the S classification, which

stratifies patients into 3 groups based on

the presence or absence of symptoms.

Patients who are asymptomatic are

classified as S1, those with local

symptoms as S2, and those with

systemic symptoms as S3. They found S

classification, in addition to TNM stage

and Fuhrman grade, to be an

independent prognostic factor among

388 patients with renal tumors.74 These

findings were replicated in a multi-

institutional study of over 2,200 patients,

where the risk of death from RCC was

2.8 and 8.8 times higher among patients

with local and systemic symptoms,

respectively, when compared to those

who were asymptomatic.75

A closely related variable which has

also shown tremendous importance in

the prognosis of patients with RCC is

performance status (PS)). The two most

commonly used scales are the

Karnosfsky and ECOG PS, both of

which attempt to quatitate the overall

impact of the disease on the health of the

patient by evaluating their ambulatory

status.48 Multiple studies have

confirmed the independent impact of PS

on survival in patients with both

metastatic and localized renal cell

carcinoma.76 ,77

Hematologic Indices

Several different hematologic indices

have demonstrated prognostic

significance in patients with RCC. A

complete blood count (CBC), which is

inexpensive and routinely obtained in


44

patients with renal tumors, may help to

predict outcomes of patients with both

metastatic and localized RCC.61, 78

Multiple studies, for example, have

found that elevation of the platelet count

is a poor prognostic indicator among

patients with advanced RCC.79-81 A

study by Gogus et al. evaluated the

significance of thrombocytosis (defined

as platelet count > 4 x 105) in

determining survival among 151 patients

undergoing radical nephrectomy for

clinically localized RCC.

Thrombocytosis was associated with

advanced T stage, node positivity, and

worse disease specific survival (45 vs.

76 months, p=0.0002).82 O’Keefe also

found that thrombocytosis was an

independent predictor of overall and

cancer specific death in patients

undergoing nephrectomy with curative

intent, even after controlling for stage,

grade, and histology.83

In addition, anemia and elevated

erythrocyte sedimentation rate (ESR)

have also been associated with a poor

prognosis among patients with RCC.84, 85

,86-88 Magera et al. from the Mayo

Clinic examined the association between

several different laboratory values and

survival after surgical resection for

clinically localized RCC. They found

that even after multivariate adjustment,

preoperative anemia (hemoglobin <13.5

g/dL in males and and <12.0 g/dL in

females) and elevated ESR (>22 mm/h

in males, > 29mm/h in females) were

associated with an increased risk of

death from RCC.87 Furthermore,

Motzer et al. found that among 670

patients with advanced RCC, low

hemoglobin, in addition to elevated

ESR, low performance status, high

serum lactate dehydrogenase, and

hypercalcemia, predicted poorer survival

in a multivariable model.89

A recent multi-institutional study

evaluated whether thrombocytosis and

anemia could improve the accuracy of

already well-established predictors of

RCC survival. In a cohort of over

eighteen hundred patients, both of these

factors were significant predictors of

cancer-specific survival in both

univariable and multivariable analysis.

However, when added to other

established predictors, including TNM

stage, grade, ECOG-PS and histologic

subtype, the ability to predict RCC-

specific survival was not improved.

Thus, the importance of these laboratory

values in clinical practice is yet to be

determined.90

Renal cell carcinoma is a tumor

known to have complex interactions

with the immune system, and markers of

a systemic inflammatory response have

been shown to correlate with disease

progression and survival. The best

studied inflammatory marker, c-reactive

protein (CRP), is an acute phase reactant

produced by the liver in response to

upregulated levels of interleukin-6

produced by the tumor. Recently

Johnson et al. demonstrated that the

absolute preoperative CRP level was an

independent predictor of relapse-free and

overall survival in the first year among

patients undergoing surgery for

clinically localized T1-T3 RCC.91 The

same group later reported that

postoperative CRP levels may be an

even better predictor of metastasis and

death in this same group of patients.92

In addition, Saito et al. found that

following CRP kinetics during the

postoperative period may help to predict

survival. Those with normal

preoperative levels of CRP experienced

the best survival and those with

preoperatively elevated levels that

normalized after surgery fared better


45

than those whose CRP remained

elevated.93 The predictive value of CRP

levels in patients undergoing surgery

with curative intent 94 ,95, 96

as well as in

patients with metastatic disease has been

demonstrated by other groups.97, 98

Several newer indices have been the

subject of recent investigation.

