Chapter 49 – Malignant Renal Tumors (Renal Cell Carcinoma)

7/25/2019 Chapter 49 – Malignant Renal Tumors (Renal Cell Carcinoma)

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chapter 49 – Malignant Renal TumorsSteven C. Campbell, MD, PhD, Brian R. ane, MD, PhD Historical Considerations

Classification

Radiographic Evaluation of Renal Masses

Renal Cell Carcinoma

Treatment of Localized Renal Cell Carcinoma

Treatment of Locally Advanced Renal Cell Carcinoma

Other Malignant Renal Tumors

Renal Cell Carcinoma

!ncidenceEtiology

"amilial Renal Cell Carcinoma and Molecular #enetics

Tumor $iology and Clinical !mplications

%athology

Clinical %resentation

&creening and Clinical Associations

&taging

%rognosis

Renal Cell Carcinoma!ncidence

RCC' (hich accounts for )* to +* of all adult malignant neoplasms' is the most lethal of the

common urologic cancers, Traditionally' +-* to .-* of patients (ith RCC have died of their

cancer' in contrast to the )-* mortality rates associated (ith prostate and /ladder carcinomas

0Landis et al' 12 %antuc3 et al' )--1/4, Appro5imately 6.'--- ne( diagnoses of RCC are

made each year in the 7nited &tates' and 1+'--- patients die of disease 0Russo et al' )--8'

Carrizosa and #odley' )--2 9emal et al' )--4, !verall, appro"imatel# $% ne& cases are

'iagnose' per $((,((( population per #ear, &ith a male)to)*emale pre'ominance o* + %

0Landis et al' 12 :allen et al' )--;2 <eCastro and Mc=iernon' )--82 :oldrich et al' )--82

Carrizosa and #odley' )--4, This is primaril# a 'isease o* the el'erl# patient, &itht#pical presentation in the si"th an' seventh 'eca'es o* li*e 0%antuc3 et al' )--1/2 :allen

et al' )--;4, !ncidence rates are 1-* to )-* higher in African Americans for un3no(n

reasons 0Cho( et al' 1' Lip(orth et al' )-->2 &tafford et al' )--84, The ma-orit# o* cases

o* RCC are believe' to be spora'ic onl# %/ to +/ are *amilial 0Lip(orth et al' )-->4,

The inci'ence o* RCC has increase' since the $90(s b# an average o* +/ per #ear *or

&hites an' 4/ per #ear *or 1*rican)1mericans, largel# relate' to the more prevalent

use o* ultrasonograph# an' CT *or the evaluation o* a variet# o* ab'ominal complaints

0Cho( et al' 12 <eCastro and Mc=iernon' )--82 =ummerlin et al' )--8/4, This trend has

correlated (ith an increased proportion of incidentally discovered and localized tumors and

(ith improved 6?year survival rates for patients (ith this stage of disease 0=onna3 and#rossman' 1862 Thompson and %ee3' 1882 =essler et al' 1.2 %antuc3 et al' )--1/2

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)

%arsons et al' )--1' =ane et al' )--84, Ho(ever' other factors must also /e at play /ecause

Cho( and colleagues 014 have documented a steadily increasing mortality rate from RCC

per unit population since the 18-s' and this (as o/served in all ethnic and /oth se5 groups,

They reported that the incidence of advanced tumors per unit population has also increased2

and although the proportion of advanced tumors has decreased' the mortality rate per unit

population has still /een negatively affected 0Cho( et al' 12 Hoc3 et al' )--)2 :allenet al' )--;2 <eCastro and Mc=iernon' )--84, This suggests that a deleterious change in tumor

/iology may have occurred during the past several decades' perhaps related to to/acco use'

dietary factors' or e5posure to other carcinogens 0Cho( et al' 12 %antuc3 et al' )--1/2

Hoc3 et al' )--)2 %arsons et al' )--)2 =ane et al' )--84,

RCC in chil'hoo' is uncommon, representing only ),+* to >,>* of all renal tumors in

children 0Castellanos et al' 1;.2 Chan et al' 18+2 "reedman et al' 1>2 Asanuma et al'

12 $roec3er' )---4, Mean age at presentation in children is 8 to years' and the incidence

is similar in /oys and in girls, 1lthough 2ilms tumor is much more common in #ounger

chil'ren, RCC is as common as 2ilms tumor 'uring the secon' 'eca'e o* li*e. RCC in

children and young adults is more li3ely to /e symptomatic and to e5hi/it papillary histology'and a predilection for locally advanced' high?grade disease' and unfavora/le histologic

su/types has also /een reported 0"reedman et al' 1>2 Rensha( et al' 12 &@nchez?Ortiz

et al' )--./2 Coo3 et al' )-->2 Estrada et al' )--64, T"E+ protein overe5pression' (hich

correlates (ith the presence of ASPL-TFE3 and PRCC-TFE3 gene translocation events

involving the and first chromosomes' is relatively common in children and young adults

(ith RCC and is uniBue to this population 0Heimann et al' )--12 #eller et al' )--84, The

clinical significance of T"E+ protein overe5pression is not (ell defined' although preliminary

data suggest that these tumors may sho( differential sensitivity to certain chemotherapeutic

agents 0Argani et al' )--)2 Heimann et al' )--12 %erot et al' )--+2 $ruder et al' )--.4, Most

stu'ies suggest that stage *or stage, chil'ren an' #oung a'ults &ith RCC ma# respon'

better to surgical therap#, and a num/er of long?term survivors have /een reported after

radical nephrectomy and lymphadenectomy for lymph nodepositive disease 0"reedman et al'

1>2 Asanuma et al' 12 A/ou El "ettouh et al' )--)2 #eller et al' )--82 &@nchez?Ortiz

et al' )--./2 #eller et al' )--84, 1n aggressive surgical approach &ith *ormal

l#mpha'enectom# has thus been recommen'e' at the time o* ra'ical nephrectom#

&hen RCC is suspecte' in chil'ren or #oung a'ults 0"reedman et al' 1>2 Asanuma et al'

12 #eller et al' )--82 &elle et al' )-->2 $osBuet et al' )--84,

Etiology

RCCs &ere tra'itionall# thought to arise primaril# *rom the pro"imal convolute'tubules, an' this is probabl# true *or the clear cell an' papillar# variants. 3o&ever, it is

no& establishe' that other histologic subt#pes o* RCC, such as chromophobe an'

collecting 'uct RCC, are 'erive' *rom the more 'istal components o* the nephron

0&tDr3el' 1>2 Oyasu' 182 %antuc3 et al' )--1a4,

The most generall# accepte' environmental ris *actor *or RCC is tobacco e"posure,

although the relative associate' riss have been mo'est, ranging *rom $.4 to %.5

compare' &ith controls 0Ta/le .64, All forms of to/acco use have /een implicated' and

ris3 increases (ith cumulative dose or pac3?years 0=antor' 1;;2 La ecchia et al' 1-2

McLaughlin et al' 162 McLaughlin and Lip(orth' )---2 Moyad' )--12 <hote et al' )--.2

Lind/lad' )--.2 Lip(orth et al' )-->2 Carrizosa and #odley' )--4, Relative ris3 is directlyrelated to duration of smo3ing and /egins to fall after cessation' further supporting a cause?



+

and?effect relationship 0La ecchia et al' 1-2 McLaughlin et al' 162 %ar3er et al' )--+/4,

To/acco use accounts for )-* to +-* of cases of RCC in men and 1-* to )-* in (omen

0McLaughlin et al' 162 McLaughlin and Lip(orth' )---4,

Table 49–5 )) 6tiolog# an' 6nvironmental 7actors o* Malignant Renal TumorsEstablished

Tobacco exposure

Obesity

Hypertension

Putative

Lead compounds

Various chemicals (e.g., aromatic hydrocarbons)

Trichloroethylene exposure

Occupational exposure (metal, chemical, rubber, and printing industries)

Asbestos or cadmium exposure

Radiation therapy

ietary (high !at"protein and lo# !ruits"$egetables)

!besit# is no& accepte' as another ma-or ris *actor *or RCC &ith an increase' relative

ris o* $.(0 *or each unit o* rising bo'# mass in'e" 0Cho( et al' )---2 $ergstrom et al'

)--12 $Forge et al' )--.2 Calle and =aa3s' )--.2 Reeves et al' )--;4, The increased

prevalence of o/esity li3ely contri/utes to the increased incidence of RCC in :estern

countries' and it has /een estimated that more than .-* of cases of RCC in the 7nited &tates

may /e causally lin3ed to o/esity 0Calle and =aa3s' )--.4, %otential mechanisms lin3ing

o/esity to RCC include lipid pero5idation leading to <GA adducts' increased insulin?li3e

gro(th factor?1 e5pression' increased circulating estrogen levels' and increased

arterionephrosclerosis and local inflammation 0=asis3e et al' 1)2 Huang et al' 182 #ago?

<ominguez et al' )--)2 Calle and =aa3s' )--.4,

3#pertension appears to be the thir' ma-or etiologic *actor *or RCC. <iuretics and other

antihypertensive medications have also /een implicated' /ut the (eight of the epidemiologic

evidence suggests that it is the underlying disorder' hypertension' rather than the treatment'

that increases the ris3 of RCC 0McLaughlin et al' 162 uan et al' 182 McLaughlin and

Lip(orth' )---2 Lip(orth et al' )-->4, The proposed mechanisms are hypertension?induced

renal inFury and inflammation or meta/olic or functional changes in the renal tu/ules that

may increase suscepti/ility to carcinogens 0Lip(orth et al' )-->4,

1lthough a number o* other potential etiologic *actors have been i'enti*ie' in animal

mo'els, inclu'ing viruses, lea' compoun's, an' more than $(( chemicals such asaromatic h#'rocarbons, no speci*ic agent has been 'e*initivel# establishe' as causative

in human RCC 0$ennington and $ec3(ith' 1.;2 =antor' 1;;4, The potential role of

trichloroethylene e5posure has /een actively investigated2 some studies sho(ed relative ris3s

ranging from t(ofold to si5fold' /ut others have argued that inherent /iases li3ely account for

these results 0amva3as et al' )---2 Mandel' )--12 Moyad' )--12 $runing et al' )--+'

Lip(orth et al' )-->2 Loc3 and Reed' )-->4, Ho(ever' $rauch and colleagues 014

reported an increased incidence and uniBue pattern of von Hippel?Lindau gene 0VHL4

mutations in this population' (hich (ould argue in favor of a potential causative role for this

compound, &lightly increased relative ris3s for RCC have /een reported for (or3ers in the

metal' chemical' ru//er' and printing industries and those e5posed to as/estos or cadmium'

/ut the data are not particularly convincing 0=olonel' 1;>2 %esch et al' )---2 Moyad' )--12



.

Hu et al' )--)2 <hote et al' )--.2 Lind/lad' )--.2 Lip(orth et al' )-->2 Carrizosa and

#odley' )--4,

Case?control studies have sho(n that RCC is more common among individuals (ith lo(

socioeconomic status and ur/an /ac3ground' although the causative factors have not /een

defined 0=antor' 1;;2 #oodman et al' 18>2 Muscat et al' 162 uan et al' 184, Thetypical modern :estern diet 0high in fat and protein and lo( in fruits and vegeta/les4'

increased inta3e of dairy products' and increased consumption of coffee or tea have /een

associated (ith RCC' /ut the relative ris3s have /een modest' and conflicting data are

availa/le in most instances 0u et al' 18>2 Lind/lad et al' 1;2 Moyad' )--12 Handa and

=reiger' )--)2 <hote et al' )--.2 Lind/lad' )--.2 Murai and Oya' )--.' Lip(orth et al' )-->2

:ol3 et al' )-->2 Carrizosa and #odley' )--4, A family history of RCC may also /e a factor2

one study sho(ed a relative ris3 of ), for individuals (ith a first? or second?degree relative

(ith RCC 0#ago?<ominguez et al' )--14,

Other potential iatrogenic causes include Thorotrast 0(hich (as used as a contrast agent in

the past4' and radiation therapy' /ut' again' the relative ris3s are lo( 0:enz' 1>;2Romanen3o et al' )---4, ogelzang and colleagues 0184 reported four cases of RCC

developing in a previously irradiated field' and a slightly increased incidence of RCC has

/een reported in men (ho received retroperitoneal irradiation for the treatment of testicular

cancer, &urvivors of childhood :ilms tumor also appear to /e at increased ris3 for RCC'

possi/ly related to prior radiation therapy or chemotherapy 0Cherullo et al' )--14, An

increased incidence of RCC is also o/served in patients (ith end?stage renal failure and

certain familial syndromes such as tu/erous sclerosis' as discussed later 0!shi3a(a et al' 1-2

$Fornsson et al' 1>2 Geumann and I/ar' 1;4,

"amilial Renal Cell Carcinoma and Molecular #enetics

&ince the early 1-s' significant advances have /een made in our understanding of the

molecular genetics of RCC, Govel familial syndromes of RCC have /een identified' and the

tumor suppressor genes and oncogenes contri/uting to the development of /oth sporadic and

familial forms of this malignancy have /een characterized 0Ta/le .>4 0Linehan et al' 162

I/ar et al' 162 &chmidt et al' 1;2 :eirich et al' 182 Choy3e et al' )--+2 Linehan et al'

)--+2 %avlovich et al' )--+2 Iimmer and !liopoulos' )--+2 %avlovich and &chmidt' )--.2

=latte and %antuc3' )--82 Gathanson and &tephenson' )--4, The impact of this ne(

information should not /e underestimated /ecause it has fundamentally changed our

perceptions a/out RCC, 2e no&, more than ever, recogni8e the 'istinct nature o* the

various histologic subt#pes o* RCC, an' a'vances in molecular genetics havecontribute' to a ma-or revision in the histologic classi*ication o* this malignant

neoplasm 0Oyasu' 182 Linehan et al' )--+2 oung et al' )--82 Roma and Ihou' )--;2

%faffenroth and Linehan' )--82 Ihou' )--4, 1 'irect an' bene*icial impact on

management o* patients has also been achieve', &ith molecular targete' agents no&

e"ten'ing survival *or patients &ith a'vance' RCC 0Linehan' )--)2 ira et al' )--;2

Hudes et al' )--;' Motzer et al' )--;2 Lane et al' )--;c2 =roog and Motzer' )--82 Clar3 and

Coo3son' )--84,

Table 49– )) 7amilial Renal Cell Carcinoma :RCC; S#n'romes

%&'RO *'T+ L'T A-OR L+'+AL A'+%TAT+O'%$on Hippel/Lindau VHL gene (chromosome 0p12/13) lear cell R

Hemangioblastomas o! the central ner$ous



6

system

Retinal angiomas

4heochromocytoma

Hereditary papillary R c/MET proto/oncogene (chromosome5607)

Type 7 papillary R

amilial leiomyomatosis andR

umarate hydratase (chromosome7681)

Type 1 papillary R

utaneous leiomyomas

9terine leiomyomas:irt/Hogg/ub; BHD1 gene (chromosome 75p71677) hromophobe R

Oncocytoma

Transitional tumors<

Occasional clear cell R

utaneous !ibro!olliculomas

Lung cysts

%pontaneous pneumothorax

Data from Linehan, 2002; Choyke et a, 2003; Linehan et a, 2003; !aran"hie an# Linehan,

2003; Pa$o$i"h et a, 2003; Pa$o$i"h an# S"hmi#t, 200%; S&#ar'han an# Linehan, 200(;

Coeman, 200); Pfaffenroth an# Linehan, 200); Han'e an# Rini, 200); an# *athan'on an#

Ste+hen'on, 200* Also =no#n as hybrid oncocytic tumors and containing !eatures o! both chromophobe R and oncocytoma.

=nudson and &trong recognized that familial forms of cancer might hold the 3ey to the

identification of important regulatory elements 3no(n as tumor suppressor genes 0=nudson'

1;12 =nudson and &trong' 1;)4, Their observations about the chil'hoo' tumor

retinoblastoma, in &hich *amilial cases ten' to be multi*ocal an' earl# onset, le' them to

propose a t&o)hit theor# o* carcinogenesis. The# h#pothesi8e' that a gene pro'uct that

coul' suppress tumor 'evelopment must be involve' an' that both alleles o* this <tumor

suppressor gene= must be mutate' or inactivate' *or tumorigenesis to occur.

"urthermore' =nudson postulated that patients (ith the familial form of the cancer are /orn

(ith one mutant allele and that all cells in that organ or tissue are at ris3' accounting for theearly onset and multifocal nature of the disease, !n contrast' sporadic tumors develop only if a

mutation occurs in /oth alleles (ithin the same cell2 and /ecause each event occurs (ith lo(

freBuency' most tumors develop late in life and in a unifocal manner 0=nudson' 1;12

=nudson and &trong' 1;)4, =nudsonJs hypothesis has proved true for retino/lastoma and a

num/er of other tumor types' including RCC 0Choy3e et al' )--+2 Linehan et al' )--+2

%avlovich et al' )--+2 Iimmer and !liopoulos' )--+2 %avlovich and &chmidt' )--.2

&udarshan and Linehan' )-->4, !dentification of familial cases of RCC (as particularly

important /ecause it allo(ed lin3age analysis /et(een affected family mem/ers,

von Hippel?Lindau <isease' VHL #ene' and #enetics of Clear Cell Renal Cell Carcinoma

The *amilial *orm o* clear cell RCC is von 3ippel)in'au 'isease. This is a relatively rare

autosomal dominant disorder that occurs (ith a freBuency of 1 per +>'--- population, Ma-or

mani*estations inclu'e the 'evelopment o* RCC, pheochromoc#toma, retinal angiomas,

an' hemangioblastomas o* the brainstem, cerebellum, or spinal cor' 0Ta/le .;4

0Horton et al' 1;>2 #o et al' 18.2 #reen' 18>2 9ennings et al' 1882 Lamiell et al' 182

Maher et al' 1-2 Geumann and I/ar' 1;2 Hansel and Rini' )--82 Gathanson and

&tephenson' )--4, All of these tumor types are highly vascular and can lead to su/stantial

mor/idity' much of (hich can /e avoided (ith prompt recognition and careful' s3illed

management, !n particular' central nervous system lesions can lead to paralysis or death and

the retinal lesions to /lindness if they are not identified and managed in an e5pedient manner,

!ther common or important mani*estations o* von 3ippel)in'au 'isease inclu'e renalan' pancreatic c#sts, inner ear tumors, an' papillar# c#sta'enomas o* the epi'i'#mis



>

0Geumann and I/ar' 1;4, 1n increase' inci'ence o* neuroen'ocrine tumors o* the

pancreas has also been reporte' in von Hippel?Lindau disease 0I/ar et al' 12 Coleman'

)--84, %enetrance for all of these traits is far from complete' and some' such as

pheochromocytomas' tend to /e clustered only in certain families 0Ta/le .84 0Geumann

and I/ar' 1;' Coleman' )--82 Gathanson and &tephenson' )--4, RCC 'evelops in about

5(/ o* patients &ith von 3ippel)in'au 'isease an' is 'istinctive *or its earl# age atonset :o*ten in the thir', *ourth, or *i*th 'eca'e o* li*e; an' *or its bilateral an'

multi*ocal involvement 0Horton et al' 1;>2 #o et al' 18.2 #reen' 18>2 9ennings et al'

1882 Lamiell et al' 182 Maher et al' 1-2 Geumann and I/ar' 1;2 ira et al' )--;2

Gathanson and &tephenson' )--4, :ith improved management of the central nervous system

manifestations of the disease' RCC has no( /ecome the most common cause of mortality in

patients (ith von Hippel?Lindau disease 0Maher et al' 1-2 Geumann and I/ar' 1;4,

&creening for von Hippel?Lindau disease and important considerations for the management

of RCC in von Hippel?Lindau disease are revie(ed later in this chapter,

Table 49–0 )) Mani*estations o* the von 3ippel)in'au S#n'romeOR*A' %&%T L%+O' +'+' (>)ye :enign retinal angiomas 8?/2?entral ner$ous system :enign hemangioblastomas 81/51@idney lear cell renal cell carcinoma 18/5 Renal cysts 11/2?