Erythrocyte polyamines are important

structures involved in DNA synthesis

and stabilization as well as cell

proliferation. Preoperative circulating

levels of two polyamines, spermine and

spermidine, were recently found to be

independent predictors of cancer specific

mortality in a group of 399 patients

treated with radical or partial

nephrectomy. Furthermore, when added

to TNM stage, Fuhrman grade, and

symptom classification, the predictive

accuracy was improved.99 Other serum

markers including VEGF,100-102

interleukin-6,102, 103 and carbonic

anhydrase IX 104-106 have shown

promise, but all of these require further

study before they are routinely used in

clinical practice.

Prognostic Models for RCC

As mentioned previously, the

umbrella of renal cell carcinoma

represents an extremely heterogenous

group of tumors. Obviously no single

factor can account for the wide

variability in outcomes observed in

individual patients. Therefore, multiple

prognostic models (nonograms) have

been developed which take into account

many of the clinical and pathologic

factors discussed in the previous

sections. These nomograms are user-

friendly and provide the clinician and

patient with the probability of a specific

outcome over time, representing an

advantage over multivariable models

which provide more abstract data that

are not immediately applicable in the

clinical setting. Therefore, these

algorithms may be used by practitioners

to guide decisions regarding surgery,

surveillance, and adjuvant therapy, as

well as for the inclusion of patients in

clinical trials. The most commonly

used nomograms are listed in Table 1.

Preoperative Models

Several groups have developed

nomograms which use preoperative

variables to help predict the

development of disease recurrence

following resection in nonmetastatic

RCC patients.107-110

Raj and associates

pooled data from over 2,500 patients

with renal masses localized to the kidney

who were treated surgically at the Mayo

Clinic and Memorial Sloan-Kettering

Cancer Center. They found that the size

of the mass, evidence of

lymphadenopathy, necrosis on imaging,

and mode of presentation were

predictors of eventual metastasis.107

They constructed a nomogram

incorporating these factors to predict the

12 year likelihood of disease

recurrence.108

Currently most patients with renal

masses undergo surgical treatment, from

which pathologic data is obtained. Lane

and Kattan point out that unfortunately,

none of these preoperative algorithms

perform as well as those which

incorporate pathologic information.111

In a study comparing the predictive

accuracy of four prognostic models,

those including pathologic data were

more accurate than those which included

only preoperative data.112 However, as

minimally invasive treatments and active

surveillance become more popular for

patients with RCC, nomograms based on

clinical information alone will assume a

more important role.

Postoperative Models


46

Numerous models have been

developed to predict clinical outcomes

based on clinical and pathologic data.

The most widely used are the Kattan

postoperative nomogram,113 ,76

the UISS

(UCLA Integrated Staging System),76

the SSIGN score (tumor Stage, tumor

Size, nuclear Grade and presence of

Necrosis),114 and the Karakiewicz

postoperative nomogram.115

Kattan et al. from the Memorial

Sloan-Kettering Cancer Center

developed a nomogram to predict the 5-

year progression-free survival of patients

undergoing radical nephrectomy for non-

metastatic RCC of various histologic

subtypes. The four factors included in

this nomogram were the presence of

symptoms, histologic subtype, tumor

size, and standard TNM stage according

to the 1997 version.113 The observation

that over 90% of patients who develop

metastases after surgery for a clinically

localized primary tumor have clear cell

histology led the group to later develop a

modified nomogram limited to patients

with clear cell histology (Figure 1).116

When applied to external populations in

Europe, the original Kattan nomogram

has demonstrated variable prognostic

accuracy ranging from 61-81%. 112, 117

In 2002 Zisman et al. published the

UCLA Integrated Staging System

(UISS) to determine the prognosis of

patients undergoing radical or partial

nephrectomy for localized and metastatic

RCC in terms of overall survival.