Adrenal gland 4heochromocytoma 7B4ancreas +slet cell tumors 71 alignant islet cell tumor 1 4ancreatic cysts 17/51pididymis ystadenoma 7/13ar ndolymphatic sac tumor 7

Data from Horton et a, ./(; reen, .)(; Lamie et a, .); !aher et a, .0;

*e&mann an# 1ar, ./; Frie#ri"h, .; Choyke et a, 2003; Linehan et a, 2003;

!aran"hie an# Linehan, 2003; Pa$o$i"h et a, 2003; S&#ara'han an# Linehan, 200(;Coeman, 200); Han'e an# Rini, 200); an# *athan'on an# Ste+hen'on, 200

Table 49–> )) ?nci'ence o* Ma-or Mani*estations o* von 3ippel)in'au Disease b#

Mutation Status+%A%T&4

HA'*+O:LA%TO A

R'AL LLAR+'OA

4HOHROO&TO A

*RL+' 9TAT+O' T&4%

7 High High Lo# ull gene deletions, partial genedeletions, nonsense mutations,and splice acceptor mutations

1A High Lo# High issense mutations in speci!icareas

1: High High High 4artial gene deletions, nonsense

mutations, and missensemutations

1 'o 'o High issense mutations in otherspeci!ic areas

A#a+te# from *athan'on an# Ste+hen'on, 200; #ata from S&#ar'han an# Linehan, 200(;

aein, 200/; an# Coeman, 200)

Early clues to the genetic elements involved in the development of RCC came from

cytogenetics, These studies demonstrated a common loss of chromosome + in 3idney cancer'

particularly the clear cell variant' and led to intensive efforts to find a tumor suppressor gene

in this region 0I/ar et al' 18;2 &eizinger et al' 1882 Hosoe et al' 1-2 Lerman et al' 114,

Reports /y =ovacs and colleagues 0184 and Cohen and associates 01;4 of translocationsinvolving chromosome + further implicated this chromosome as an important regulatory



;

element, &outhern /lot testing and analysis for restriction fragment length polymorphisms

(ith a (ide variety of genetic mar3ers su/seBuently demonstrated loss of heterozygosity in

distinct regions on the short arm of chromosome + 0revie(ed /y 9ennings et al' 164,

Sophisticate' molecular genetic linage stu'ies in patients &ith von 3ippel)in'au

'isease eventuall# le' to the i'enti*ication o* the VHL tumor suppressor gene 0Latif et al'

1+4, This gene, &hich is locate' at chromosome +p%5)%, has no& been completel#se@uence', an' its role as a tumor suppressor gene *or both the spora'ic an' the

*amilial *orms o* clear cell RCC has been con*irme' 0#narra et al' 1.2 Linehan et al'

162 I/ar' 162 "urge and Teh' )--2 Gathanson and &tephenson' )--4, The VHL gene

consists of three e5ons' and it encodes a protein of )1+ amino acids, A large num/er of

common mutations or Khot spots in the gene have /een identified' and a direct correlation

/et(een genotype and phenotype has /een esta/lished in some cases 0#narra et al' 1.2

Linehan et al' 162 I/ar' 162 $rauch et al' )---2 %avlovich and &chmidt' )--.2 =aelin'

)--;4, "or instance' missense mutations 0type ) mutations4 that result in a full?length /ut

nonfunctional protein are commonly found in families (ith von Hippel?Lindau disease that

develop pheochromocytomas' (hereas deletions leading to a truncated protein 0type 1

mutations4 are typically found in families that do not develop pheochromocytomas 0see Ta/le.84 0Crossey et al' 1.2 Linehan et al' 162 Maher and =aelin' 1;2 Geumann and I/ar'

1;2 :alther et al' 1c2 Hes et al' )---2 "riedrich' )--12 %avlovich and &chmidt' )--.2

&udarshan and Linehan' )-->2 Coleman' )--84, The identification of this tumor suppressor

gene represented a maFor advance in the field and reBuired close colla/oration /et(een

clinical urologic?oncologists and molecular geneticists, The important historical steps in

solving this challenging puzzle (ere revie(ed /y Linehan and colleagues 0164 and I/ar

0164' (ho spearheaded this important effort,

1s &ith most tumor suppressor genes, both alleles o* the VHL gene must be mutate' or

inactivate' *or 'evelopment o* the 'isease the observe' inheritance patterns have

con*orme' to Anu'sons h#potheses. As e5pected' almost all patients (ith von Hippel?

Lindau disease (ere found to have germline mutations of one allele of the VHL tumor

suppressor gene' and autosomal dominant inheritance from the affected parent (as confirmed

0#narra et al' 1.2 Linehan et al' 16' )--+4, The second allele is commonly lost /y gene

or chromosome deletion 0I/ar' 164, Also' as predicted' most sporadic clear cell RCCs (ere

found to har/or mutations or other genetic mechanisms' such as hypermethylation' that

inactivated /oth alleles of the VHL gene 0I/ar' 162 Linehan et al' )--+2 Gathanson and

&tephenson' )--4, Ho(ever' they differ in that /oth mutations must /e acBuired after /irth'

accounting for the late onset and the unifocal nature of the sporadic form of the disease,

&u/seBuent (or3 has focused on the function of the HL protein and its potentialmechanisms of action, The HL protein is 3no(n to /ind to elongins $ and C' C7L?)' and

R$1 to form an E+ u/iBuitin ligase comple5 and there/y modulates the degradation of

important regulatory proteins 0#orospe et al' 12 Liszt(an et al' 12 I/ar et al' 12

:iesener et al' )--12 #eorge and =aelin' )--+2 Linehan et al' )--+2 %avlovich and &chmidt'

)--.2 &udarshan and Linehan' )-->2 ira et al' )--;4, 1 criticall# important *unction o*

the 3 protein comple" is to target the h#po"ia)in'ucible *actors $ an' % :3?7)$ an'

3?7)%; *or ubi@uitin)me'iate' 'egra'ation, eeping the levels o* 3?7s lo& un'er

normal con'itions. The 3?7s are intracellular proteins that pla# an important role in

regulating cellular responses to h#po"ia, starvation, an' other stresses. ?nactivation or

mutation o* the VHL gene lea's to '#sregulate' e"pression o* the 3?7s 0Ma5(ell et al'

12 u et al' )--14' an' the# begin to accumulate in the cell. This, in turn, lea's to aseveral*ol' upregulation o* the e"pression o* vascular en'othelial gro&th *actor



8

:67;, the primar# angiogenic gro&th *actor in RCC, contributing to the pronounce'

neovascularit# associate' &ith clear cell RCC 0#narra et al' 1>2 !liopoulos et al' 1>2

#unningham et al' )--12 !garashi et al' )--)2 Linehan et al' )--+2 &udarshan and Linehan'

)-->2 ira et al' )--;4, H!"s also upregulate the e5pression of tumor gro(th factor?'

platelet?derived gro(th factor 0%<#"4' glucose transporter 0#lut 14' erythropoietin' and

car/onic anhydrase ! 0CA?!4' a tumor?associated antigen (ith specificity for clear cellRCC 0"ig, .4 0I/ar et al' 12 :y3off et al' )---2 Turner et al' )--)2 :iesener et al'

)--)2 Linehan et al' )--+2 #ra/maier et al' )--.2 &udarshan and Linehan' )-->2 ira et al'

)--;4, !n addition' the HL protein appears to influence the cell cycle' cellular

differentiation' and intracellular processing of important matri5 molecules such as

fi/ronectin' and it may impact the metastatic process /y upregulating the chemo3ine receptor

CCR., All of these functions may contri/ute to the pathogenesis and distinctive character of

this disease 0Lieu/eau?Teillet et al' 182 =amada et al' )--12 $indra et al' )--)2 Hergovich

et al' )--+2 Linehan et al' )--+2 Ga et al' )--+2 %avlovich and &chmidt' )--.2 =latte and

%antuc3' )--84,

Figure 49–9 :iologic !unctions o! the $on Hippel/Lindau (VHL) protein. The #ild/type VHL protein targets hypoxia/inducible!actor/C (H+/C) !or degradation. utation o! the VHL gene allo#s H+/C to accumulate, leading to increased expression o!$ascular endothelial gro#th !actor (V*), platelet/deri$ed gro#th !actor (4*), *lut 7, and trans!orming gro#th !actor/C(T*/C). This, in turn, has important implications #ith respect to tumor angiogenesis, metabolic acti$ity, and autocrine andparacrine stimulation. R, renal cell carcinoma.(From Linehan WM, Walther MM, Zbar B. The genetic basis of cancer of the i!ne". # $rol %&&'1)&*%1+')%.-



Other genetic elements potentially involved in the development of sporadic clear cell RCC

include additional loci on the short arm of chromosome + and the TP43 and PTE* tumor

suppressor genes, &ophisticated molecular analyses' including complete gene seBuencing and

assessment for inactivation of the promoter /y hypermethylation' has failed to reveal VHL

gene a/normalities in a small proportion of sporadic clear cell RCCs' and the search for

additional regulatory elements has continued 0Clifford et al' 18/2 Hamano et al' )--)2$an3s et al' )-->4, Loss of heterozygosity has also /een o/served at +p1)?p1. and +p)1,)?

p)1,+ and is particularly common in tumors (ith (ild?type HL status 0&hridhar et al' 1;2

van den $erg and $uys' 1;2 Clifford et al' 18a2 Lott et al' 182 elic3ovic et al' )--12

$odmer et al' )--)4, The functional importance of these loci is suggested /y e5periments

sho(ing that the transfer of fragments of chromosome + containing only these genetic

elements can suppress tumorigenesis in RCC cell lines 0an den $erg and $uys' 1;2 Lovell

et al' 12 $odmer et al' )--)4, A candidate tumor suppressor gene at +p1) has /een

descri/ed and may contri/ute to a VHL?independent path(ay to RCC 0Lovell et al' 14,

!ncreased immunostaining for T%6+ has /een reported in >* to .-* of RCCs' (ith some

studies suggesting a correlation (ith tumor grade and stage 0Reiter et al' 1+2 7hlman et al'

1.2 Haitel et al' 14, Ho(ever' the data regarding TP43 in RCC have /een controversial'and no clear consensus is availa/le at this time, Of more relevance is the PTE* tumor

suppressor gene' (hich is do(nregulated in a su/set of RCC tumors 0Alimov et al' 12

=ondo et al' )--12 $renner et al' )--)2 elic3ovic et al' )--)2 Horiguchi et al' )--+2 &hin

et al' )--+2 Hara et al' )--.2 Ro// et al' )--;2 Hager et al' )--;2 %antuc3 et al' )--;2 =latte

and %antuc3' )--84, The %TEG protein inhi/its phosphatidylinositol?+?3inasedependent

activation of protein 3inase $ 0A3t4' a 3ey intermediary in the mammalian target of

rapamycin 0mTOR4 path(ay 0=im et al' )--4, oss o* PT6E lea's to constitutive

activation o* mT!R, &hich promotes tumorigenesis, an' this path&a# has proven to be

*ertile groun' *or pharmacologic intervention 0see Tumor $iology and Clinical

!mplications and Chapter 6-4 0Hudes et al' )--;2 =latte and %antuc3' )--82 =im et al' )--2

Hudes' )--/4,

Oncogenes' such as c? !5C ' c? ER66.' c? Ha-RAS ' c? F7S ' and RAF-.' have also /een studied

in clear cell RCC' /ut the availa/le data suggest limited involvement 0&lamon et al' 18.4,

<o(nregulation of <GA mismatch repair genes may contri/ute to genetic insta/ility in RCC

and allo( accumulation of multiple genetic defects 0<eguchi et al' )--+4,

"amilial %apillary Renal Cell Carcinoma and #enetics of %apillary Renal Cell Carcinoma

Several stu'ies have 'ocumente' 'istinct c#togenetic *in'ings in non–clear cell

histiot#pes o* RCC chromosome + an' VHL gene abnormalities are uncommon in thesevariants 0&tDr3el et al' 1;2 Oyasu' 182 &udarshan and Linehan' )-->2 ira et al' )--;4,

These observations suggeste' a 'istinct genetic basis *or non–clear cell RCC. Papillar#

RCC, the secon' most common histologic subt#pe o* RCC, is characteri8e' b# trisom#

*or chromosomes 0 an' $0 as &ell as abnormalities on chromosomes $, $%, $, %(, an' F

0&tDr3el et al' 1;2 Oyasu' 182 %avlovich et al' )--+4, !n 16' I/ar and colleagues at the

Gational Cancer !nstitute reported a secon' *amilial s#n'rome o* RCCGhere'itar#

papillar# RCC :3PRCC;. This follo(ed a num/er of isolated case reports that suggested

clustering of papillary RCCs (ithin certain families 0I/ar et al' 1.4, !n I/ar and

colleaguesN series 0164 there (ere 1- families (ith .1 affected mem/ers 0) men and 1)

(omen4, Median age at diagnosis (as .6 years' and most patients developed multifocal and

/ilateral papillary RCC, T#pe $ papillar# RCC is t#picall# *oun' in this s#n'rome ratherthan t#pe %, &hich is commonl# seen in the here'itar# leiom#omatosis an' RCC



1-

s#n'rome. 7nli3e von Hippel?Lindau disease' most patients (ith H%RCC do not develop

tumors in other organ systems 0Czene and Hemmin3i' )--+2 %faffenroth and Linehan' )--82

Gathanson and &tephenson' )--4, Mean survival in affected individuals (as only 6) years in

I/ar and colleaguesN series' although the num/er of patients dying of RCC (as not defined,

The development of C=< due to a com/ination of malignant replacement of the renal mass

and loss of functioning nephrons secondary to various interventions is a potential contri/utor to mor/idity and mortality in this syndrome 0Ornstein et al' )---4, CT is the preferred

imaging modality for patients (ith H%RCC /ecause it has the greatest sensitivity for

detecting the small' hypovascular lesions that are common in this syndrome 0&udarshan and

Linehan' )-->2 %faffenroth and Linehan' )--82 Gathanson and &tephenson' )--4,

Stu'ies o* *amilies &ith 3PRCC 'emonstrate an autosomal 'ominant mo'e o*

transmission, similar to all o* the *amilial RCC s#n'romes, and provide insight into the

molecular genetics of H%RCC as (ell as a su/set of patients (ith sporadic papillary RCC

0I/ar et al' 162 &chmidt et al' 1;2 Linehan et al' )--+' ira et al' )--;4, Again' molecular

lin3age analysis in affected families played a 3ey role in the discovery of this gene' (hich

(as localized to chromosome ;B+1, Ho(ever' in this case' the inciting event is activation of a proto?oncogene' rather than inactivation of a tumor suppressor gene, Missense mutations o*

the c) MET proto)oncogene at 0@+$ &ere *oun' to segregate &ith the 'isease, implicating

it as the relevant genetic locus 0&chmidt et al' 1;2 %avlovich et al' )--+4, The protein

product of this gene is the receptor tyrosine 3inase for the hepatocyte gro(th factor 0also

3no(n as scatter factor4' and its activation leads to cellular proliferation and other potentially

tumorigenic effects 0ira et al' )--;4, Most o* the mutations in 3PRCC have been *oun'

in the t#rosine inase 'omain o* c) MET an' apparentl# lea' to constitutive activation

0&chmidt et al' 1;2 %avlovich et al' )--+2 &udarshan and Linehan' )-->4, The mutated

MET protein can transform G!H +T+ murine fi/ro/lasts and is tumorigenic in

immunodeficient murine models, Trisomy for chromosome ;' (hich is commonly found in

H%RCC' develops primarily through duplication of the chromosome har/oring the mutant

allele of the c? !ET proto?oncogene and effectively increases the dosage of the activated

receptor 0Ihuang et al' 182 &udarshan and Linehan' )-->2 Hansel and Rini' )--84,

Relatively early onset and multifocality in H%RCC are due to inheritance of the mutated "-

!ET gene' (hich places all the cells in the 3idney at ris3 from /irth' /ut the incomplete

penetrance and varia/le clinical courses associated (ith this syndrome suggest that additional

genetic loci or epigenetic phenomena may modulate the phenotype 0Choy3e et al' )--+2

Linehan et al' )--+2 %avlovich et al' )--+2 %avlovich and &chmidt' )--.2 &chmidt at al' )--.2

ira et al' )--;4, &chmidt and colleagues 0)--.4 have descri/ed three more families (ith

H%RCC and have sho(n age?dependent penetrance and a varia/le clinical course according

to the site of mutation and family involved, 2hereas tumors in 3PRCC ten' to be lessaggressive than their spora'ic counterparts, it is clear that some can metastasi8e an'

become lethal 0&chmidt et al' )--.2 ira et al' )--;4, Schmi't an' colleagues report c-

MET mutations in $+/ o* patients &ith spora'ic papillar# RCC, suggesting that this

molecular 'e*ect also contributes to a subset o* this 'isease population 0&chmidt et al'

12 &udarshan and Linehan' )-->2 ira et al' )--;4, &mall molecule inhi/itors of the c?

!ET receptor are currently in development and may prove useful for the management of

H%RCC and the su/set of patients (ith sporadic RCC (ho har/or this mutation 0$ellon et al'

)--82 Hansel and Rini' )--82 %faffenroth et al' )--84,

Hereditary Leiomyomatosis and Renal Cell Carcinoma



11

?n %(($, aunonen an' colleagues 'escribe' a ne& *amilial renal cancer s#n'rome in

&hich patients commonl# 'evelop cutaneous an' uterine leiom#omas an' t#pe %

papillar# RCC 0Choy3e et al' )--+2 =iuru and Launonen' )--.2 %avlovich and &chmidt'

)--.2 &udarshan and Linehan' )-->2 &udarshan et al' )--;4, Mean age at diagnosis is in the

early .-s 0Hansel and Rini' )--82 Gathanson and &tephenson' )--4, Renal tumors in this

s#n'rome are unusual *or *amilial RCC in that the# are o*ten solitar# an' unilateral,an' the# are more liel# to be aggressive than other *orms o* *amilial RCC 0Linehan

et al' )--+2 Maranchie and Linehan' )--+2 %avlovich and &chmidt' )--.2 &udarshan and

Linehan' )-->2 #ru// et al' )--;2 Hansel and Rini' )--84, Collecting duct RCC' another

highly malignant variant of RCC' has also /een o/served in this syndrome' (hich (as named

here'itar# leiom#omatosis an' renal cell cancer :3RCC; s#n'rome 0Linehan et al'

)--+2 #ru// et al' )--;2 Gathanson and &tephenson' )--4, The histologic hallmar3 of these

tumors is large' prominent eosinophilic nuclei and nucleoli (ith perinucleolar clearing

0#ru// et al' )--;2 Merino et al' )--;4,

The 3RCC locus &as mappe' to a region on $@4%)44, an' this &as later sho&n to be

the site o* the *umarate h#'ratase gene 0Tomlinson et al' )--)2 Linehan et al' )--+2 Toroet al' )--+2 %avlovich and &chmidt' )--.2 Alam et al' )--64, "umarate hydratase is an

essential enzyme in the =re/s cycle of o5idative meta/olism, Again' autosomal 'ominant

inheritance (as o/served' and this appears to /e a tumor suppressor gene rather than an

oncogene 0Linehan et al' )--+2 %avlovich and &chmidt' )--.4, The mechanistic lin3 /et(een

a meta/olic enzyme located in the mitochondria and tumorigenesis is still an enigma and

remains an active area of investigation 0%ollard et al' )--+2 %avlovich and &chmidt' )--.4,

One hypothesis is that fumarate accumulation may sta/ilize H!"?1 /y preventing its

hydro5ylation' (hich targets it for degradation 0!saacs et al' )--62 &udarshan and Linehan'

)-->2 Ratcliffe' )--;2 Coleman' )--82 Hansel and Rini' )--82 %faffenroth and Linehan'

)--84,

%enetrance for RCC in HLRCC is lo(er than for the cutaneous and uterine manifestations'

(ith only a minority 0)-*4 of patients developing RCC 0Choy3e et al' )--+2 &udarshan and

Linehan' )-->2 %faffenroth and Linehan' )--82 Gathanson and &tephenson' )--4, !n

contrast' almost all individuals (ith this syndrome (ill develop cutaneous leiomyomas and

uterine fi/roids 0if female4' usually manifesting at the age of )- to +6 years 0&udarshan and

Linehan' )-->2 ira et al' )--;4, A high proportion of (omen have had a hysterectomy for

fi/roids /efore formal diagnosis of HLRCC 0Coleman' )--84, Leiomyosarcomas of the

uterus have /een reported in HLRCC' although they appear to /e uncommon 0&udarshan and

Linehan' )-->2 %faffenroth and Linehan' )--82 Gathanson and &tephenson' )--4, Prompt

surgical management o* the renal tumors is recommen'e' in this s#n'rome, given theirten'enc# to&ar' invasive an' aggressive behavior 0Linehan et al' )--+2 #ru// et al'

)--6/' )--;2 &udarshan and Linehan' )-->2 ira et al' )--;2 Coleman' )--84, This is in

contrast to other *amilial s#n'romes o* RCC, *or &hich management ten's to be more

conservative, as discussed later 0#ru// et al' )--;2 ira et al' )--;2 %faffenroth and Linehan'

)--84,

$irt?Hogg?<u/ &yndrome

Birt)3ogg)DubH s#n'rome, in &hich patients 'evelop cutaneous *ibro*olliculomas, lung

c#sts, spontaneous pneumothoraces, an' a variet# o* renal tumors primaril# 'erive'

*rom the 'istal nephron, is name' a*ter three Cana'ian ph#sicians &ho *irst 'escribe'the cutaneous lesions in $900 0Toro et al' 12 Linehan et al' )--+2 %avlovich et al' )--+'



1)

)--62 %avlovich and &chmidt' )--.2 Adley et al' )-->2 Hansel and Rini' )--84, The renal

tumors t#picall# inclu'e chromophobe RCC, oncoc#tomas, an' h#bri' or transitional

tumors that e"hibit *eatures o* both o* these entities. Ho(ever' other forms of RCC'

including a su/stantial proportion of clear cell RCC' have /een o/served in this syndrome

0%avlovich et al' )--)2 Adley et al' )-->4, !verall penetrance *or renal tumors is %(/ to

4(/, but &hen the# occur the# are o*ten bilateral an' multi*ocal 0Choy3e et al' )--+2%avlovich et al' )--)2 Linehan et al' )--+2 %avlovich and &chmidt' )--.P %faffenroth and

Linehan' )--82 Toro et al' )--84, Average age at renal tumor diagnosis is appro5imately 6-

years 0%avlovich et al' )--64, Most renal tumors in $irt?Hogg?<u/ syndrome have limited

/iologic aggressiveness' although metastatic /ehavior and lethality have /een reported

0%avlovich et al' )--64

The BHD gene responsible *or this s#n'rome has been mappe' to chromosome

$0p$%@$$.% and is no( fully seBuenced 0=hoo et al' )--14, Recent stu'ies have sho&n that

the gene pro'uct is *olliculin, (hich appears to /e a tumor suppressor gene' although its

function (ith respect to this syndrome is still under investigation 0Adley et al' )-->2 ira

et al' )--;2 Toro et al' )--84, One hypothesis is that folliculin may interface (ith the mTOR path(ay 0Toro et al' )--82 Gathanson and &tephenson' )--4, #ermline mutations in this

gene have /een found in 88* of 3indreds 0Toro et al' )--84, As (ith all of the other (ell?

characterized familial RCC syndromes' an autosomal 'ominant pattern o* inheritance is

o/served and genetic testing is no( availa/le 0see Ta/le .>4 0Choy3e et al' )--+2

Maranchie and Linehan' )--+2 %avlovich et al' )--62 Adley et al' )-->2 Toro et al' )--84,

Tumor $iology and Clinical !mplications

Resistance to Cytoto5ic Therapy

RCC is a prototype of the chemorefractory tumor /ecause it has only demonstrated limited or

modest responses to traditional chemotherapeutics 0Motzer and Russo' )---2 Rini et al'

)--4, Stu'# o* the tumor biolog# o* RCC provi'es insight into its re*ractor# nature

an', through eluci'ation o* the 67 an' mT!R path&a#s, is beginning to #iel' agents

&ith clinical bene*it *or a'vance' 'isease 0Ta/le .4 0Rini et al' )--4,

Table 49–9 )) Tumor Biolog# an' Clinical ?mplications:+OLO*+HARATR+%T+

L+'+AL +4L+AT+O'%

xpression o! multidrugresistance

ontributes to chemore!ractory nature o! R

+mmunogenic 7>/1> response rate #ith inter!eron or +L/1

0>/2> complete response rate #ith high/dose +L/1 Angiogenic Vascular in$asion can lead to $enous tumor thrombus

1>/8> response rates #ith agents targeting V* (be$aciDumab) or the V*receptor (sunitinib, sora!enib, etc.)

4rolonged recurrence/!ree sur$i$al and o$erall sur$i$al #ith some antiangiogenic agents

ependence on mTORpath#ay

Agents targeting mTOR prolong sur$i$al in patients #ith poor/ris= R (temsirolimus)and demonstrate responses in patients !ailing prior targeted molecular therapies(e$erolimus)

+L/1, interleu=in/1E R, renal cell carcinomaE V*, $ascular endothelial gro#th !actor.



1+

E5pression of multidrug resistance 0M<R4 proteins' such as M<R?1 0also 3no(n as %?

glycoprotein4 and M<R?related proteins' (hich act as energy?dependent efflu5 pumps for a

(ide variety of hydropho/ic compounds' contri/ute to the chemorefractory nature of

advanced RCC 0Mic3isch' 1.2 Chapman and #oldstein' 164, Ho(ever' the resistance of

RCC to cisplatin and other agents that are not handled /y M<R proteins' and the

do(nregulation of M<R?1 in high?grade tumors and metastases 0To/e et al' 164' suggestsredundancy in resistance mechanisms, The ancillary /enefit of this refractoriness has /een an

impetus for clinical investigations of immunomodulators and targeted?molecular therapies'

(hich have mar3edly altered our paradigms for the management of patients (ith advanced

RCC 0see Chapter 6-4,

!mmuno/iology and !mmune Tolerance

Several lines o* evi'ence 'emonstrate that RCC is immunogenic, an' this no&le'ge

has stimulate' intensive e**orts to harness the immune s#stem to improve outcomes *or

patients &ith a'vance' 'isease. Tumor?infiltrating immune cells can /e readily isolated

from RCC' including 014 cytoto5ic T cells (ith specificity for antigens on tumor cells and 0)4dendritic cells and helper T cells' (hich e5press interleu3in 0!L4?1 and !L?) and function as

antigen?presenting cells 0"in3e et al' 1)2 #audin et al' 162 Elsasser?$eile et al' 12

&ch(aa/ et al' 14, !* the tumor)associate' antigens *or RCC, carbonic anh#'rase ?I

:C1)?I or ME)9; has 'emonstrate' the most speci*icit# 0Liao et al' 1;2 Mc=iernan

et al' 1;2 &huch et al' )--84, This antigen, &hich is recogni8e' b# the %5( monoclonal

antibo'#, is e"presse' almost ubi@uitousl# b# clear cell RCC an' onl# rarel# b# other

RCC subt#pes. !mmunohistochemical analysis of CA?! e5pression has /een investigated as

a diagnostic and a prognostic mar3er for clear cell RCC 0$ui et al' )--+2 <ivgi et al' )--;2

Lei/ovich et al' )--;4, !n normal tissues' the e5pression of CA?! is restricted to the gastric

mucosa' large /ile ducts' and pancreas' and its e5pression in normal renal epithelial cells is

suppressed /y (ild?type HL protein 0Mc=iernan et al' 1;2 !vanov et al' 182 issers

et al' 14, CA?! has also /een investigated for reverse transcriptase?polymerase chain

reaction detection of circulating RCC cells in the peripheral /lood 0Mc=iernan et al' 12

<e la Taille et al' )---2 Ohlmann et al' )-->4' and CA?! /ased tumor vaccine protocols

have /een developed 0Hernandez et al' )--)2 Lamers et al' )-->2 =im et al' )--;4,

Radioactively la/eled #)6- has sho(n promise for the detection of RCC metastases /y

radionuclide scanning 0$rou(ers et al' )--+4' and more recently /y positron emission

tomography 0<ivgi et al' )--;4, All these potential applications of CA?! are' at present'

promising /ut e5perimental,

1 secon' class o* *actors that ma# mo'ulate immunotherapeutic responses in i'ne#cancer is the B0 *amil# o* cell sur*ace gl#coproteins, &hich are e"presse' on various

immune an' nonimmune cells 0Thompson et al' )--;/4, $;?H1 is a T?cell coregulatory

molecule that is normally e5pressed /y macrophage lineage cells' can /e induced on activated

T lymphocytes' and is a/errantly e5pressed /y RCC 0Thompson et al' )--;/4, Tumor?

associated $;?H1 impairs antigen?specific T?cell function' and /loc3ade of $;?H1 has /een

sho(n to potentiate antitumoral responses in preclinical models 0Thompson et al' )--.4,

ConseBuently' /loc3ade of tumor?associated $;?H1 has garnered much attention in the recent

literature as a potential means to /oost antitumoral immune responses, Thompson and

associates 0)-->4 have sho(n that $;?H1 e5pression /y clear cell RCC tumors correlates

(ith aggressive pathologic features and is associated (ith an increased ris3 of disease

progression' even after multivariate adFustment, ConseBuently' a/rogation of $;?H1 signaling



1.

is /eing investigated as a means to facilitate the response of RCC to various

immunotherapeutics 0Thompson et al' )--;/4,

Clinical observations such as vali'ate' responses to immunotherap#, prolonge' 'isease

stabili8ation, an' occasional spontaneous tumor regression also support the

immunogenicit# o* RCC. The response of RCC to immunomodulators' such as interleu3in0!L4?)' interferon?alfa' and tumor?infiltrating lymphocytes' argues in favor of an important

role for the immune system in the tumor /iology of RCC 0Rosen/erg et al' 182 Motzer and

Russo' )---2 Coppin et al' )--64, ?n'ee', high)'ose ?)% remains the onl# treatment &ith

curative potential *or patients &ith metastatic RCC, &ith 'urable an' complete

regression o* 'isease accomplishe' in a *inite proportion :+/)5/; o* patients 0Coppin

et al' )--84, The estimate' inci'ence o* spontaneous regression o* RCC has range' *rom

(.+/ to as high as 0/, although most e"perience' clinicians believe that the lo&er

*igure is more accurate 0Oliver et al' 182 ogelzang et al' 1)4, Most spontaneous

regressions have been note' in patients &ith pulmonar# metastases an' have occurre'

a*ter c#tore'uctive nephrectom#, /ut regression of primary RCC has also /een reported in

the a/sence of any form of treatment 0ogelzang et al' 1)4, Remission can be 'urable,an' this phenomenon, although rare, is thought to be real an' has been assume' to be

'ue to immune surveillance, although other possi/ilities cannot /e e5cluded 0%apac' 182

oung' 182 Coppin et al' )--84,

Jn*ortunatel#, response rates o* immunotherap# *or RCC have been 'isappointing,

t#picall# ranging *rom $5/ to %(/, 'espite a variet# o* creative treatment strategies,

suggesting immune tolerance 0Motzer and Russo' )---2 Gg et al' )--)2 Coppin et al' )--84,

1 number o* observations support impaire' immune surveillance in RCC, an' a variet#

o* mechanisms a**ecting virtuall# all levels o* regulation o* the immune s#stem have

been propose'. <efects in transcriptional regulation via nuclear factor?3appa$ 0G"?Q$4 are

present in the tumor?infiltrating lymphocytes and dendritic cells of >-* of RCCs 0"in3e et al'

)--12 Thornton et al' )--.4, <efective G"?Q$ signaling impairs lymphocyte function'

predisposes lymphocytes to apoptosis' and leads to deficient recruitment and activation of

dendritic cells 0Ale5ander et al' 1+2 =olen3o et al' 1;2 Troy et al' 182 Ling et al' 182

7zzo et al' 1a2 =allfelz et al' 14, !mproved understanding of the mechanisms

contri/uting to immunotolerance in RCC should suggest novel and rational strategies for

improving outcomes for patients (ith advanced disease, "or e5ample' in addition to its

antiangiogenic activity' sunitini/ also appears to stimulate antitumor immunity /y reversing

myeloid?derived suppressor cell?mediated immunosuppression 0=o et al' )--4, Although the

current targeted therapies appear to have significant impact on other aspects of RCC

pathogenesis' such as angiogenesis' it remains to /e seen (hether augmentation of theantitumoral immune responses seen (ith some agents contri/utes to their clinical activity,

Angiogenesis and Targeted %ath(ays

RCC has long been recogni8e' as one o* the most vascular o* cancers as re*lecte' b# the

'istinctive neovascular pattern e"hibite' on renal angiograph# 0"ig, .1-4, <ependence

on angiogenesis is also suggested /y preclinical studies demonstrating /loc3ade of the gro(th

and metastasis of RCC /y several (ell?esta/lished antiangiogenic agents 0"uFio3a et al' 1>2

Tan et al' 1>2 <hana/al et al' 12 <revs et al' )---4, The primar# angiogenesis in'ucer

in clear cell RCC appears to be 67, &hich is suppresse' b# the &il')t#pe 3

protein un'er normal con'itions an' is 'ramaticall# upregulate' 'uring tumor'evelopment 0#narra et al' 1>2 !liopoulos et al' 1>2 Tomisa(a et al' 12 #unningham



16

et al' )--12 !garashi et al' )--)2 Linehan et al' )--+2 &udarshan and Linehan' )-->2 ira et al'

)--;2 Lane et al' )--;d4, !ncreased levels of E#" have /een found in the serum and urine

of patients (ith RCC' and a correlation (ith stage and grade has /een reported 0Tsuchiya

et al' 182 Chang et al' )--12 Horstmann et al' )--64, Elevated serum levels of /asic

fi/ro/last gro(th factor and other putative angiogenesis inducers for this malignant neoplasm

have also /een reported in RCC patients compared (ith normal control su/Fects 0Camp/ell'1;2 &laton et al' )--12 Currie et al' )--)2 agasa3i et al' )--+4, "unctional relevance of

E#" has /een demonstrated /y studies sho(ing increased levels of E#" transcript in

most hypervascular tumors' (hereas the less common hypovascular counterparts e5hi/it

reduced e5pression of E#" 0Ta3ahashi et al' 1.4,

Figure 49–10 'eo$ascularity associated #ith renal cell carcinoma. Renal angiogram sho#s le!t renal mass exhibitingmar=edly increased neo$ascularity #ithin renal tumor.(e/rinte! 0ith /ermission, le2elan! linic enter for Me!ical 3rt 4 5hotogra/h" 6 %&&)7%&&8. 3ll ights eser2e!.-

67 is actuall# a *amil# consisting o* several subt#pes, most o* &hich are regulate' b#

3?7s an' 3 0also see earlier under "amilial Renal Cell Carcinoma and Molecular

#enetics4 an' bin' to one or more o* the correspon'ing 67 receptor *amil# members

0Lane et al' )--;d4, E#"R?1 0"lt?14 and E#"R?) 0=<R"l3?14 are receptor tyrosine

3inases that are the target of several multityrosine 3inase inhi/itors (ith activity againstRCC 0Carmeliet' )--62 Hic3lin and Ellis' )--64, 7pon /inding of ligand 0E#"4' 3ey



1>

tyrosine residues along the intracellular portion of the E#"R are phosphorylated' (hich

leads to the /inding of specific intracellular factors and activation of corresponding path(ays,

%ath(ays 3no(n to /e activated /y phosphorylation of E#"Rs include the Raf?ME=?Er3

and phosphatidylinositol?+?3inaseA3tmTOR path(ays that promote endothelial cell

survival and proliferation 0Carmeliet' )--62 Hic3lin and Ellis' )--64, Ho(ever' the

promiscuity of the interactions /et(een the various ligands' receptors' and do(nstreameffectors leads to a host of effects that may /e difficult to predict in the a/sence of analyses

investigating the complete microenvironment of the cancer or endothelial cell, This

promiscuity is li3ely a maFor reason that t(o therapeutic agents that have the Ksame mode of

action are found to have disparate clinical or off?target effects, ?n contrast, bevaci8umab is

a monoclonal antibo'# that bin's to 67 an' se@uesters the ligan' so that it cannot

interact &ith 67R its clinical activit# is there*ore almost certainl# 'irectl# relate' to

this activit#.

iven the 'epen'ence o* RCC on angiogenesis an' the absence o* generall# e**ective

*orms o* s#stemic therapies, it is not surprising that RCC has been targete' *or

antiangiogenic approaches. !nitial clinical trials identified several antiangiogeniccompounds such as TG%?.;-' roBuinime5' and thalidomide (ith limited activity in patients

(ith advanced RCC 0de :it et al' 1;2 &tadler et al' 184, Thalidomide' for e5ample' has

sho(n only rare responses despite its potent antiangiogenic effects' and to5icity can /e

su/stantial' including throm/otic events and neurologic mor/idity 0<aliani et al' )--)2

Escudier et al' )--)/2 Gathan et al' )--)2 "anelli et al' )--+2 Matthe(s and McCoy' )--+4,

More promising initial results (ere reported for /evacizuma/' a humanized anti?E#"

anti/ody' (hich (as associated (ith a significant delay in time to progression for patients

(ith metastatic RCC compared (ith place/o 0ang et al' )--+a4, $evacizuma/ therapy

commonly leads to shrin3age in the total tumor /urden' although in this initial e5perience

o/Fective partial responses (ere uncommon and there (ere no complete responses' consistent

(ith a tumoristatic rather than a tumoricidal mechanism of action, 1 number o* other

multiple inase inhibitors that target the 67 path&a# &ere subse@uentl# teste' in

clinical trials an' *oun' to have substantial activit# in patients &ith a'vance' RCC,

culminating in approval o* t&o agents, sunitinib :Sutent; an' sora*enib :Ee"avar;, *or

this in'ication b# the J.S. 7oo' an' Drug 1'ministration :7D1; in December %((5 an'

Kanuar# %(( 0Motzer et al' )--6' )-->4, These agents are no( commonly used for front?

line and treatment?refractory metastatic RCC 0see further details in Chapter 6-4, &everal other

antiangiogenic compounds are currently in clinical trials investigating these and other

potential applications for the treatment of advanced RCC,

!n general' antiangiogenic agents offer a num/er of potential advantages in that they are notgenoto5ic and target sta/le endothelial cells rather than genetically unsta/le tumor cells, They

are thus unli3ely to induce secondary cancers or tumor resistance, !n addition' many

antiangiogenic agents have proved to /e synergistic (ith one another and (ith cytoto5ic

therapies' and their side effects should not overlap those of conventional forms of therapy

0Camp/ell' 1;2 Lane et al' )--;d4,

&ignal Transduction' Cell Cycle Regulation' and Other Targeted Molecular %ath(ays

1berrant activation o* a''itional signal trans'uction path&a#s in RCC ma# also

contribute to altere' cell c#cle inetics an' represent e"cellent targets *or therapeutic

intervention. !ne such regulator# path&a# in RCC is the mammalian target o* rapam#cin :mT!R; path&a#, &hich inter*aces &ith 1t :protein inase B; an' the



1;

PTEN tumor suppressor gene 0$renner et al' )--)2 elic3ovic et al' )--)2 Horiguchi et al'

)--+2 &hin et al' )--+2 Hara et al' )--.2 Ro// et al' )--;2 %antuc3 et al' )--;2 =latte and

%antuc3' )--84, E5pression of mTOR is upregulated /y various gro(th factors or /y

mutation or loss of PTE* 0=im et al' )--4, Through comple5 path(ays involving a variety

of intermediaries' the mTOR path(ay leads to increased e5pression of H!"?1 and other

gro(th?promoting and potentially tumorigenic seBuelae 0=latte and %antuc3' )--82 =im et al')--4, ?nhibition o* mT!R &ith temsirolimus :Torisel;, no& also 7D1 approve', has

#iel'e' prolonge' survival in patients &ith poor)ris, metastatic RCC, con*irming the

clinical relevance o* this path&a# 0Hudes et al' )--;2 Hudes' )--/4,

!ther important gro&th regulator# elements in RCC inclu'e the insulin)lie gro&th

*actor a"is 0Ta3ahashi et al' )--64' telomerase, an' BC%. !nsulin?li3e gro(th factor

receptor e5pression has /een documented in RCC' and %ar3er and colleagues 0)--+a4 have

correlated this (ith decreased survival, !ncreased telomerase activity' (hich has /een found

in 6>* to +* of RCCs' may also affect the cell cycle /y maintaining telomere length

0Mehle et al' 1>2 oshida et al' 182 Orlando et al' )--14, %rogressive telomere loss

occurs each time a normal cell divides and eventually leads to gro(th inhi/ition and cellular senescence, !ncreased e5pression of $CL)' (hich protects against programmed cell death'

has also /een reported in RCC and may contri/ute to tumor via/ility and treatment failure

0Huang et al' 12 #o/e et al' )--)4,

%roliferative inde5' as defined /y proliferating cell nuclear antigen 0%CGA4 or =i?>; staining'

has correlated (ith pathologic parameters and clinical outcomes in RCC' suggesting that

regulation of the cell cycle plays an important role in the tumor /iology of RCC 0deRiese

et al' 1+2 <elahunt et al' 162 Tannapfel et al' 1>2 $ui et al' )--.2 Tollefson et al' )--;4,

?ncrease' e"pression o* tumor gro&th *actor)L an' its receptor t#rosine inase, the

epi'ermal gro&th *actor receptor :67R;, have been reporte' in RCC and may

contri/ute to tumorigenesis /y promoting cell proliferation or transformation through an

autocrine mechanism 0#omella et al' 182 Mydlo et al' 182 &argent et al' 182 Lager

et al' 1.2 Moch et al' 1;2 Ramp et al' 1;4, The functional relevance of E#"R in the

development of RCC has also /een suggested /y preclinical studies testing the efficacy of the

C))6 monoclonal anti/ody' (hich neutralizes E#"R and /loc3s tumor gro(th and metastasis

0%re(ett et al' 182 $rou(ers et al' )--.4, 7nfortunately' phase !! clinical trials using agents

that target E#"R' including erlotini/ 0Tarceva4' gefitini/ 0!ressa4' and A$?E#"'

demonstrated a lac3 of su/stantial activity in patients (ith advanced RCC 0Rini et al' )--84,

$ased on these disappointing results' agents targeting the E#"R path(ay have fallen out of

favor' although there may /e a role for their use in patients (ith cancers that e5press high

levels of E#"R 0Ravaud et al' )--84,

The hepatoc#te gro&th *actor an' its receptor, the c) MET proto)oncogene, ma# also

contribute to the pathogenesis o* RCC 0&(eeney et al' )--)a4, The role of activating

mutations of the c? !ET proto?oncogene in the etiology of hereditary papillary RCC has

already /een discussed' /ut data suggest that upregulated e5pression of this ligand may occur

in most of the histologic su/types of RCC 0Gatali et al' 1>2 %isters et al' 1;2 &chmidt

et al' 1;2 Clifford et al' 18a2 Horie et al' 14, Hepatocyte gro(th factor is e5pressed /y

pro5imal tu/ular cells in the normal 3idney' (here it is involved in the /ranching

tu/ulogenesis of the developing 3idney and regeneration after renal inFury, !n vitro'

hepatocyte gro(th factor has mitogenic and morphogenic effects on renal epithelial cells

0Clifford et al' 18a4, !ncreased serum levels of hepatocyte gro(th factor have also /eenreported in most patients (ith RCC' independent of histologic su/type' and activation of this



18

factor /y phosphorylation at t(o sites is associated (ith cancer progression 0%etri et al' 1;2

Miyata et al' )-->4, Ta3en together' these data suggest that hepatocyte gro(th factor and its

receptor may play an important role in the tumor /iology of RCC' although constitutive

activation of the receptor' (hich may /e the most potent mechanism' appears to /e primarily

limited to familial papillary RCC,

%roteases' Adhesion' and the E5tracellular Matri5

!nteractions among cancer cells' adFacent cells' and the surrounding matri5 can strongly

influence their pathogenic potential, Altered intracellular processing and secretion of

fi/ronectin and other matri5 proteins is found in RCC' representing one conseBuence of VHL

gene mutation 0Lieu/eau?Teillet et al' 182 Ohh et al' 184, This fundamental defect most

li3ely has important effects on tumor /iology' given the important role of the matri5 in

regulating cellular differentiation and tumor invasiveness and metastasis, !ncreased

e5pression of proteases' such as plasmin and the matri5 metalloproteinases' has correlated

(ith reduced survival in RCC and may also contri/ute to the aggressive /ehavior of RCC

0:alther et al' 1;a2 =ugler et al' 184, <o(nregulation of E?cadherin and cadherin?>'(hich mediate adhesion /et(een cancer cells' is (ell documented in RCC and has correlated

(ith poor outcomes in most studies 0Morton et al' 162 %aul et al' )--.4, A/errant regulation

of ?catenins' the cytoplasmic proteins that /ind cadherins and mediate their effects on the

cytos3eleton' has also /een o/served in RCC' and a correlation (ith compromised survival

has /een reported 0&himazui et al' 1>2 %aul et al' 1;4,

Other studies have defined the adhesion molecules that facilitate interactions /et(een tumor

cells and endothelial cells in RCC, &tein/ach and colleagues 01>4 have sho(n that sialyl?