The UISS uses stage, grade, and

ECOG PS to stratify patients into five

groups, with the 5-year survival of

groups I-V being 94%, 67%, 39%, 23%,

and 0%, respectively.76 The UCLA

group subsequently modified the UISS

into an outcome algorithm to stratify

patients into low, intermediate, and high

risk groups based on the same set of

variables (Figures 2a and 2b).118 This

modified system has been validated in

several external patient groups,

including a cohort of over four thousand

patients from 8 international centers

where the predictive accuracy was found

to be 81%.77, 119 77

The group from the Mayo Clinic

developed an outcome prediction model

for patients with clear cell RCC treated

by radical nephrectomy. In their series

of 1801 patients, four factors, 1997

TNM stage, tumor size >5 cm, nuclear

grade, and tumor necrosis were all

associated with death from RCC on

multivariable analysis. The investigators

thus created the SSIGN scoring

algorithm (with scores ranging from 0-

10) based on these four factors to predict

cancer specific survival rates at 1, 3, 5,

7, and 10 years (Tables 2a and 2b). For

example, the 5-year disease specific

survival rate of patients with a SSIGN

score of 0-1 was 99%, compared with

7% for those with a score of 10.114

European and Japanese studies have

subsequently confirmed the prognostic

accuracy of the SSIGN algorithm.120-122

Finally, in 2007 Karakiewicz et al.

attempted to improve upon the accuracy

of the above mentioned models

discussed above by including more

variables which have traditionally been

shown to predict survival among patients

with RCC. The cohort upon which the

model was developed included over

2500 patients with various stages of

RCC treated at five different centers.

Their final model ultimately

incorporated TNM stage, tumor size,

histologic subtype, age, sex, and

symptoms at presentation in order to

predict, 1, 2, 5, and 10-year cancer

specific mortality (Figure 3). The

internally validated accuracy of the

nomogram was 86%. In the same study


47

an external validation of this nomogram

yielded a predictive accuracy of about

88%, which was better than that of the

UISS when tested on the same group of

patients.115

Models for Metastatic RCC

Several models have been developed

to predict survival in patients with

metastatic RCC. In 2002 Motzer et al.

developed the Memorial Sloan-Kettering

Cancer Center prognostic classification

which stratifies patients into good,

intermediate, and poor prognosis groups

based on the number of adverse factors

present. These adverse factors include

Karnofsky index <80%, LDH >1.5 times normal, hemoglobin < than 13 if male or 11.5 if female, corrected calcium >10,

and interval between RCC diagnosis and

beginning of systemic treatment < 1

year. The median survival was 30

months for the good risk patient group (0

factor present), 14 months for

intermediate risk group (1-2 factors

prsent), and 5 months for the poor risk

group (>2 factors present). This is the most widely used model by practicing

physicians for counseling patients with

metastatic RCC and for determining

inclusion in clinical trials.123

Summary

It has become increasingly clear in

recent years that renal cancer is not one

disease but rather a heterogeneous

family of different tumor types that vary

histologically, genetically and

molecularly. This variability has been

underscored by the fact that these tumor

subtypes may respond quite differently

to various systemic therapies used for

the treatment of renal cancer. In

addition to tumor subtype, other

variables (including stage, grade, patient

age, tumor size and many others) have

been shown to be affect prognosis, even

within an individual subtype of renal

cancer. It is therefore critical that health

care professionals who treat these

tumors be familiar with the impact that

tumor subtype and other variables may

have in predicting the outcomes and

response to therapy of their individual

patients. In doing so, health care

providers should understand and employ

the various prognostic nomograms that

may be used to better define individual

patient prognosis and direct the optimum

therapeutic approach to their patients.