Le(is5endothelial leu3ocyte adhesion molecule?1 and LA?.vascular cell adhesion

molecule?1 interactions regulate this process' (hich presuma/ly influences the a/ility of

tumor cells to move into or out of the vascular system during the metastatic cascade,

%athology

Most RCCs are roun' to ovoi' an' circumscribe' b# a pseu'ocapsule o* compresse'

parench#ma an' *ibrous tissue rather than a true histologic capsule. Jnlie upper tract

transitional cell carcinomas, most RCCs are not grossl# in*iltrative, &ith the notable

e"ception o* collecting 'uct RCC an' some sarcomatoi' variants 0"arro(' 1;4, Tumor

size has averaged /et(een . and 8 cm in most series /ut can vary from a fe( millimeters to

large enough to fill the entire a/domen, Tumors smaller than + cm (ere previously classified

as /enign adenomas' /ut some small tumors have /een associated (ith metastases 0Gguyenand #ill' )--4' and most pathologists agree that &ith the e"ception o* oncoc#tomas an'

some small :$ cm; lo&)gra'e papillar# a'enomas there are no reliable histologic or

ultrastructural criteria to 'i**erentiate benign *rom malignant renal epithelial tumors

0"arro(' 1;2 E/le et al' )--.4 0see Chapter 614, :hen they are /ivalved' RCCs consist of

yello(' tan' or /ro(n tumor interspersed (ith fi/rotic' necrotic' or hemorrhagic areas2 fe(

are uniform in gross appearance, Cystic degeneration is found in 1-* to )6* of RCCs and

appears to /e associated (ith a /etter prognosis compared (ith purely solid RCC 0Corica

et al' 12 =oga et al' )---2 Onishi et al' )--12 Gassir et al' )--)2 !mura et al' )--.2

:e/ster et al' )--;4, Calcification can /e stippled or plaBueli3e and is found in 1-* to )-*

of RCCs,



1

Euclear *eatures can be highl# variable. ra'ing has been base' primaril# on nuclear

si8e an' shape an' the presence or absence o* prominent nucleoli. 7uhrmans s#stem

0Ta/le .1-4 has been most generall# a'opte' an' is no& recogni8e' as an in'epen'ent

prognostic *actor *or RCC generall# an' *or clear cell RCC in particular 0"uhrman et al'

18)2 %antuc3 et al' )--1a2 Lang et al' )--62 Lohse et al' )--62 Ihou' )--4,

Table 49–$( )) 7uhrmans Classi*ication S#stem *or Euclear ra'e in Renal Cell

CarcinomaGRADE NUCLEAR !"E NUCLEAR #U$L!NE NUCLE#L!

7 7 mm Round, uni!orm Absent or inconspicuous

1 72 mm +rregular %mall ($isible at 8F magni!ication)

0 1 mm +rregular 4rominent

8 G1 mm :iDarre, o!ten multilobed 4rominent, hea$y chromatin clumps present

Aggressive local /ehavior is not uncommon (ith RCC and can /e e5pressed in a variety of

(ays, 7ran invasion an' per*oration o* the renal capsule, renal sinus, or collectings#stem are *oun' in appro"imatel# %(/ o* cases, although 'isplacement o* these

structures is a more common *in'ing. "urther spread to involve adFacent organs or the

a/dominal (all is often precluded /y the #erota fascia' although some high?grade RCCs are

a/le to overcome this natural /arrier, !ne uni@ue *eature o* RCC is its pre'ilection *or

involvement o* the venous s#stem, &hich is *oun' in $(/ o* RCCs, more often than in

any other tumor type 0&3inner et al' 1;)2 &chefft et al' 1;84, This is most commonly

manifested in the form of a contiguous tumor throm/us that can e5tend into the inferior vena

cava 0!C4 as high as the right atrium 0$lute et al' )--;4, Many such tumor throm/i are

highly vascularized /y arterial /lood flo( 0Govic3 et al' 1-4' and some directly invade the

(all of the renal vein or vena cava' (hich correlates (ith compromised prognosis 0Iini et al'

)--84,

Most spora'ic RCCs are unilateral an' uni*ocal. Bilateral involvement can be

s#nchronous or as#nchronous an' is *oun' in %/ to 4/ o* spora'ic RCCs, although it

is consi'erabl# more common in patients &ith *amilial *orms o* RCC, such as von

3ippel)in'au 'isease 0"arro(' 1;2 Linehan et al' )--+4, Multicentricit#, &hich is

*oun' in $(/ to %(/ o* cases, is more common in association &ith papillar# histolog#

an' *amilial RCC 0Mu3amel et al' 1882 Cheng et al' 112 :hang et al' 162 Camp/ell

et al' 1;a2 Richstone et al' )--.2 =ram/ec3 et al' )--84, &atellite lesions are often small

and difficult to identify /y preoperative imaging' intraoperative ultrasonography' or visual

inspection2 they appear to /e the main factor contri/uting to local recurrence after partial

nephrectomy 0Camp/ell et al' 1>a2 Richstone et al' )--.4, Microsatellite anal#sissuggests a clonal origin *or most multi*ocal RCC &ithin the same i'ne# 09un3er et al'

)--)4' but tumor in the contralateral i'ne# is liel# to be an in'epen'ent gro&th i* it is

s#nchronous or a metastasis i* it is as#nchronous 0=ito et al' )--)4, Molecular analyses'

such as gene e5pression profiling' may help to determine (hether an asynchronous tumor is a

second primary tumor or a metastasis 0Lane et al' )--4,

1ll RCCs are, b# 'e*inition, a'enocarcinomas, 'erive' *rom renal tubular epithelial

cells 0Iam/rano et al' 12 %antuc3 et al' )--1a2 Rensha(' )--)2 Ihou' )--4, Most RCCs

share ultrastructural *eatures, such as sur*ace microvilli an' comple" intracellular

-unctions, &ith normal pro"imal tubular cells, an' are believe' to be 'erive' *rom this

region o* the nephron 0revie(ed in "arro(' 1;4, &imilarly' immunohistochemistry for



)-

lectins and other cell surface antigens has supported derivation from the pro5imal convoluted

tu/ule 0=im and =im' )--)4, 3o&ever, more recent 'ata suggest that this in*ormation

applies primaril# to the more common clear cell an' papillar# variants o* RCC 0Ta/le

.114' &hereas most other histologic subt#pes o* RCC appear to be 'erive' *rom more

'istal elements o* the nephron 0&tDr3el et al' 1;2 Iam/rano et al' 12 %antuc3 et al'

)--1a2 Rensha(' )--)2 Linehan et al' )--+2 %avlovich and &chmidt' )--.4,

Table 49–$$ )) Pathologic Subt#pes o* RCC%ist&l&g'* Fa(ilial )&r( ad

geeti+ )a+t&rsGr&ss+hara+teristi+s

,i+r&s+&-i+-ath&l&gi++hara+teristi+s

#ther+hara+teristi+s

lear cell R

(5>/B>)

$on Hippel/Lindaudisease

VHL gene (0p12/13) mutation orhypermethylation

hromosome 0pdeletions

Also, loss o!chromosome Bp,?p, 786E gain o!chromosome 26

ell/circumscribed,lobulated,golden yello#tumor

'ecrosis andhemorrhage

common

Venousin$ol$ementalso common

ysticdegeneration

Hyper$asculartumor

'ests or sheetso! clear cells #ithdelicate $ascular net#or=

+HIJK lo#

@s,IMK $imentin, A,A/+N

Originate !romproximal tubule

Aggressi$ebeha$ior morecommon

Tumor shrin=agecommon #ith

targetedmoleculartherapy

ay respond toimmunotherapy

ultilocular cysticclear cell R(uncommon)

+dentical to clearcell R

ell/circumscribedmass o! smalland large cysts

ysts lined bysingle layer o!grade 7 clearcells

'o expansi$enodules o! tumor cells

Almost uni!ormlybenign clinicalbeha$ior

4apillary R

(7>/72>)

Type 7 H4R

Type 1 HLR

Acti$ation o! c/MET oncogene (5607/08) by mutationcommon in H4Rbut uncommon(7>) in sporadiccases

Trisomy o!chromosome 5 and75E loss o! &

leshy tumor#ith !ibrous

pseudocapsule

'ecrosis andhemorrhage arecommon

Hypo$asculartumor 4apillary

structures #ithsingle layer o!cells around!ibro$ascularcores

Type 7basophilic cells#ith lo#/gradenuclei

Type 1eosinophilic cells#ith high/gradenuclei

+H L@s,@5 (type 7 Ptype 1), AAR

Originate !romproximal tubule

ommonlymulticentric

ommon in

AR

Type 7 goodprognosis

Type 1 #orseprognosis

hromophobe R(0>/2>)

:irt/Hogg/ub;syndrome

umaratehydratase gene(7681/80) mutation

Loss o! multiplechromosomes (7,1, 3, 7, 70, 75, 17)

ell/circumscribed,homogeneous

Tan or lightbro#n cutsur!ace

Q4lant cells #ithpale cytoplasm,perinuclearclearing orQhalo, nuclearQraisins, andprominent cellborders

4ositi$e Halecolloidal ironstaining

+H di!!use @5

Originate !romintercalated cellso! collecting duct

*enerally goodprognosis,althoughsarcomatoid$ariantassociated #ithpoor prognosis

ollecting ductcarcinoma (S7>)

9n=no#n

ultiplechromosomal

losses

irm, centrallylocated tumor#ith in!iltrati$e

borders

Light gray totan/#hite

omplex, highlyin!iltrati$e cords#ithin in!lamed

(desmoplastic)stroma

High/grade

Originate !romcollecting duct

4oor prognosis

ay respond tochemotherapy



)1

nuclei, mitoses

Renal medullarycarcinoma (rare)

Associated #ithsic=le cell trait

+n!iltrati$e, gray/#hite

xtensi$ehemorrhageand necrosis

4oorlydi!!erentiatedcells #ith laceli=eappearance

+n!lammatoryin!iltrate

Originate !romcollecting duct

ismal prognosis

9nclassi!ied R(7>/0>)

9n=no#n Varied Varied Origin notde!ined

*enerally poorprognosis

R associated #ithNp77.1translocations"TFE' gene !usions (rare)

Various mutationsin$ol$ingchromosomeNp77.1 resulting inTFE' gene !usion

ell/circumscribed,tan/yello#tumor

VariableE o!tenclear cells #ithpapillaryarchitecture

+H nuclearTFE'

Occur in childrenand youngadultsE 8> o!pediatric R

t(NE75) present#ith ad$ancedstage and !ollo#indolent course

t(NE7) can recur#ith late lymphnode metastases

4ost/neuroblastomaR (rare) 9n=no#n ellcircumscribed

Oncocytic orclear cells #ithsolid andpapillaryarchitecture

Occursexclusi$ely inchildren #ithpriorneuroblastoma

ucinous tubularand spindle cellcarcinoma (rare)

9n=no#n

ell/circumscribed,tan/#hite/pin=tumors centeredin medulla

ixture o!tubules andspindle/shapedepithelial cellsEmucinbac=ground

a$orableprognosis

From Ee 8*, Sa&ter , E+'tein 89, et a Pathoo:y an# :eneti"' of t&mo&r' of the &rinary

'y'tem an# mae :enita or:an' Lyon Fran"e<= 9ARC Pre''; 200%; #ata from Storke, ./;

Ren'ha>, 2002; 1amrano et a, .; Pant&"k et a, 200.; Linehan et a, 2003; Pa$o$i"h

an# S"hmi#t, 200%; atte et a, 200); an# 1ho&, 200

AR, ac6uired renal cystic diseaseE HLR, hereditary leiomyomatosis and R syndromeE H4R, hereditary papillaryR syndromeE +H, immunohistochemistryE R, renal cell carcinoma.

* %arcomatoid $ariants o! all o! these subtypes ha$e been described and are associated #ith compromised prognosis.. +mmunohistochemistry using these mar=ers can help to di!!erentiate bet#een R subtypes./ yto=eratin (@) lo# (or high)/molecular/#eight cyto=eratins (@s).

Since the earl# $99(s the histologic classi*ication o* RCC has un'ergone several ma-or

revisions 0Iam/rano et al' 12 Rensha(' )--)2 Linehan et al' )--+2 E/le et al' )--.2 Ihou')--4, Traditionally' RCC (as divided into four histologic su/typesP clear cell' granular cell'

tu/ulopapillary' and sarcomatoid, On the /asis of advances in the molecular genetics of RCC

and a more discerning interpretation of histologic and ultrastructural features' a ne(er

classification scheme (as proposed /y =ovacs 01+4, This classification system (as

approved /y an international consensus (or3shop of clinicians and researchers in the field

0:eiss et al' 162 &tDr3el et al' 1;2 Iam/rano et al' 12 %antuc3 et al' )--1a2 Rensha('

)--)2 Linehan et al' )--+2 %avlovich and &chmidt' )--.4, !n this system' granular cell tumors

(ere reclassified into other categories /ased on distinct histopathologic features'

chromopho/e RCC (as recognized as a ne( RCC su/type' and sarcomatoid features (ere

categorized as variants of other histologic su/types rather than a distinct tumor type 0:eiss

et al' 162 &tDr3el et al' 1;2 Oyasu' 182 Iam/rano et al' 12 Rensha(' )--)2 Linehanet al' )--+2 %avlovich and &chmidt' )--.4, Current practice is to i'enti*# the primar#



))

histologic subt#pe an' comment on the presence an' e"tent o* sarcomatoi'

'i**erentiation rather than to separate these tumors into a 'istinct categor#, although

the prognostic implications have not change' 0Mian et al' )--)2 Cheville et al' )--.2 E/le

et al' )--.2 Ihou' )--4, <epending on (ell?defined histologic and ultrastructural criteria'

granular cell tumors (ere reclassified as papillary RCC' eosinophilic variants of

chromopho/e RCC' or com/ined (ith clear cell RCC 0:eiss et al' 162 =ovacs et al' 1;2&tDr3el et al' 1;2 Oyasu' 182 Iam/rano et al' 12 Rensha(' )--)2 Ihou' )--4,

Another important development (as the identification of renal medullary carcinoma that is

common in young African?Americans (ith sic3le cell trait 0<avis et al' 16/2 &tDr3el et al'

1;2 Ha3imi et al' )--;4, :ith additional advances in ancillary pathologic studies' including

electron microscopy' immunohistochemistry' molecular genetics and cytogenetics' several

additional uniBue su/types of RCC have /een identified since the implementation of the 1+

classification system, $ased on these findings' an updated classification of malignant

epithelial tumors of the 3idney (as presented /y the :orld Health Organization in )--. 0see

Ta/le .112 E/le et al' )--.4,

The %((4 2orl' 3ealth !rgani8ation classi*ication re*lects current un'erstan'ing o* RCC not as a single malignant neoplasm but rather a group comprising several

'i**erent tumor subt#pes, each &ith a 'istinct genetic basis an' uni@ue clinical *eatures

0see Ta/le .114, !mportant changes include the addition of several RCC su/types (ith

distinct pathologic and clinical features that (ere previously grouped (ithin Kconventional

or unclassified RCC' such as RCC associated (ith %11,) translocationsTFE3 gene fusions'

(hich has microscopic features of /oth clear cell and papillary RCC and occurs primarily in

children and young adults 0Argani et al' )--12 Camparo et al' )--82 #eller et al' )--84' and

the indolent mucinous tu/ular and spindle cell carcinoma 0Hes et al' )--)2 "erlicot et al )--62

"ine et al' )-->4, &ophisticated gene e5pression profiling and proteomic analyses support the

individuality of each of these tumor su/types and hold great promise for differentiating

additional su/types in the future 0Ta3ahashi et al' )--+' )--.2 Amy?$azille et al' )--.2 "urge

et al' )--.2 &ugimura et al' )--.2 ang et al' )--.' )-->2 oung et al' )--84, This is clearly a

field in evolution' (ith changes stimulated /y /asic science advances and astute clinical

o/servation,

Clear Cell Renal Cell Carcinoma

Clear cell RCC accounts *or 0(/ to >(/ o* all RCCs, representing the gar'en variet#

o* RCC formerly 3no(n as Kconventional RCC 0&tDr3el et al' 1;2 E/le et al' )--.2 Rini

et al' )--4, These tumors are t#picall# #ello& &hen the# are bivalve' an' are highl#

vascular, containing a net(or3 of delicate vascular sinusoids interspersed /et(een sheets or acini of tumor cells 0"ig, .114, !n microscopic e"amination, clear cell RCC can inclu'e

clear cell, granular cell, or mi"e' t#pes. Clear cells are typically round or polygonal (ith

a/undant cytoplasm containing glycogen' cholesterol' cholesterol esters' and phospholipids'

all of (hich are readily e5tracted /y the solvents used in routine histologic preparations'

contri/uting to the clear appearance of the tumor cells 0"arro(' 1;4, Ho(ever' granular

cells' (hich have eosinophilic cytoplasm and a/undant mitochondria' can predominate, T(o

to 6 percent of clear cell RCC demonstrate sarcomatoid features' and clear cell RCC is more

li3ely to e5hi/it venous tumor e5tension than any other su/type of RCC 0Ra//ani et al'

)--.4, ?n general, patients &ith clear cell RCC have a &orse prognosis compare' &ith

papillar# or chromophobe RCC, even a*ter strati*ication *or stage an' gra'e 0Lau et al'

)--)2 Cheville et al' )--+2 $ec3 et al' )--.4, 3o&ever, most respon'ers inimmunotherap# protocols have ha' clear cell RCC, an' these protocols are no& being



)+

reserve' primaril# *or this population 0Childs et al' )---2 <rachen/erg and Childs' )--+4,

Chromosome + alterations an' VHL mutations are common in clear cell RCC, an'

mutation or inactivation o* this gene has been *oun' in a ma-orit# o* spora'ic cases

0Clifford et al' 18/2 Iam/rano et al' 12 Rensha(' )--)2 Linehan et al' )--+4, The

familial form of clear cell RCC' the von Hippel?Lindau syndrome' has already /een

revie(ed,

Figure 49–11 A lear cell renal cell carcinoma (R) #ith typical golden yello# color. Lo#/po#er $ie# o! typicalmicroscopic appearance o! a lo#/grade clear cell R demonstrating a delicate $ascular net#or= interspersed #ithinhomogeneous nests o! cells #ith clear cytoplasm.(o9rtes" of Dr. Ming Zho9, le2elan!, :H.-

%apillary Renal Cell Carcinoma

Papillar# RCC, &hich has also been 'esignate' chromophilic RCC in previous

classi*ication schemes, is the secon' most common histologic subt#pe 0&tDr3el et al' 1;2

E/le et al' )--.2 %ignot et al' )--;2 #ontero et al' )--84, ?t represents $(/ to $5/ o* all

RCCs, although it is more commonl# *oun' in patients &ith en')stage renal *ailure an'

ac@uire' renal c#stic 'isease 0!shi3a(a and =ovacs' 1+2 &tDr3el et al' 1;4, On

microscopic e5amination' most tumors in this category consist of /asophilic or eosinophilic

cells arranged in papillary or tu/ular configuration2 previously' more than 6-* or ;6* of the

tumor had to e5hi/it such architectural features to Bualify as a papillary RCC 0"ig, .1)4,

!ne uni@ue *eature o* papillar# RCC is its ten'enc# to&ar' multicentricit#, &hich

approaches 4(/ in man# series 0Rensha( and Corless' 162 Amin et al' 1;a2 Camp/ell

et al' 1;/2 Cho( et al' )--12 Ihou' )--4,



).

Figure 49–12 A 4apillary renal cell carcinoma (R) o!ten presents as multiple, small mildly enhancing renal tumors, asdemonstrated on this T image. icroscopic appearance o! type 7 papillary R demonstrating basophilic cells #ith

scant cytoplasm and lo#/grade nuclei. C +n contrast, type 1 papillary R consists o! eosinophilic cells #ith abundantgranular cytoplasm and high/grade nuclei.(o9rtes" of Dr. Ming Zho9, le2elan!, :H.-

T(o distinct variants of papillary RCC have /een descri/ed /y characteristic cytogenetics'

immunostaining profiles and gene e5pression profiling 0see "ig, .1)4 0Rensha( et al'

1;2 &tDr3el et al' 1;2 Oyasu' 182 <elahunt et al' )--12 E/le et al' )--.2 ang et al'

)--64, T#pe $ papillar# RCC, the more common *orm, consists o* basophilic cells &ith

scant c#toplasm t#pe % papillar# RCC inclu'e potentiall# more aggressive variants

&ith eosinophilic cells an' abun'ant granular c#toplasm 0<elahunt et al' )--12Amsellem?Ouazana et al' )--)2 Leroy et al' )--)2 Rensha(' )--)2 Choy3e et al' )--+2

#una(an et al' )--+2 %ignot et al' )--;4, The t&o subt#pes o* papillar# RCC correspon'

&ith t&o *amilial RCC s#n'romes here'itar# papillar# RCC s#n'rome :t#pe $; an'

here'itar# leiom#omatosis an' RCC s#n'rome :t#pe %; 0Rosner et al' )--4, Although

mounting molecular and genetic evidence indicate that these ) su/types appear to represent

distinct entities' su/classification of papillary RCC into type 1 and type ) is not routinely

practiced (ithin the community of genitourinary pathologists at present 0E/le et al' )--.2

ang et al' )--62 %ignot et al' )--;4, "irst' although patients (ith hereditary leiomyomatosis

and RCC syndrome have compromised survival relative to those (ith hereditary papillary

RCC syndrome' oncologic outcomes in patients (ith sporadic forms of these entities are not

(ell defined 0%ignot et al' )--;2 #ontero et al' )--84, Moreover' evolving definitions of these



)6

entities and corresponding differences in interpretation and classification may contri/ute to

the current lac3 of consensus a/out this issue 0%ignot et al' )--;2 #ontero et al' )--84,

The c#togenetic abnormalities associate' &ith papillar# RCC are characteristic an'

inclu'e trisom# o* chromosomes 0 an' $0 an' loss o* the F chromosome 0=ovacs et al'

184, Other common findings include gain of chromosomes 1)' 1>' and )- and loss of heterozygosity on chromosome 1. 0Oyasu' 182 $runelli et al' )--+/2 =uroda et al' )--+a2

%avlovich and &chmidt' )--.2 Ihou' )--4, VHL mutations are rare in papillary RCC'

confirming distinct genetic path(ays to tumorigenesis 0=enc3 et al' 1>2 Iam/rano et al'

12 Linehan et al' )--+2 Rosner et al' )--4, %apillary RCC is more li3ely to /e

hypovascular' perhaps o(ing to the lac3 of VHL mutations that regulate E#"' the primary

proangiogenic molecule in RCC 0$lath et al' 1;>2 Herts et al' )--)2 =im 9= et al' )--)4, As

discussed earlier' activating mutations of the c? !ET proto?oncogene located on chromosome

;' (hich encodes the receptor for hepatocyte gro(th factor' appear to /e common and

pathogenic in inherited papillary RCC 0&chmidt et al' 1;2 %avlovich and &chmidt' )--.4,

!ndeed' this genetic defect is no( /eing targeted for novel treatment approaches (ith use of

small molecule inhi/itors 0&chmidt et al' 1;2 Linehan et al' )--+2 Rosner et al' )--4,!nterestingly' these mutations have /een detected in only a/out 1-* of sporadic papillary

RCCs' suggesting divergent molecular path(ays 0&chmidt et al' 14,

The prognosis associated (ith papillary RCC remains controversial, Many older studies

suggested a tendency to(ard lo(?grade disease' and one literature revie( indicated that 8-*

of papillary RCCs are confined to the 3idney' (hich has o/vious prognostic implications

0$lath et al' 1;>2 Mancilla?9imenez et al' 1;>2 $ocz3o et al' 1;2 Mydlo and $ard' 18;2

"arro(' 1;2 Cho( et al' )--14, On the other hand' more recent studies contain a some(hat

increased proportion of high?grade and advanced tumors' often leading to the patientJs demise

due in part to the ineffectiveness of current systemic therapies against papillary RCC 0Lager

et al' 162 Amin et al' 1;a2 Rensha(' )--)2 Margulis et al' )--84, One recent study

indicates that although venous tumor throm/us (as less common (ith papillary RCC than

clear cell RCC' outcomes in this su/group of patients (ere compromised 0Margulis et al'

)--84, Conversely' although lymph node involvement (as more common (ith papillary RCC

than clear cell RCC in the same study' patients (ith lymphatic involvement (ith papillary

RCC had higher cancer?specific survival at 6 years 0>6* vs, 1*' P S ,-+4, 1t present, most

authors believe that papillar# RCC, an' t#pe $ papillar# RCC in particular, carr# a

better prognosis than clear cell RCC &hen compare' gra'e *or gra'e an' stage *or

stage 0Moch et al' )---2 Lau et al' )--)2 Amin et al' )--)2 $ec3 et al' )--.2 Ihou' )--4,

Papillar# a'enomas are small :N5 mm; tumors that resemble papillar# RCC un'er themicroscope, are o*ten &ell encapsulate' an' lo& gra'e, an' are commonl# *oun' at

autops# 0"arro(' 1;2 Rensha(' )--)4, These lesions' (hich possess many of the same

genetic alterations found in larger papillary RCCs' are /enign neoplasms 0see Chapter 614,

Chromopho/e Renal Cell Carcinoma

Chromophobe RCC, *irst 'escribe' b# Theones an' colleagues in $9>5, is a 'istinctive

histologic subt#pe o* RCC that appears to be 'erive' *rom the cortical portion o* the

collecting 'uct 0&tDr3el et al' 1;4, ?t represents +/ to 5/ o* all RCCs 0Oyasu' 182

E/le et al' )--.2 =latte et al' )--8a4, The tumor cells typically e5hi/it a relatively transparent

cytoplasm (ith a fine reticular pattern that has /een descri/ed as a Kplant cell appearance0"ig, .1+4, The chromopho/ic nature of this classic variant is responsi/le for the name of



)>

this histologic su/type 0Gagashima' )---2 =uroda et al' )--+a4, Ho(ever' eosinophilic

variants of chromopho/ic RCC have also /een descri/ed and constitute a/out +-* of cases

0Theones et al' 1882 &tDr3el et al' 1;2 Latham et al' 12 =uroda et al' )--+a4, !n either

case' a perinuclear clearing or <halo= is t#picall# *oun' an' electron microscopic

*in'ings consist o* numerous $5() to +(()nm microvesicles, &hich are the single most

'istinctive an' 'e*ining *eature o* chromophobe cell carcinoma 0Gagashima' )---2=rishnan and Truong' )--)4, These microvesicles characteristicall# stain positive *or 3ale

colloi'al iron, in'icating the presence o* a mucopol#sacchari'e uni@ue to chromophobe

RCC 0see "ig, .1+4 0Theones et al' 1884, Most chromopho/e RCCs also stain positive for

various cyto3eratins and most are negative for vimentin 0Cochand?%riollet et al' 1;4,

enetic anal#sis has reveale' multiple chromosomal losses, most *re@uentl# the &hole

chromosomes $, %, , $(, $+, $0, an' %$, an' *lo& c#tometric anal#sis has 'emonstrate'

h#po'iploi' DE1 content in most cases 0&ch(erdtle et al' 1>2 $ugert et al' 1;2 !B/al

et al' )---2 %olasci3 et al' )--)4, &ome studies have reported an increased incidence of TP43

mutations in this histologic su/type and upregulated e5pression of the c? 9T oncogene has

also /een reported 0Contractor et al' 1;2 amaza3i et al' )--+2 %an et al' )--.2 %etit et al'

)--.2 Huo et al' )--64, Chromopho/e RCC is commonly seen in the $irt?Hogg?<u/syndrome' /ut most cases are sporadic 0%avlovich et al' )--)4,

Figure 49–13 A hromophobe renal cell carcinoma (R) typically appears as a #ell/circumscribed, homogeneous, tantumor. hromophobe R #ith admixture o! classic (chromophobic) and eosinophilic cells. haracteristic !eatures include



);

distinct cytoplasmic borders, perinuclear halos, and nuclear Qraisins. The classic $ariant is notable !or its Qplant cellappearance. C hromophobe R stains positi$e !or Hale colloidal iron and demonstrates multiple micro$esicles onanalysis by electron microscopy.(o9rtes" of Dr. Ming Zho9, le2elan!, :H.-

Most stu'ies o* the clinical behavior o* chromophobe RCC suggest a better prognosis

*or locali8e' chromophobe RCC than *or clear cell RCC but a poor outcome in the

subset o* patients &ith sarcomatoi' *eatures or metastatic 'isease 0%olasci3 et al' )--)2

Lau et al' )--)2 Cindolo et al' )--6a2 Cheville et al' )--+2 %eyromaure et al' )--+2 $ec3 et al'

)--.2 =latte et al' )--8a4, Most early reports suggested a tendency to remain localized

despite gro(th to large size' as (ell as a predominance of lo(?grade disease 0Theones et al'

1884, &u/seBuent reports have verified that chromopho/e RCC generally presents at an

earlier stage' (ith more than -* of patients remaining cancer free for 6 or more years after

treatment 0Crotty et al' 162 Camp/ell et al' 1>/2 %eyromaure et al' )--+2 Cindolo et al')--6a2 =latte et al' )--8a4, Ho(ever' a more adverse prognosis has /een reported for high?

grade tumors' including those (ith sarcomatoid differentiation 0Camp/ell et al' 1>/2

Rensha( et al' 12 =uroda et al' )--+a2 =latte et al' )--8a4, Lymph node and distant

metastases are commonly seen (ith such variants' and systemic disease is poorly responsive

to !L?) 0Rensha( et al' 12 Motzer et al' )--)2 =latte et al' )--8a4, !nitial data (ith the

mTOR inhi/itor temsirolimus indicate that this agent may have some activity for metastatic

chromopho/e RCC2 among 18 patients receiving treatment' 1> had sta/le disease and 1 had a

partial response 0&tadler et al' )--;4, Clearly' further clinical evaluation (ill /e reBuired to

identify the most effective therapeutic agents for patients (ith metastatic' nonclear cell

RCC,

Collecting <uct Carcinoma

Carcinoma o* the collecting 'ucts o* Bellini is a relativel# rare subt#pe o* RCC,

accounting *or less than $/ o* all RCCs 0=ennedy et al' 1-2 Rumpelt et al' 112 Carter

et al' 1)2 &tDr3el et al' 1;2 &rigley and E/le' 182 &(artz et al' )--)4, Many reported

cases have occurred in younger patients' often in the third' fourth' or fifth decades of life

0Carter et al' 1)4, Most patients are symptomatic at presentation' and up to 6-* have

metastatic disease at the time of detection 0To3uda et al' )-->4, ?e@ e&ro+ae&' agglutinin 1

reactivity and positivity for E?cadherin and c?=!T help to distinguish this entity from

aggressive papillary RCC' /ut this staining profile can also /e present in urothelial carcinoma

and differential diagnosis often reBuires careful e5amination of multiple sections 0Rumpelt

et al' 112 Oyasu' 182 %olasci3 et al' )--)2 =o/ayashi et al' )--84, E5pression of high?

molecular?(eight cyto3eratin (as initially /elieved to support a collecting duct origin' /ut

more recent studies suggest that this is not a relia/le mar3er for collecting duct carcinoma

0Rumpelt et al' 112 Oyasu' 182 %olasci3 et al' )--)2 =o/ayashi et al' )--84, &mall

collecting duct carcinomas can arise in a medullary pyramid' /ut most are large' infiltrative

masses and e5tension into the corte5 is common 0%ic3hardt et al' )--12 =o/ayashi et al'

)--84, On microscopic e5amination' these tumors consist of an admi5ture of dilated tu/ules

and papillary structures typically lined /y a single layer of cu/oidal cells' often creating a

co//lestone appearance, <eletions on chromosome 1B and monosomy of chromosomes >' 8'

11' 18' )1' and have /een reported' /ut the num/er of tumors analyzed thus far has /eenlimited 0"uzesi et al' 1)2 &teiner et al' 1>2 %olasci3 et al' )--)4, Most reporte' cases o*



)8

collecting 'uct carcinoma have been high gra'e, a'vance' stage, an' unresponsive to

conventional therapies 0Carter et al' 1)2 Chao et al' )--)/2 %olasci3 et al' )--)2 MeFean

et al' )--+2 To3uda et al' )-->2 =o/ayashi et al' )--84, Reflecting the fact that collecting duct

RCC may share features in common (ith transitional cell carcinoma' some patients (ith

advanced collecting duct RCC have responded to cisplatin? or gemcita/ine?/ased

chemotherapy 0Milo(s3y et al' )--)2 %eyromaure et al' )--+2 =o/ayashi et al' )--84,

Renal Medullary Carcinoma

Renal me'ullar# carcinoma is a subt#pe o* RCC that occurs almost e"clusivel# in

association &ith the sicle cell trait. ?t is t#picall# 'iagnose' in #oung 1*rican)

1mericans, o*ten in the thir' 'eca'e o* li*e, an' man# cases are both locall#)a'vance'

an' metastatic at the time o* 'iagnosis 0<avis et al' 16/2 %olasci3 et al' )--)2 &(artz

et al' )--)2 Ihou' )--4, Most patients do not respond to therapy and succum/ to their

disease in a fe( to several months 0<avis et al' 16/2 Herring et al' 1;2 "igenshau et al'

182 %olasci3 et al' )--)4, Mean survival in <avis and co(or3ersN series 016/4' (hich

consisted of +. patients' (as only 16 (ee3s, This tumor shares man# histologic *eatures&ith collecting 'uct carcinoma, an' some consi'er it a subt#pe o* collecting 'uct

carcinoma or at least a closel# relate' tumor 0&tDr3el et al' 1;2 %olasci3 et al' )--)2

&(artz et al' )--)4, Renal medullary carcinoma is thought to arise from the calyceal

epithelium near the renal papillae /ut is often highly infiltrative 0<avidson et al' 162 <avis

et al' 16/4, The site of origin 0renal papillae4 and association (ith sic3le cell trait suggest

that a relatively hypo5ic environment may contri/ute to tumorigenesis,

&arcomatoid <ifferentiation

Sarcomatoi' 'i**erentiation is *oun' in $/ to 5/ o* RCCs, most commonl# in

association &ith clear cell RCC or chromophobe RCC, but variants o* most other

subt#pes o* RCC have been 'escribe' 0:eiss et al' 162 &tDr3el et al' 1;2 Oyasu' 182

<elahunt' 12 de%eralta?enturina et al' )--12 =uroda et al' )--+e2 Cheville et al' )--.2

Ihou' )--4, Most authors no( /elieve that sarcomatoid lesions represent poorly

differentiated regions of other histologic su/types of RCC rather than independently derived

tumors 0<eLong et al' 1+2 Oyasu' 182 <elahunt' 12 E/le et al' )--.4, A thorough

search for epithelial?derived malignant components is almost al(ays fruitful2 it is rare to find

a truly pure sarcomatoid renal mass 0<elahunt' 14, 7or this reason, this entit# is no

longer recogni8e' as a 'istinct histologic subt#pe o* RCC 0E/le et al' )--.4, Sarcomatoi'

'i**erentiation is characteri8e' b# spin'le cell histolog#, positive staining *or vimentin,

in*iltrative gro&th pattern, aggressive local an' metastatic behavior, an' poor prognosis0"ig, .1.4 0Ro et al' 18;2 <eLong et al' 1+2 Cangiano et al' 12 E/le et al' )--.4,

!nvasion of adFacent organs is common' and median survival has /een less than 1 year in

most series 0Ro et al' 18;2 Cangiano et al' 12 Escudier et al' )--)a2 Mian et al' )--)2

Ganus et al' )--.2 <allNOglio et al' )--62 Ihou' )--4, Multimodal approaches should /e

considered if performance status allo(s /ased on the e5tremely poor prognosis (ith surgery

alone and selected reports demonstrating modestly improved response rates in patients

receiving !L?)/ased immunotherapy' chemotherapy' or targeted molecular therapy after

surgery 0Cangiano et al' 12 $angalore et al' )--12 "uFi(ara et al' )--82 Rini et al' )--4,



)

Figure 49–14 A lear cell renal cell carcinoma (R) #ith sarcomatoid di!!erentiation demonstrating extension into theperinephric !at. High/grade R #ith typical spindle/cell appearance on the le!t indicating a component o! sarcomatoiddi!!erentiation.(o9rtes" of Dr. Ming Zho9, le2elan!, :H.-

7nclassified Renal Cell Carcinoma

Jnclassi*ie' RCC represents a small minorit# o* cases :+/; o* presume' RCC &ith

*eatures that remain in'eterminate even a*ter care*ul anal#sis 0Iisman et al' )--)a4,

Most are poorl# 'i**erentiate' an' are associate' &ith a highl# aggressive biologic

behavior an' a particularl# poor prognosis 0Iisman et al' )--)a2 =ara3ie(icz et al' )--;4,

!ncluded (ithin this Kcatch?all category are RCCs (ith e5tensive sarcomatoid differentiation

and no discerni/le epithelial component, Advances in molecular diagnostics' such as gene

e5pression profiling' may ena/le further classification of unusual tumors that previously

(ould have fallen into this category and identify candidate path(ays for targeted molecular

therapeutics 0ang et al' )-->2 oung et al' )--84,

Clinical %resentation

Because o* the se@uestere' location o* the i'ne# &ithin the retroperitoneum, man#renal masses remain as#mptomatic an' nonpalpable until the# are a'vance'. 2ith the

more pervasive use o* noninvasive imaging *or the evaluation o* a variet# o* nonspeci*ic

s#mptom comple"es, more than 5(/ o* RCCs are no& 'etecte' inci'entall# 0%antuc3

et al' )---4, &everal studies have sho(n that such tumors are more li3ely to /e confined to

the 3idney' and a positive impact on survival has /een reported' although the potential

contri/utions of lead and length time /iases have not /een defined 0=onna3 and #rossman'

1862 Thompson and %ee3' 1882 =essler et al' 1.2 Tsui et al' )---/2 %arsons et al' )--12

Lee et al' )--)2 Leslie et al' )--+2 Gguyen et al' )-->2 <eCastro and Mc=iernan' )--82 =ane

et al' )--84,

S#mptoms associate' &ith RCC can be 'ue to local tumor gro&th, hemorrhage,paraneoplastic s#n'romes, or metastatic 'isease 0Ta/le .1)4, "lan3 pain is usually due