FIGURE LEGENDS


48

Figure 1 Legend: Nomogram predicting the probability of freedom from recurrence after nephrectomy for

clear cell RCC. Instructions for use: Locate the tumor size on the size axis. Draw a line upwards to the

Points axis to determine how many points the patient receives for the tumor size. Repeat this process for

the other axes, each time drawing a line straight upward to the Points axis. Sum the points achieved for

each predictor and locate this sum on the Total points axis. Draw a straight line down to find the

probability that the patient will remain free of recurrence for 5 years. (Reproduced from Sorbellini et al. J

Urol 2005;731(1):50 with permission)

Figure 2a Legend: Decision box A assigns N0M0 nephrectomized patients in to risk groups. Progress from

top to bottom using the 1977 AJCC stage, grade, and ECOG PS. Decision box B assigns N+/M+ patients.

(Reproduced from Zisman et al. J Clin Oncol 2002;20:4559 with permission)


49

Figure 2b Legend: Disease-specific survival divided into N0M0 and N+/M+ patients and into the

corresponding risk groups. LR= low risk, IM= intermediate risk, and HR= high risk. (Reproduced from

Zisman et al. J Clin Oncol 2002;20:4559 with permission)

Figure 3 Legend: Karakiewicz nomogram predicting renal cell carcinoma (RCC)-specific survival at 1, 2,

5, and 10 years. (Reproduced from Karakiewicz et al. J Clin Oncol 2007;25:1316 with permission)


50

TABLES

Table 1. Commonly Used Nomograms in RCC

Table 2a. The SSIGN scoring algorithm. The scores from each category in this table are added together and the total is used to determine survival according to table 2b. (Data from Frank et al. J Urol 2005;173:48-51 with permission)

SSIGN Score

% Estimated Cancer Specific Survival

1-year

3-year

5-year

7-year

10-year

0-1 100 99.7 99.4 98.7 97.1

2 99.1 95.9 94.8 90.3 85.3

3 97.4 90.3 87.8 81.8 77.9

4 95.4 87.1 79.1 70.8 66.2

5 91.1 71.3 65.4 57.1 50.0

6 87.0 69.8 54.0 46.4 38.8

7 80.3 52.4 41.0 34.0 28.1

8 65.1 38.9 23.6 12.7 12.7

9 60.5 26.8 19.6 18.1 14.8

≥ 10 36.2 11.9 7.4 4.6 4.6 Table 2b. Estimated cancer specific survival following radical nephrectomy for clear cell RCC by SSIGN Score (Data from Frank et al. J Urol 2005;173:48-51 with permission)

ABBREVIATIONS USED

AJCC = American Joint Committee on

Cancer

CBC = complete blood count

CT = computed tomography

CRP = c-reactive protein

ECOG = Eastern Cooperative Oncology

Group

ESR = erythrocyte sedimentation rate

MET = hepatocyte growth factor

receptor

PN = partial nephrectomy

PRCC = papillary renal cell carcinoma

PS = performance status

RCC = renal cell carcinoma

RN = radical nephrectomy

TFE3 = transcription factor E3

Preoperative Models Cindolo Preoperative Prognostic Model 107 Raj Preoperative Nomogram 108 Postoperative Models

Kattan Postoperative Nomogram 116 UCLA Integrated Staging System 117,118 SSIGN Score 114 Karakiewicz Postoperative Nomogram 115 Models for Metastatic RCC

MSKCC Prognostic Classsification 123

Feature Score

T stage: pT1 0 pT2 1 pT3 2 pT4 2 N stage: pNx or pN0 0 pN1 or pN2 2 M stage: pM0 0 pM1 4 Tumor size (cm): < 5 0 ≥ 5 2 Nuclear Grade: 1 0 2 0 3 1 4 3 Necrosis: Absent 0 Present 2


51

UICC = International Union Against

Cancer

VEGF = vascular endothelial growth

factor

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Renal Tumors: The Good, the Bad, and the Ugly...Renal Tumors: The Good, the Bad, and the Ugly Robert...

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