+-

to hemorrhage and clot o/struction' although it can also occur (ith locally advanced or

invasive disease, The classic tria' o* *lan pain, gross hematuria, an' palpable

ab'ominal mass is no& rarel# *oun' 09ayson and &anders' 1.4, This is fortunate /ecause

this constellation of findings almost al(ays denotes advanced disease' and some refer to it as

the Ktoo late triad, $efore the advent of ultrasonography and CT' most patients (ith RCC

presented (ith one or more of these signs or symptoms' and many (ere incura/le, Other indicators of advanced disease include constitutional symptoms' such as (eight loss' fever'

and night s(eats' and physical e5amination findings such as palpa/le cervical

lymphadenopathy' nonreducing varicocele' and /ilateral lo(er e5tremity edema due to

venous involvement, A minority of patients present (ith symptoms directly related to

metastatic disease' such as /one pain or persistent cough, 1 less common but important

presentation o* RCC is that o* spontaneous perirenal hemorrhage, although the

un'erl#ing mass is o*ten obscure' b# the bloo'. Ihang and colleagues 0)--)4 have sho&n

that more than 5(/ o* patients &ith perirenal hematoma o* unclear etiolog# have an

occult renal tumor, most o*ten 1M or RCC. Repeat CT a fe( months later (ill often

provide a definitive diagnosis,

Table 49–$% )) Clinical Presentation o* Renal Cell Carcinoma

!+idetal

L&+al $u(&r Gr&th

• Hematuria

• lan= pain

• Abdominal mass

• 4erirenal hematoma

,etastases

• 4ersistent cough

• :one pain

• er$ical lymphadenopathy

• onstitutional symptoms

• eight loss"!e$er"malaise

#bstru+ti& &) the !)eri&r 5ea Cava

• :ilateral lo#er extremity edema

• 'onreducing or right/sided $aricocele

Parae&-lasti+ 'dr&(es

• Hypercalcemia

• Hypertension

• 4olycythemia

• %tau!!ers syndrome

Paraneoplastic s#n'romes are *oun' in %(/ o* patients &ith RCC, and fe( tumors areassociated (ith the diversity of such syndromes 0Ta/le .1+4, !n fact' RCC &as previousl#

re*erre' to as the internists tumor because o* the pre'ominance o* s#stemic rather than

local mani*estations 0&ufrin et al' 182 #old et al' 1>2 Moein and <ehghani' )---2

<eLuca et al' )--)2 =amra et al' )--)2 Hagel et al' )--62 Costanzi et al' )--84, Go(' a more

appropriate name (ould /e the radiologistJs tumor' given the freBuency of incidental

detection 0%arsons et al' )--12 <eCastro and Mc=iernan' )--82 =ane et al' )--84,

Gevertheless' it is still important to evaluate for paraneoplastic phenomena /ecause they can

/e a source of maFor mor/idity and can affect clinical decision ma3ing, 7nder normal

circumstances' the 3idney produces 1')6?dihydro5ycholecalciferol' renin' erythropoietin' and

various prostaglandins' all of (hich are tightly regulated to maintain homeostasis, RCC may

produce these su/stances in pathologic amounts' and it may also ela/orate a variety of other physiologically important factors' such as parathyroid hormoneli3e peptides' lupus?type



+1

anticoagulant' human chorionic gonadotropin' insulin' and various cyto3ines and

inflammatory mediators 0&ufrin et al' 182 #old et al' 1>2 Ather et al' )--)2 Elias' )--64,

These su/stances are /elieved to /e responsi/le for the development of constitutional

symptoms such as (eight loss' fever' and anemia as (ell as some of the distinct

paraneoplastic syndromes o/served (ith this malignancy 0Altundag et al' )--62 Elias' )--64,

Table 49–$+ )) ?nci'ence o* S#stemic S#n'romes 1ssociate' &ith Renal Cell

Carcinoma6NDR#,E 7

le$ated erythrocyte sedimentation rate 22.3

Hypertension 05.2

Anemia 03.0

achexia, #eight loss 08.2

4yrexia 75.1

Abnormal li$er !unction 78.8

Hypercalcemia 8.?

4olycythemia 0.2

'euromyopathy 0.1

Amyloidosis 1.

From o# P8, Fefer A, Thom+'on 8A Paraneo+a'ti" manife'tation' of rena "e

"ar"inoma Semin ?ro 7n"o .(;.%=2.(22

3#percalcemia has been reporte' in up to $+/ o* patients &ith RCC an' can be 'ue to

either paraneoplastic phenomena or osteol#tic metastatic involvement o* the bone

0&ufrin et al' 182 #old et al' 1>2 Magera et al' )--.2 =latte et al' )--;d2 %epper et al'

)--;2 &ch(arz/erg and Michaelson' )--4, The production of parathyroid hormoneli3e

peptides is the most common paraneoplastic etiology' although tumor?derived 1')6?

dihydro5ycholecalciferol and prostaglandins may contri/ute in a minority of cases 0#old/erg

et al' 1>.2 Mangin et al' 1882 &ufrin et al' 182 #old et al' 1>2 :alther et al' 1;/2Magera et al' )--.2 Massfelder et al' )--.2 =latte et al' )--;d2 %epper et al' )--;4, Recent

data suggest that the e5pression of parathyroid hormoneli3e peptides is suppressed /y the

(ild?type HL protein' and these peptides may act as potent gro(th factors for RCC

0Massfelder et al' )--.4, This may account in part for the o/servation that patients (ith RCC

(ho present (ith hypercalcemia have a compromised prognosis' (ith a relative ris3 of death

from cancer progression of 1,;8 compared (ith patients (ith normal serum calcium levels

0Magera et al' )--.4, The signs an' s#mptoms o* h#percalcemia are o*ten nonspeci*ic an'

inclu'e nausea, anore"ia, *atigue, an' 'ecrease' 'eep ten'on re*le"es. Me'ical

management pre'ominates an' inclu'es vigorous h#'ration *ollo&e' b# 'iuresis &ith

*urosemi'e an' the selective use o* bisphosphonates, corticosteroi's, or calcitonin

0revie(ed in #old et al' 1>2 Coleman' )--.2 %epper et al' )--;2 &ch(arz/erg and

Michaelson' )--4, Bisphosphonate therap# is no& establishe' as stan'ar' o* care *or

patients &ith h#percalcemia o* malignanc#, as long as renal *unction is a'e@uate

0&ch(arz/erg and Michaelson' )--4, Ioledronic acid' . mg intravenously every . (ee3s'

appears to /e particularly effective in patients (ith RCC /ut must /e (ithheld in the presence

of renal insufficiency 0Lipton et al' )--+' )--.2 Coleman et al' )--.2 &ch(arz/erg and

Michaelson' )--4, !ndomethacin has also proved useful in a minority of cases 0#old et al'

1>2 :alther et al' 1;/4, More definite management includes nephrectomy and occasional

metastasectomy' depending on the clinical circumstances, &ystemic therapy to reduce the

/urden of disease is also desira/le /ut difficult to achieve in patients (ith RCC 0#old/erg

et al' 18-4, Hypercalcemia related to e5tensive osteolytic metastases is much more difficultto palliate /ecause it is not amena/le to surgical approaches' /ut many such patients may



+)

respond to /isphosphonate therapy 0Lipton et al' )--+' )--.2 Coleman et al' )--.4, &ome

patients (ith hypercalcemia related to osteolytic metastases may also /enefit from focused

radiation therapy if limited sites of involvement can /e identified 0#old et al' 1>4,

3#pertension an' pol#c#themia are other important paraneoplastic s#n'romes

commonl# *oun' in patients &ith RCC 0Moein and <ehghani' )---4, Hypertensionassociated (ith RCC can /e secondary to increased production of renin directly /y the tumor2

compression or encasement of the renal artery or its /ranches' effectively leading to renal

artery stenosis2 or arteriovenous fistula (ithin the tumor 0Ro/ertson et al' 1>;2 &ufrin et al'

184, Less common causes include polycythemia' hypercalcemia' ureteral o/struction' and

increased intracranial pressure associated (ith cere/ral metastases 0&ufrin et al' 184,

%olycythemia associated (ith RCC can /e due to increased production of erythropoietin'

either directly /y the tumor or /y the adFacent parenchyma in response to hypo5ia induced /y

tumor gro(th 0#ross et al' 1.2 :iesener et al' )--;4,

!ne o* the more *ascinating paraneoplastic s#n'romes associate' &ith RCC is

nonmetastatic hepatic '#s*unction, or Stau**er s#n'rome, &hich has been reporte' in+/ to %(/ o* cases 0&tauffer' 1>12 Rosen/lum' 18;2 #ianna3os et al' )--62 Moria et al'

)-->2 oung et al' )--84, Almost all patients (ith &tauffer syndrome have an elevated serum

al3aline phosphatase level' >;* have elevated prothrom/in time or hypoal/uminemia' and

)-* to +-* have elevated serum /iliru/in or transaminase levels 0&ufrin et al' 184, Other

common findings include throm/ocytopenia and neutropenia' and typical symptoms include

fever and (eight loss' (hich is not surprising given that many patients are found to har/or

discrete regions of hepatic necrosis 0&ufrin et al' 182 #old et al' 1>4, Hepatic metastases

must /e e5cluded, $iopsy' (hen indicated' often demonstrates nonspecific hepatitis

associated (ith a prominent lymphocytic infiltrate 0Hanash' 18)4, Elevated serum levels of

!L?> have /een found in patients (ith &tauffer syndrome' and it is /elieved that this and other

cyto3ines may play a pathogenic role 0$lay et al' 1;4, Hepatic function normalizes after

nephrectomy in >-* to ;-* of cases, %ersistence or recurrence of hepatic dysfunction is

almost al(ays indicative of the presence of via/le tumor and thus represents a poor

prognostic finding 0revie(ed in &ufrin' 184,

A variety of other less common /ut distinct paraneoplastic syndromes associated (ith RCC

have /een revie(ed /y &ufrin and colleagues 0184' including Cushing syndrome'

hyperglycemia' galactorrhea' neuromyopathy' clotting disorders' and cere/ellar ata5ia 0Ather

et al' )--)2 =amra et al' )--)2 Hagel et al' )--62 Mohammed et al' )-->2 Ammar et al' )--84,

?n general, treatment o* paraneoplastic s#n'romes associate' &ith RCC has re@uire'surgical e"cision or s#stemic therap# an', e"cept *or h#percalcemia, me'ical therapies

have not prove' help*ul.

&creening and Clinical Associations

1 number o* *actors mae screening *or RCC appealing 0Cohn and Camp/ell' )---2

Herts' )--62 Carrizosa and #odley' )--4, Most important, RCC remains primaril# a

surgical 'isease re@uiring earl# 'iagnosis to optimi8e the opportunit# *or cure.

7nfortunately' our a/ility to salvage patients (ith advanced disease remains limited,

Consistent (ith these o/servations' several studies have demonstrated an apparent advantage

to early or incidental diagnosis of RCC 0=onna3 and #rossman' 1862 Thompson and %ee3'



++

1882 =essler et al' 1.2 Cohn and Camp/ell' )---2 Tsui et al' )---/2 %arsons et al' )--12

Lee et al' )--)2 Leslie et al' )--+4,

The primar# *actor that limits the &i'esprea' implementation o* screening *or RCC is

the relativel# lo& inci'ence o* RCC in the general population 0appro5imately 1) cases per

1--'--- populationyear4 0:allen et al' )--;2 <eCastro and Mc=iernon' )--82 :oldrichet al' )--82 Carrizosa and #odley' )--4, !n this setting a screening test must /e almost 1--*

specific to avoid an unaccepta/ly high false?positive rate' (hich (ould lead to unnecessary'

e5pensive' and potentially harmful diagnostic or therapeutic procedures, !n addition' even if

the test (ere 1--* sensitive and specific' the yield from screening (ould /e so lo( that it

(ould not /e considered cost effective 0Cohn and Camp/ell' )---2 Carrizosa and #odley'

)--4, Even (hen one considers populations (ith esta/lished ris3 factors for RCC' such as

male se5' increased age' and heavy to/acco use' generalized screening (ould /e difficult to

Fustify /ecause the increase in relative ris3 associated (ith each of these factors is at /est

t(ofold to threefold 0%aganini?Hill et al' 1882 Cohn and Camp/ell' )---2 Carrizosa and

#odley' )--4, Another confounding factor is the prevalence of clinically insignificant

tumors such as renal adenomas' (hich are found at autopsy in 1-* to )-* of individuals'and other /enign or slo(?gro(ing tumors 0ipell' 1;12 $osnia3 et al' 162 Cohn and

Camp/ell' )---2 %antuc3 et al' )---2 %arsons et al' )--14, There is clearly a ris3 that such

clinically insignificant lesions could /e detected' leading to unnecessary evaluation and

treatment 0%antuc3 et al' )---2 %arsons et al' )--14, 1ll these *actors recommen' against

generali8e' screening e**orts *or the 'etection o* RCC.

Revie& o* the literature 'escribing the use o* 'ipstic anal#sis *or hematuria an'

ultrasonograph# or CT *or screening *or RCC supports these conclusions 0Cohn and

Camp/ell' )---2 Herst' )--62 Carrizosa and #odley' )--4, 7rinalysis is simple and

ine5pensive' /ut the yield of RCC in several screening studies has /een e5ceedingly lo(

0Mohr et al' 18>2 Thompson' 18;2 Mariani et al' 182 Mura3ami et al' 1-4, !n part' this

may /e /ecause small RCCs are often not associated (ith hematuria 0gross or microscopic4

/ecause this is a parenchymal rather than an urothelium?/ased malignant neoplasm 0Tosa3a

et al' 1-4, The incidence of RCC in ultrasound or CT screening studies has ranged from )+

to +-- per 1--'--- population' and an apparent advantage of screening has /een de/ated

/ecause an increased proportion of organ?confined tumors has /een found in screened

populations compared (ith historical controls 0&ohma et al' 182 Tosa3a et al' 1-2 &pouge

et al' 1>2 Tsu/oi et al' )---2 "ilipas et al' )--+2 "enton and :eiss' )--.2 Herts' )--62

Malae/ et al' )--62 Turney et al' )-->2 Carrizosa and #odley' )--4, Ho(ever' although the

yield of RCC has /een higher than e5pected' it is still relatively lo(2 and it is unli3ely that

such efforts (ould /e considered cost effective 0Cohn and Camp/ell' )---2 Herts' )--64,Overall' the yield of RCC in such studies is an order of magnitude lo(er than the yield from

prostate?specific antigen/ased screening for prostate cancer' and many of the same

controversies a/out lead and length time /iases that have plagued the de/ate a/out screening

for prostate cancer also apply to RCC 0Cohn and Camp/ell' )---2 %antuc3 et al' )---2

%arsons et al' )--12 "enton and :eiss' )--.2 Herts' )--62 Carrizosa and #odley' )--4,

$ecause of these considerations' it is difficult to Fustify generalized screening efforts for RCC

given the currently availa/le technology,

&everal investigators are no( reporting novel molecular assays to detect RCC?related

/iomar3ers in the urine or serum that may su/stantially alter our perspective a/out screening

for RCC, These assays can detect microsatellite alterations in the <GA' VHL gene mutationsor hypermethylation' e5pression of RCC?specific proteins such as CA?' or upregulation of



+.

angiogenic factors' including E#" 0Eisen/erger et al' 12 <e la Taille et al' )---2 Chang

et al' )--12 Ashida et al' )--+2 $attagli et al' )--+2 Chen and #etzen/erg' )--.2 HoBue et al'

)--.2 7zzo et al' )--.4, %roteomic profiling of the urine to detect RCC?specific mar3ers also

holds much promise for the future 0Rogers et al' )--+4,

7or no&, ho&ever, the *ocus o* screening *or RCC must be on &ell)'e*ine' targetpopulations, such as patients &ith en')stage renal 'isease an' ac@uire' renal c#stic

'isease, tuberous sclerosis, an' *amilial RCC 0Ta/le .1.4, Eighty percent of patients

(ith end?stage renal disease eventually develop acBuired renal cystic disease' and 1* to )*

of this su/group develops RCC 0!shi3a(a et al' 18-' 1-2 Matson and Cohen' 1-2 Levine

et al' 112 Cheu3 et al' )--)2 $ro(n' )--.4, !verall, the relative ris o* RCC in patients

&ith en')stage renal 'isease has been estimate' to be 5) to %()*ol' higher than that in

the general population 0!shi3a(a et al' 1-' 11' )--.2 Matson and Cohen' 1-2 Levine

et al' 112 Levine' 1)2 Co(ie' )--)2 <enton et al' )--)2 $ro(n' )--.2 "arivar?Mohseni

et al' )-->4, "ifteen percent of patients (ith RCC in the setting of end?stage renal disease

have metastases at the time of presentation' and many such patients die of malignant

progression 0Levine et al' 112 $ro(n' )--.2 !shi3a(a' )--.4, #iven these considerations'screening for RCC is recommended in this population' (hich is su/stantial' representing

almost +--'--- patients in the 7nited &tates alone, There are' ho(ever' a num/er of pro/lems

associated (ith screening this population of patients, These include concerns a/out short life

e5pectancy' increased incidence of adenomas 0)-* to .-* vs, 1-* to )-* in the general

population4' comple5ity of imaging given the altered architecture associated (ith acBuired

renal cystic disease' and inevita/le cost?related issues 0Mindell' 182 Levine et al' 11'

1;2 &arasin et al' 162 Co(ie' )--)4, 1 reasonable compromise *or patients &ith en')

stage renal 'isease is to target those &ithout other ma-or comorbi'ities, to 'ela#

screening until the thir' #ear on 'ial#sis, an' to tae into account the se" an' t#pe o*

renal replacement therap#, although 'ata about the last *actors are a'mitte'l#

controversial 0$ro(n' )--.2 Carrizosa and #odley' )--4, !shizu3a and colleagues 0)---4

have demonstrated elevated serum levels of E#" in dialysis patients (ith RCC' suggesting

a potential role for /iomar3ers for screening this population in the future, !nterestingly' recent

data suggest that renal transplant recipients remain at high ris3 for RCC in the native 3idneys'

and Geuzillet and colleagues 0)--64 have recommended continued periodic radiologic

screening even after transplantation 0!anhez et al' )--;4,

Table 49–$4 )) Screening *or Renal Cell Carcinoma Target PopulationsPatiets ith Ed8tage Real Disease

%creen only patients #ith long li!e expectancy and minimal maUor comorbidities.

4er!orm periodic ultrasound examination or T scan beginning during third year on dialysis.Patiets ith & v& %i--el8Lidau 'dr&(e

Obtain biannual abdominal T or ultrasound study beginning at age 72 to 1 years.

4er!orm periodic clinical and radiographic screening !or nonrenal mani!estations.

Relatives &) Patiets ith v& %i--el8Lidau 'dr&(e

Obtain genetic analysis.

+! positi$e, !ollo# screening recommendations !or patients #ith =no#n $on Hippel/Lindau syndrome.

+! negati$e, less stringent !ollo#/up is re6uired.

Relatives &) Patiets ith #ther Fa(ilial F&r(s &) Real Cell Car+i&(a

Obtain periodic ultrasound or T study and consider genetic analysis.

Patiets ith $uber&us +ler&sis

4er!orm periodic screening #ith ultrasound examination or T scan.

Patiets ith Aut&s&(al8D&(iat P&l'+'sti+ ide' Disease

Routine screening is not Uusti!ied.



+6

1n increase' inci'ence o* RCC has also been 'ebate' in tuberous sclerosis, an

autosomal 'ominant 'isor'er in &hich patients can 'evelop a'enoma sebaceum :a

'istinctive sin lesion;, epileps#, mental retar'ation, an' renal c#sts an' 1Ms 0&hapiro

et al' 18.2 $ernstein et al' 18>2 :ashec3a and Hanna' 112 Aoyama et al' 1>2 $Fornsson

et al' 1>2 Ro/ertson et al' 1>2 &ampson' 1>2 Tello et al' 182 Choy3e et al' )--+2

Lendvay and Marshall' )--+2 Garayanan' )--+2 Cohen and Ihou' )--62 Rad3o(s3i et al')-->4, Many cases of RCC in this syndrome have /een characterized /y early onset and

multifocality' suggesting a genetic predisposition 0:ashec3a and Hanna' 112 Lendvay and

Marshall' )--+4, !n addition' the E3er rat' (hich is mutant for the rodent homologue of the

TSC2 gene responsi/le for the development of tu/erous sclerosis in humans' develops RCC at

high freBuency' as do TSC2?deficient 3noc3out mice 0eung et al' 1.2 =o/ayashi et al'

1;' 12 Hino et al' 12 Lendvay and Marshall' )--+2 Mc<orman and :olf' )--)4,

"urthermore' an increased incidence of TSC2 mutations has /een found in human RCC

0<uffy et al' )--)2 Lendvay and Marshall' )--+4' and Liu and colleagues 0)--+4 have sho(n

that loss of this tumor suppressor gene leads to upregulated e5pression of E#" through an

mTOR and H!"?)mediated mechanism' analogous to the role of the HL protein, Such

biologic an' clinical observations argue in *avor o* an increase' pre'isposition *or RCCin this s#n'rome, &hich is consistent &ith most, although a'mitte'l# not all, relevant

'emographic 'ata 0&hapiro et al' 18.2 $ernstein et al' 18>2 :ashec3a and Hanna' 112

Aoyama et al' 1>2 $Fornsson et al' 1>2 Ro/ertson et al' 1>2 &ampson' 1>2 Tello et al'

182 Lendvay and Marshall' )--+2 Martignoni et al' )--+2 Cohen and Ihou' )--62

Ra3o(s3i et al' )-->2 Gathanson and &tephenson' )--4, 1 reasonable conclusion is that

perio'ic renal imaging shoul' be pursue' in patients &ith tuberous sclerosis such a

polic# &ill also *acilitate *ollo&)up *or the 'evelopment an' progression o* 1M.

&creening for RCC in autosomal dominant polycystic 3idney disease 0A<%=<4 (as

previously recommended' /ut several factors have prompted a reassessment of this policy,

More recent stu'ies suggest no signi*icantl# increase' ris o* RCC in 1DPAD, and

imaging is e5tremely difficult in this population related to the altered intrarenal architecture

0Torres et al' 1862 #regoire et al' 18;2 =eith et al' 1.2 &essa et al' 1;2 &oderdahl et al'

1;2 Cohn and Camp/ell' )---2 #upta et al' )---2 Mosetti et al' )--+4, The increased

incidence of adenomas in A<%=< (ould also mitigate against a potential /enefit of

screening 0Torres et al' 1862 #regoire et al' 18;4, Taen together, these consi'erations

suggest that screening *or RCC in patients &ith 1DPAD shoul' not be pursue'.

Special consi'eration shoul' also be given to von 3ippel)in'au 'isease in an#

'iscussion o* the value o* screening *or RCC. This syndrome should /e considered in any

patient (ith early?onset or multifocal RCC or RCC in com/ination (ith any of the follo(ingPa history of visual or neurologic disorders2 a family history of /lindness' central nervous

system tumors' or renal cancer2 or coe5istent pancreatic cysts' epididymal lesions' or inner

ear tumors 0Geumann and I/ar' 1;2 Choy3e et al' )--+2 Linehan et al' )--+2 %avlovich and

&chmidt' )--.2 ira et al' )--;2 %faffenroth and Linehan' )--82 Coleman' )--82 Hansel and

Rini' )--82 Gathanson and &tephenson' )--4, Patients suspecte' o* having von 3ippel)

in'au 'isease, or the appropriate relatives o* those &ith 'ocumente' 'isease, shoul'

strongl# consi'er genetic evaluation. The entire VHL gene has no( /een seBuenced and

sophisticated molecular analysis is readily availa/le and offers a num/er of important

advantages 0I/ar et al' 12 Linehan et al' )--+2 ira et al' )--;2 %faffenroth and Linehan'

)--84, Patients &ith germline mutations can be i'enti*ie' an' o**ere' clinical an'

ra'iographic screening that can i'enti*# the ma-or mani*estations o* von 3ippel)in'au'isease at a pres#mptomatic phase, allo&ing potential amelioration o* the consi'erable



+>

morbi'it# associate' &ith this s#n'rome 0#lenn et al' 1)2 Maranchie and Linehan' )--+2

ira et al' )--;2 %faffenroth and Linehan' )--84, !nvestigators at the Gational !nstitutes of

Health have recommended that such patients /e evaluated (ith 014 annual physical

e5amination and ophthalmologic evaluation /eginning in infancy2 0)4 estimation of urinary

catecholamines at the age of ) years and every 1 to ) years thereafter2 0+4 MR! of the central

nervous system /iannually /eginning at the age of 11 years2 0.4 ultrasound e5amination of thea/domen and pelvis annually /eginning at the age of 11 years' follo(ed /y CT every >

months if cysts or tumors develop2 and 064 periodic auditory e5aminations 0Choy3e et al'

162 "riedrich' 12 Maranchie and Linehan' )--+4, Less intensive protocols have also

/een advocated' although all relevant organ systems should /e addressed 0"raser et al' )--;2

"oul3es and Hodgson' 184, !ndividuals (ho are found to /e (ild type for /oth alleles of

VHL also /enefit /ecause they can /e spared much of the e5pense and an5iety associated

(ith such intensive surveillance protocols,

Molecular screening is also available *or patients suspecte' o* having here'itar#

papillar# RCC an' other *amilial *orms o* RCC and should /e discussed (ith appropriate

family mem/ers 0&chmidt et al' 1;2 Linehan et al' )--+2 I/ar et al' )--;2 ira et al' )--;2%faffenroth and Linehan' )--82 Coleman' )--82 Hansel and Rini' )--' Gathanson and

&tephenson' )--4, Again' individuals at ris3' as defined /y the presence of mutations of the

c? !ET proto?oncogene or other relevant genetic alterations' and those (ith suggestive

clinical or family histories should /e evaluated (ith a/dominal ultrasonography or CT at

periodic intervals, "urther testing may /e indicated according to the syndrome involved,

&taging

Jntil the $99(s the most commonl# use' staging s#stem *or RCC &as Robsons

mo'i*ication o* the s#stem o* 7locs an' Aa'es#, an' this schema is still embe''e' in

the min'set o* man# urologists 0"ig, .164 0Ro/son' 1>+2 Ro/son et al' 1>4, !n

retrospect' the limitations of this classification scheme are readily evident, The primary

pro/lem can /e found in stage !!!' (here tumors (ith lymphatic metastases' a very poor

prognostic finding' (ere com/ined (ith those (ith venous involvement' many of (hich can

/e treated and potentially cured (ith an aggressive surgical approach 0#ettman and $lute'

)--)2 Lei/ovich et al' )--+c2 Gguyen and Camp/ell' )-->4, "urther imprecision resulted

from the fact that the e5tent of venous involvement (as not delineated in this system' and

tumor size' an important prognostic parameter' (as not incorporated, The net effect (as that

the prognostic significance of the various stages (as /lunted' (ith some studies reporting

eBuivalent survival for patients (ith stage !! and stage !!! tumors 0&3inner et al' 1;14,



+;

Figure 49–1: %taging o! renal cell carcinoma as proposed by Holland, in accordance #ith classi!ication systems de$elopedby Robson, urphy, and loc=s and @ades=y. A, aortaE +V, in!erior $ena ca$a.(From Hollan! #M. ancer of the i!ne"* nat9ral histor" an! staging. ancer 18)''%*1&'&.

The tumor, no'es, an' metastasis :TEM; s#stem propose' b# the Jnion ?nternational

Contre le Cancer :J?CC; represente' a ma-or improvement because it separate'

tumors &ith venous involvement *rom those &ith l#mphatic invasion an' 'e*ine' the

anatomic e"tent o* 'isease more e"plicitl# 0$eahrs et al' 1882 Lei/ovich et al' )--+/2

Gguyen and Camp/ell' )-->2 <eCastro and Mc=iernon' )--84, Another advantage of the

TGM system is that it has facilitated comparison of clinical and pathologic data from various

centers across the glo/e 0Leung and #havamian' )--)2 Lei/ovich et al' )--+/2 Gguyen and

Camp/ell' )-->4,

?n %((9 the 1merican Koint Committee on Cancer :1KCC; propose' a revision o* theTEM s#stem that is no& the recommen'e' staging s#stem *or RCC 0Ta/le .164 0Edge



+8

et al' )-1-4, The TGM classification for RCC has undergone several modifications in the past

+ decades in an effort to more accurately reflect tumor /iology and prognosis and to guide

clinical management, !t is important to /e cognizant of these changes (hen comparing

studies from different eras 0Gguyen and Camp/ell' )-->4, ?n $990 the previous 'ivision o*

stages T$ an' T% at tumor si8e o* %.5 cm &as aban'one' because several stu'ies sho&e'

no prognostic signi*icance at this level. 1nal#sis o* the Surveillance, 6pi'emiolog#, an'6n' Results :S66R; program 'atabase 'emonstrate' survival 'i**erences associate'

&ith 5), 0.5), an' $()cm cut points, an' the 0)cm cut point bet&een stages T$ an' T%

&as a'opte' because it re*lecte' the mean tumor si8e in the 'atabase 0#uinan et al'

16a2 #ettman et al' )--1/2 "iccarra et al' )-->2 &alama et al' )--64, ?n the %((% version

stage T$ &as sub'ivi'e' T$a represents tumor si8e o* 4 cm or less, an' T$b represents

tumor si8e bet&een 4 an' 0 cm, re*lecting 'ata in the literature 'emonstrating e"cellent

outcomes *or patients &ith small :N4 cm;, unilateral, con*ine' tumors manage' b#

either partial or ra'ical nephrectom# 0$utler et al' 1.2 Lerner et al' 1>2 Hafez et al'

12 !garashi et al' )--12 "ran3 et al' )--.a' )--6/' Gguyen and Camp/ell' )-->4, The

most recent change *or organ)con*ine' tumors is a sub'ivision o* T% tumors T%a tumor

represents tumors bet&een 0 an' $( cm, an' T%b represents tumors greater than $( cm0see Ta/le .164' supported /y a num/er of studies demonstrating prognostic relevance at

this /rea3point 0"ran3 et al' )--6/2 =latte et al' )--;c4,

Table 49–$5 )) ?nternational TEM Staging S#stem *or Renal Cell Carcinoma$; Pri(ar' $u(&r

TN 4rimary tumor cannot be assessed

T 'o e$idence o! primary tumor

T7 Tumor 5. cm and con!ined to the =idney

T7a Tumor 8. cm and con!ined to the =idney

T7b Tumor P8. cm and 5. cm and con!ined to the =idney

T1 Tumor P5. cm and con!ined to the =idney

T1a Tumor P5. cm and 7. cm and con!ined to the =idney

T1b Tumor P7. cm and con!ined to the =idney

T0 Tumor extends into maUor $eins or perinephric tissues but not into the ipsilateral adrenal gland and not beyond the*erota !ascia

T0a Tumor grossly extends into the renal $ein or its segmental (muscle containing) branches or tumor in$adesperirenal and"or renal sinus !at but not beyond the *erota !ascia

T0b Tumor grossly extends into the $ena ca$a belo# the diaphragm

T0c Tumor grossly extends into the $ena ca$a abo$e the diaphragm or in$ades the #all o! the $ena ca$a

T8 Tumor in$ades beyond the *erota !ascia (including contiguous extension into the ipsilateral adrenal gland)

N; Regi&al L'(-h N&des

'N Regional lymph nodes cannot be assessed

' 'o regional lymph nodes metastasis

'7 etastasis in regional lymph node(s)

,; Distat ,etastases

N istant metastasis cannot be assessed

'o distant metastasis7 istant metastasis present

tage Gr&u-ig

%tage + T7 '

%tage++

T1 '

%tage+++

T7 or T1 '7

T0 Any '

%tage+V

T8 Any '

Any T Any ' 7

!o#ifie# from E#:e S6, 6yr# DR, Com+ton CC, et a, e#itor' A8CC "an"er 'ta:in: man&a

/th e# *e> 5ork= S+rin:er; 20.0



+

!ther ma-or revisions in %((9 inclu'e' a reclassi*ication o* tumors &ith a'renal

metastasis, venous thrombi, an' l#mphatic involvement, representing a substantial

'eparture *rom previous staging para'igms *or RCC 0Ta/le .1>4 0Edge et al' )-1-4,

Contiguous e"tension o* tumor into the ipsilateral a'renal glan' is no& classi*ie' as T4

an' metastatic involvement o* either a'renal as M$, re*lecting liel# patterns o*

'issemination. The poor prognosis of adrenal involvement from RCC is (ell documentedand supported this important change 0&agalo(s3y et al' 1.2 &andoc3 et al' 1;2 %aul et al'

)--1a2 on =no/loch et al' )--.2 Lam et al' )--6a2 &hvarts et al' )--6a2 &iemer et al' )--62

Thompson et al' )--6a2 Gguyen and Camp/ell' )-->2 =ir3ali et al' )--;4, The *avorable

prognosis o* isolate' renal venous thrombi prompte' a 'o&ngra'ing *rom stage T+b to

stage T+a in the %((9 version 0Moinzadeh and Li/ertino' )--.2 <e=ernion' )--62

Lei/ovich et al' )--62 &hvarts et al' )--6a2 Thompson et al' )--6a2 "icarra and Arti/ani'

)-->2 #ofrit et al' )--;2 "icarra et al' )--;/2 Margulis et al' )--;c4, 7inall#, l#mphatic

e"tension, &hich previousl# &as sub'ivi'e' base' on the number o* involve' no'es, has

no& been compresse' to simpli*# this aspect o* the staging process, because prognostic

relevance o* the previous version &as not observe' 0Edge et al' )-1-4,

Table 49–$ )) %($( Revision o* 1KCC Staging *or Ai'ne# Cancer :0th 6'ition;

Summar# o* Substantial Changes

i$ision o! T1 organ con!ined

T1a 5/7 cm

T1b P7 cm

9pgrading o! adrenal in$ol$ement

T8 i! contiguous extension into ipsilateral adrenal

7 other#ise

o#ngrading o! isolated renal $enous thrombus

4re$iously T0b, no# T0a

ompression o! nodal in$ol$ement

Any nodal in$ol$ement no# '7

Recommendation that all potentially ad$erse !eatures be captured at least parenthetically

or example, T0b (tumor #ith in!erior $ena ca$a thrombus belo# le$el o! diaphragm, also exhibiting extension intothe perinephric !at)

Data from E#:e S6, 6yr# DR, Com+ton CC, et a, e#itor' A8CC "an"er 'ta:in: man&a /th

e# *e> 5ork= S+rin:er; 20.0 + %/)

TGM staging classically is defined /y the most advanced feature demonstrated /y the tumor'

yet important prognostic information can /e lost in the process, Many tumors e5hi/it multiple

adverse findings' such as high?level tumor throm/us along (ith ipsilateral adrenal

involvement, !deally all of the relevant anatomic staging information (ould /e captured' atleast parenthetically 0e,g,' pT. ipsilateral adrenal involvement2 also e5hi/iting !C throm/us

a/ove the diaphragmU4, "uture staging systems (ill ideally capture all of this information'

/ecause a num/er of investigators have demonstrated strong prognostic relevance to such

com/inations of parameters 0Lie/ovich et al' )--62 &hvarts et al' )--6a2 Thompson et al'

)--6a2 "uFita et al' )--;2 "icarra et al' )--;a' )--;/2 =latte et al' )--;c2 Terrone et al' )--84,

The clinical staging o* renal malignant 'isease begins &ith a thorough histor#, ph#sical

e"amination, an' -u'icious use o* laborator# tests 0Gguyen and Camp/ell' )-->2 <eCastro

and Mc=iernon' )--84, Presentation &ith s#stemic s#mptoms such as signi*icant &eight

loss :O$(/ o* bo'# &eight;, cache"ia, or poor per*ormance status all suggest a'vance'

'isease, as 'o ph#sical e"amination *in'ings o* a palpable mass or l#mpha'enopath#. Anonreducing varicocele and lo(er e5tremity edema suggest venous involvement, A/normal



.-

liver function test results' elevated serum al3aline phosphatase or lactate dehydrogenase level

or sedimentation rate' hypercalcemia' and significant anemia point to the pro/a/ility of

advanced disease 0#el/' 1;2 &rigley et al' 1;2 Gguyen and Camp/ell' )-->2 Lane and

=attan' )--84,

The ra'iographic staging o* RCC can be accomplishe' in most cases &ith a high)@ualit#ab'ominal CT scan an' a routine chest ra'iograph, (ith selective use of MR! and other

studies as indicated 0revie(ed in $echtold and Iagoria' 1;2 Choy3e et al' )--12 #riffin

et al' )--;' Ihang et al' )--;a2 Gg et al' )--82 Herts' )--4, MR! can /e reserved primarily

for patients (ith locally advanced malignant disease' eBuivocal venous involvement' or

allergy to intravenous contrast material 0Choy3e' 1;2 %retorius et al' )---2 Choy3e et al'

)--12 Ihang et al' )--;a2 Herts' )--4, CT findings suggestive of e5tension into the

perinephric fat include perinephric stranding 0"ig, .1>4' (hich is a nonspecific finding' or

a distinct soft tissue density (ithin the perinephric space' (hich is a more definitive /ut

uncommon finding 0$echtold and Iagoria' 1;2 Herts' )--4, Overall' the accuracy of CT

or MR! for detection of involvement of the perinephric fat is lo(' reflecting the fact that

e5tracapsular spread often occurs microscopically 0%retorius et al' )---2 Choy3e et al' )--12Leung and #havamian' )--)2 =amel et al' )--.2 Ihang et al' )--;a4, Many of these

potentially locally advanced cases are managed (ith radical nephrectomy' so the clinical

relevance of this imprecision in staging is /lunted, !psilateral adrenal involvement can /e

assessed (ith reasona/le accuracy through a com/ination of preoperative CT and

intraoperative inspection, Patients &ith an enlarge' or in'istinct a'renal glan' on CT,

e"tensive malignant replacement o* the i'ne#, or palpabl# abnormal a'renal glan' are

at ris *or ipsilateral a'renal involvement an' shoul' be manage' accor'ingl#

0&agalo(s3y et al' 1.2 &andoc3 et al' 1;2 %aul et al' )--1a2 &a(ai et al' )--)2 =o/ayashi

et al' )--+2 Ihang et al' )--;a2 Gg et al' )--82 Lane et al' )--4, 6nlarge' hilar or

retroperitoneal l#mph no'es % cm or more in 'iameter on CT almost al&a#s harbor

malignant change, but this shoul' be con*irme' b# surgical e"ploration or percutaneous

biops# i* the patient is not a surgical can'i'ate. Man# smaller no'es prove to be

in*lammator# rather than neoplastic an' shoul' not preclu'e surgical therap# 0&tuder

et al' 1-2 Choy3e et al' )--12 !srael and $osnia3' )--+a2 Ihang et al' )--;a2 $ach and

Ihang' )--82 Gg et al' )--82 Herts' )--4, MR! can add specificity to the evaluation of

retroperitoneal nodes /y distinguishing vascular structures from lymphatic ones 0$echtold

and Iagoria' 1;2 $assignani' )-->4, MR? is still the premier stu'# *or evaluation o*

invasion o* tumor into a'-acent structures an' *or surgical planning in these

challenging cases 0$echtold and Iagoria' 1;2 Choy3e' 1;2 %retorius et al' )---2 Choy3e

et al' )--12 $assignani' )-->2 $ach and Ihang' )--82 Herts' )--4, O/literation of the fat

plane /et(een the tumor and adFacent organs 0e,g,' the liver4 can /e a misleading finding onCT and should prompt further imaging (ith MR!, !n reality' surgical e5ploration is often

reBuired to ma3e an a/solute differentiation,



.1

Figure 49–1< ontrast/enhanced T scan sho#s right renal tumor #ith perinephric stranding suggesting in$asion o! theperinephric !at.

The sensitivities o* CT *or 'etection o* renal venous tumor thrombus an' ?C

involvement are 0>/ an' 9/, respectivel# 0$echtold and Iagoria' 1;2 Ihang et al'

)--;a2 Gg et al' )--82 Herts' )--4, CT findings suggestive of venous involvement includevenous enlargement' a/rupt change in the cali/er of the vein' and intraluminal areas of

decreased density or filling defects, The diagnosis is strengthened /y the demonstration of

collateral vessels, Most false?negative findings occur in patients (ith right?sided tumors in

(hom the short length of the vein and the mass effect from the tumor com/ine to ma3e

detection of the tumor throm/us difficult 0$echtold and Iagoria' 1;2 Herts' )--4,

"ortunately' most such cases are readily identified and dealt (ith intraoperatively, MR? is

&ell establishe' as the premier stu'# *or the evaluation an' staging o* ?C tumor

thrombus, although recent 'ata suggest that multiplanar CT is liel# e@uivalent

0Choy3e et al' 18;2 #oldfar/ et al' 1-2 =allman et al' 1)2 $echtold and Iagoria' 1;2

Choy3e' 1;2 Oto et al' 182 &un et al' 12 %retorius et al' )---2 &ohai/ et al' )--)2

!srael and $osnia3' )--+a2 Ergen et al' )--.2 Hallscheidt et al' )--62 Ihang et al' )--;a2 Gget al' )--84, MR! and multiplanar CT are noninvasive methods that provide relia/le

information a/out /oth the cephalad and caudal e5tent of the throm/us and can often

distinguish /land from tumor throm/us 0%retorius et al' )---2 Choy3e et al' )--1' $assignani'

)-->2 $ach and Ihang' )--82 Herts' )--4, enacavograph# is no& best reserve' *or

patients &ith e@uivocal MR? or CT *in'ings or *or patients &ho cannot tolerate or have

other contrain'ications to cross)sectional imaging. Transesophageal echocardiography

also appears to /e accurate for esta/lishing the cephalad e5tent of the tumor throm/us' /ut it

is invasive and provides no distinct advantages over MR! or CT in the preoperative setting

0#lazer and Govic3' 1;4, <oppler ultrasonography is operator dependent and does not

provide the anatomic resolution availa/le (ith MR! or multiplanar CT 0Ha//ou/ et al' 1;4,



.)

Metastatic evaluation in all cases shoul' inclu'e a routine chest ra'iograph, care*ul an'

s#stematic revie& o* the ab'ominal an' pelvic CT or MR? *in'ings, an' liver *unction

tests 0Choy3e et al' 18;2 #riffin et al' )--;2 Ihang et al' )--;a2 Gg et al' )--82 Herts'

)--4, Most investigators agree that a bone scintiscan can be reserve' *or patients &ith

elevate' serum alaline phosphatase or bone pain an' that a chest CT scan can be

reserve' *or patients &ith pulmonar# s#mptoms or an abnormal chest ra'iograph 0Limand Carter' 1+2 &eaman et al' 1>2 Choy3e et al' )--14, 3o&ever, patients &ith locall#

a'vance' 'isease, enlarge' retroperitoneal l#mph no'es, or signi*icant comorbi'

'isease ma# man'ate more thorough imaging to rule out metastatic 'isease an' to ai' in

treatment planning 0Choy3e et al' )--12 #riffin et al' )--;4, As al(ays' evaluation and

management must /e individualized on the /asis of the clinical circumstances, &hvarts and

colleagues 0)--.4 have sho(n that performance status is a po(erful predictor of /one

metastasis, !n their analysis' patients (ith good performance status 0Eastern Cooperative

Oncology #roup performance status score of -4' no evidence of e5traosseous metastases' and

no /one pain (ere at e5tremely lo( ris3 and did not /enefit from /one scintigraphy, They

recommended a /one scintiscan for all other patients' and the incidence of /one metastasis in

this group (as a/ove 16*,

Positron emission tomograph# :P6T; has also been investigate' *or patients &ith high

ris o* metastatic RCC, &ith most stu'ies sho&ing goo' speci*icit# but suboptimal

sensitivit#. 1t present its best role is *or patients &ith e@uivocal *in'ings on conventional

imaging. !n this setting an a/normal %ET scan may indicate metastatic disease and could

strongly influence further evaluation and management 0Hoh et al' 182 Ramdave et al' )--12

Gimeh et al' )--)2 9advar et al' )--+2 =ang et al' )--.2 La(rentschu3 et al' )-->2 #riffin

et al' )--;2 %o(les et al' )--;2 $ouchelouche et al' )--82 Gieh' )--4, %ETCT com/ined

(ith radiola/eled monoclonal anti/ody to CA? is also /eing e5plored in this population for

molecular imaging of clear cell RCC 0$rou(ers et al' )--)2 <ivgi et al' )--;2 Ihang' )--84,

$iopsy of the primary tumor andor potential metastatic sites is also selectively reBuired as

part of the staging process,

%rognosis

?mportant prognostic *actors *or cancer)speci*ic survival in patients &ith locali8e' RCC

inclu'e speci*ic clinical signs or s#mptoms, tumor)relate' *actors, an' various

laborator# *in'ings 0Ta/le .1;4 0Lane and =attan' )--84, !verall, tumor)relate' *actors

such as pathologic stage, tumor si8e, nuclear gra'e, an' histologic subt#pe have the

greatest utilit# on an in'epen'ent basis. 3o&ever, an integrative approach, combining a

variet# o* *actors that have prove' to have in'epen'ent value on multivariate anal#sis,appears to be most po&er*ul 0=attan et al' )--12 Iisman et al' )--1/2 "ran3 et al' )--)2

&or/ellini et al' )--62 Lane and =attan' )--82 %ar3er et al' )--2 !s/arn and =ara3ie(icz'

)--4, %atient?related factors' such as age' C=<' and co?mor/idity' have a significant impact

on overall survival in some patients and should /e a primary consideration during treatment

planning for patients (ith localized RCC 0Hollings(orth et al' )-->2 $erger et al' )--2

%ettus et al' )--84,

Table 49–$0 )) Prognostic 7actors *or Renal Cell CarcinomaANA$#,!C CL!N!CAL %!$#L#G!C ,#LECULAR

Tumor siDe

Venousin$ol$ement

4er!ormance status(@arno!s=y, O*)

%ystemic symptoms

'uclear grade

Histologicsubtype

Hypoxia/inducible !actors A/+N, +*/7,V*, V*Rs, A/N++, NR0, NR8, H+

ostimulatory molecules :5/H7, :5/H0



.+

xtension intocontiguousorgans

Adrenalin$ol$ement(direct ormetastatic)

Lymph nodemetastases

istantmetastases

etastaticburden o!disease

(cachexia, loss o!P7> o! body #eight)

%ymptomatic $s.incidental presentation

Anemia

Hypercalcemia

le$ated lactate

dehydrogenasele$ated erythrocytesedimentation rate

le$ated /reacti$eprotein

Thrombocytosis

le$ated al=alinephosphatase

4resence o!sarcomatoid!eatures

4resence o!histologicnecrosis

Vascular

in$asion+n$asion o!perinephric orrenal sinus !at

ollectingsystem in$asion

%urgical marginstatus

(tumor cell"$ascular), :5/H8, 4/7

ell cycle regulators 4T', T420, :cl1,yclin A, @'7:, %=p1

Adhesion molecules pA, A, /ad, C/catenin, ad/3

Other !actors @i/35, N+A4, %ur$i$in, phA1,%mac"+A:LO, 4'A, a$eolin/7, AR, 88,

Annexin ++, *elsolin, Vimentin, A/712),aberrant 'A methylation, 'aW,@W/AT4ase C7 subunit, $itamin receptor, retinoid N receptor

!o#ifie# from Lane 6R, attan !B Pro:no'ti" mo#e' an# a:orithm' in rena "e

"ar"inoma ?ro Cin *orth Am 200);34=(.324

Clinical findings suggestive of a compromised prognosis in patients (ith presumed localized

RCC include symptomatic presentation' (eight loss of more than 1-* of /ody (eight' and poor performance status 0#el/' 1;2 &rigley et al' 1;2 =attan et al' )--12 Iisman et al'

)--1/2 =im HL et al' )--+2 =onta3 and Camp/ell' )--+2 &chips et al' )--+2 %atard et al'

)--.a4, Anemia' throm/ocytosis' hypercalcemia' al/uminuria' elevated serum al3aline

phosphatase' C?reactive protein' lactate dehydrogenase' or erythrocyte sedimentation rate'

and other paraneoplastic signs or symptoms have also correlated (ith poor outcomes for

patients (ith RCC 0#el/' 1;2 &rigley et al' 1;2 &ym/as et al' )---2 9aco/sen et al' )---2

ON=eefe et al' )--)2 =im HL et al' )--+2 =onta3 and Camp/ell' )--+2 aglio et al' )--+2

%atard et al' )--.a2 =ara3ie(icz et al' )--;2 Magera et al' )--84, Although a/normal values

are more common in patients (ith advanced RCC' some of these a/normalities' including

hypercalcemia' anemia' and elevated erythrocyte sedimentation rate' (ere independent

predictors of cancer?specific mortality in patients (ith localized clear cell RCC after

accounting for other maFor prognostic factors 0Magera et al' )--84,

Pathologic stage has prove' to be the single most important prognostic *actor *or RCC

0Thrasher and %aulson' 1+2 <elahunt' 182 =onta3 and Camp/ell' )--+2 Lei/ovich et al'

)--6a2 Lane and =attan' )--82 =anao et al' )--4, The RCC TGM staging system clearly

distinguishes /et(een patient groups (ith different predicted cancer?specific outcomes 0Ta/le

.184' confirming that the e5tent of locoregional or systemic disease at diagnosis is the

primary determinant of outcome for this disease 0$assil et al' 1862 Hermane3 and &chrott'

1-2 =onta3 and Camp/ell' )--+2 Lane and =attan' )--84, %revious studies confirmed that

the )--) modification of the TGM system provided /etter prognostic a/ility than its predecessors 0"icarra et al' )--62 "ran3 et al' )--6a4' and it is anticipated that the )-1- TGM

staging system (ill impart further improvements 0"ran3 et al' )--6a2 Lei/ovich et al' )--6a2

Thompson et al' )--6a4,

Table 49–$> )) TEM Stage an' 5)Fear Survival *or Renal Cell CarcinomaF!ND!NG R##N

$AGE$N, =2002> $N, =2009> :86EAR UR5!5AL

=7>

Organ con!ined (o$erall) + T7/1' T7/1' 5/?

8. cm + T7a' T7a' ?/7

P8. cm to 5. cm + T7b' T7b' B/?

P5. to 7. cm + T1' T1a' 32/B

P7. cm + T1' T1b' 2/5+n$asion o! perinephric or renal sinus !at ++ T0a' T0a' 2/5

+n$asion o! renal $ein or branches +++A T0b' T0a' 8/3



..

+n$asion o! +V belo# diaphragm +++A T0c' T0b' 0/2

+n$asion o! +V abo$e diaphragm or in$asion o! + #all

+++A T0c' T0c' 1/8

irect adrenal in$ol$ement ++ T0a' T8' /0

Locally ad$anced (in$asion beyond *erota!ascia)

+VA T8' T8' /1

Lymphatic in$ol$ement +++: (Any)T'7/1 (Any)T'7 /1

%ystemic metastases +V: (Any)T(Any)'7

(Any)T(Any)'7

/7

Data from 6&ter et a, .%; Sa:ao>'ky et a, .%; Tar:on'ki et a, .%; &inan et a, .4;

Lerner et a, .(; San#o"k et a, ./; Hafe et a, .; !oter et a, .; 9:ara'hi et a, 200.; Pa& et a,

200.a; Va''ei et a, 200.; Pant&"k et a, 2002a; ontak an# Cam+e, 2003; $on noo"h et a, 200%;

Patar# et a, 200%; Phii+' an# Tanea, 200%; Leio$i"h et a, 2004; Siemer et a, 2004; Thom+'on et a,

2004a; !ar:&i' et a, 200/; Lane an# attan, 200); Botko>i" et a, 200); 6e#ke et a, 200; 6ertini et a,

200; Cam+e et a, 200; Cho&eiri, 200; anao et a, 200; an# Sh&"h et a, 200

+V, in!erior $ena ca$a.

Several stu'ies 'emonstrate 5)#ear survival rates o* 0(/ to 9(/ *or organ)con*ine'

'isease an' 'ocument a $5/ to %(/ re'uction in survival associate' &ith invasion o*

the perinephric *at 0=onta3 and Camp/ell' )--+2 Lei/ovich et al' )--6a2 Lane and =attan'

)--84, Renal sinus involvement is classi*ie' along &ith perinephric *at invasion as T+a,

an' several stu'ies suggest that these patients ma# be at even higher ris *or metastasis

relate' to increase' access to the venous s#stem 0$onsi/ et al' )---2 7zzo et al' )--)2

Thompson et al' )--6a2 Margulis et al' )--;/2 $ed3e et al' )--2 $ertini et al' )--4,

Collecting s#stem invasion has also been sho&n to con*er poorer prognosis in other&ise

organ)con*ine' RCC 07zzo et al' )--)2 =latte et al' )--;a4, Several reports have sho&n

that most patients &ith 'irect or metastatic ipsilateral a'renal involvement, &hich is

*oun' in $/ to %/ o* cases, eventuall# succumb to s#stemic 'isease progression,

suggesting a hematogenous route of dissemination or a highly invasive phenotype0&agalo(s3y et al' 1.2 &andoc3 et al' 1;2 %aul et al' )--1/2 on =no/loch et al' )--.2

&iemer et al' )--62 Thompson et al' )--6a4, The most recent staging system no( reclassifies

tumor as T. if there is direct invasion of the adrenal gland or other(ise as M1' to reflect this

poor prognosis 0#uinan et al' 1;2 Thompson et al' )--6a4,

enous involvement &as once thought to be a ver# poor prognostic *in'ing *or RCC, but

several reports 'emonstrate that man# patients &ith tumor thrombi can be salvage'

&ith an aggressive surgical approach. These stu'ies 'ocument 45/ to 9/ 5)#ear

survival rates *or patients &ith venous tumor thrombi as long as the tumor is other&ise

con*ine' to the i'ne# 0Govic3 et al' 1-2 Thrasher and %aulson' 1+2 &taehler and

$r3ovic' )---2 Vue3 et al' )--12 Iisman et al' )--+2 Lei/ovich et al' )--6/2 $lute et al')--;2 Hafer3amp et al' )--;2 =latte et al' )--;/2 :ot3o(icz et al' )--82 &u/ramanian et al'

)--4, At one e5treme' #olim/u and associates 018>4 reported 8.* 6?year survival in the

/est of circumstancesWtumor throm/us limited to the main renal vein and tumor other(ise

confined to the 3idney, Patients &ith venous tumor thrombi an' concomitant l#mph no'e

or s#stemic metastases have mare'l# 'ecrease' survival, an' those &ith tumor

e"ten'ing into the perinephric *at have interme'iate survival 0Montie et al' 112 #lazer

and Govic3' 1>2 #ettman et al' 12 Gaitoh et al' 12 &(eeney et al' )--)/2 $issada

et al' )--+2 =im HL et al' )--.c2 Moinzadeh and Li/ertino' )--.2 Lei/ovich et al' )--6/2

=latte et al' )--;/2 :ot3o(icz et al' )--84, The most recent version of the TGM system

advocates capturing all such adverse features during the staging process,



.6

The prognostic significance of the cephalad e5tent of tumor throm/us has /een controversial'

and it is difficult to compare various series /ecause of selection /iases and related covaria/les

0Lei/ovich et al' )--6/2 :ot3o(icz et al' )--84, !n several series the incidence of advanced

locoregional or systemic disease increased (ith the cephalad e5tent of the tumor throm/us'

accounting for the reduced survival associated (ith tumor throm/us e5tending into or a/ove

the level of the hepatic veins 0&osa et al' 18.2 Thrasher and %aulson' 1+2 =im HL et al')--.a2 :ot3o(icz et al' )--84, Ho(ever' other data suggest that the cephalad e5tent of tumor

throm/us is not of prognostic significance as long as the tumor is other(ise confined

0Li/ertino et al' 18;2 #lazer and Govic3' 1>2 &taehler and $r3ovic' )---2 $lute et al'

)--;4, Direct invasion o* the &all o* the vein appears to be a more important prognostic

*actor than level o* tumor thrombus an' is no& classi*ie' as pT+c in'epen'ent o* the

level o* tumor thrombus 0Hatcher et al' 112 Iini et al' )--84,

The ma-or 'rop in prognosis comes in patients &hose tumor e"ten's be#on' the erota

*ascia to involve contiguous organs :stage T4;, &hich is rarel# associate' &ith 5)#ear

survival, an' in patients &ith l#mph no'e or s#stemic metastases 0Thrasher and %aulson'

1+2 Thompson et al' )--6a4, #mph no'e involvement has long been recogni8e' as a'ire prognostic sign because it is associate' &ith 5) an' $()#ear survival rates o* 5/ to

+(/ an' (/ to 5/, respectivel# 0$assil et al' 1862 %hillips and TaneFa' )--.4, S#stemic

metastases also porten' a particularl# poor prognosis *or RCC, tra'itionall# &ith $)

#ear survival o* less than 5(/, 5)#ear survival o* 5/ to +(/, an' $()#ear survival o*

(/ to 5/, although these numbers have improve' mo'estl# in the era o* targete'

treatments 0Motzer et al' 12 Motzer and Russo' )---2 Ggrier et al' )--)2 &ella et al'

)--+2 Rini et al' )--4, Patients presenting &ith s#nchronous metastases *are &orse, (ith

many patients dying of disease progression (ithin a year 0Motzer et al' 1' )--.2 Me3hail

et al' )--62 Lei/ovich et al' )--6/2 Rini et al' )--4, 7or patients &ith as#nchronous

metastases the metastasis)*ree interval has prove' to be a use*ul prognosticator because

it re*lects the tempo o* 'isease progression 0Maldazys and de=ernion' 18>2 Ggrier et al'

)--)2 Motzer et al' )--.2 Me3hail et al' )--62 Rini et al' )--4, !ther important prognostic

*actors *or patients &ith s#stemic metastases inclu'e per*ormance status, number an'

sites o* metastases, anemia, h#percalcemia, elevate' alaline phosphatase or lactate

'eh#'rogenase levels, thromboc#tosis, an' sarcomatoi' histolog# 0Maldazys and

de=ernion' 18>2 Motzer et al' 12 Motzer and Russo' )---2 Ggrier et al' )--)2 Lei/ovich

et al' )--+/2 Motzer et al' )--.2 Me3hail et al' )--62 Escudier et al' )--;2 Choueiri et al'

)--;2 Lane and =attan' )--84, The presence o* bone, brain, an'or liver metastases, an'

multiple metastatic sites have been associate' &ith *urther compromise in prognosis

0Ggrier et al' )--)2 Lei/ovich et al' )--6/2 Me3hail et al' )--62 Escudier et al' )--;4, These

factors have /een used to effectively categorize patients (ith metastatic RCC as lo('intermediate' and poor ris3' (ith corresponding differences in median survival 0Ta/le .14

0Motzer et al' 12 $oumerhi et al' )--+2 Motzer et al' )--.2 Me3hail et al' )--62 Choueiri

et al' )--;2 Escudier et al' )--;4, These ris3 groups provide important information for

determining the li3elihood of /enefit a patient may e5pect to receive after cytoreductive

nephrectomy andor resection of other metastatic disease,

Table 49–$9 )) ?ntegrate' Pre'ictive Tools *or Renal Cell Carcinoma!N$!$U$!#N$UD6

E$$!NG $U,#RU$6PE

PR#GN#$!C !ND!CA$#R PR#GN#$!C!NF#R,A$!#N

F#R,A$

Pre&-erative

le$eland linic,Lane et al(1B)

LocaliDed,amenable to 4'

All Tumor siDe, symptoms, gender,age, smo=ing

Histology 'omogram



.>

%@"ayolinic, RaU et al(1B)

LocaliDed All Tumor siDe, symptoms, gender,lymphadenopathy, necrosis onimaging

Recurrence 'omogram

@eio (-apan),@anao et al(1?)

LocaliDed,metastatic

All T' stage %ur$i$al 'omogram

P&st&-erative

%@, @attanet al (17)

LocaliDed All T' stage, tumor siDe, histology,symptoms

Recurrence 'omogram

9LA, Xismanet al (17b)

LocaliDed All T' stage, nuclear grade,per!ormance status

%ur$i$al Algorithm,decisionboxes

9LA, Xismanet al (11c)


All T' stage, nuclear grade,per!ormance status, metastasis(9+%%)

%ur$i$al Algorithm,decisionboxes

ayo linic,ran= et al(11)


lear cell T' stage, tumor siDe, nucleargrade, histologic necrosis (%%+*')

%ur$i$al Algorithm

ayo linic,Leibo$ich et al(10a)

LocaliDed lear cell T' stage, tumor siDe, nucleargrade, histologic necrosis

Recurrence Algorithm

9LA, HL @imet al (18b)


All T' stage, per!ormance status,metastasis, expression o! T420,

$imentin, A/+N in patients #ithmetastatic disease

%ur$i$al 'omogram

%@,%orbellini et al(12)

LocaliDed lear cell T' stage, tumor siDe, nucleargrade, histologic necrosis,micro$ascular in$asion, symptoms

Recurrence 'omogram

ulti/institutional,@ara=ie#icDet al (15)

LocaliDed All T' stage, tumor siDe, nucleargrade, histologic subtype, localsymptoms, age, gender

%ur$i$al 'omogram

ayo linic,4ar=er et al(1?)

LocaliDed lear cell xpression o! :5/H7, sur$i$in, @i/35 (:io%core)

%ur$i$al Algorithm

9LA, @latteet al (1?)

LocaliDed lear cell xpression o! @i/35, T420,endothelial V*R/7, epithelialV*R/7, epithelial V*/

%ur$i$al 'omogram

,etastati+

%@, otDer et al (7???) 9ntreated All 'o prior nephrectomy (metastasis#ithin 7/1 yr o! presentation),anemia, abnormal correctedcalcium, ele$ated LH, lo#per!ormance status

%ur$i$al Algorithm

le$eland linic,e=hail et al(12)

9ntreated All etastasis at or #ithin 71 mo o!nephrectomy, anemia, abnormalcorrected calcium le$el, ele$atedLH, number o! metastatic sites,prior radiotherapy

%ur$i$al Algorithm

ayo linic,Leibo$ich et al(12a)

A!ternephrectomy

lear cell etastasis at or #ithin 1 yr o!nephrectomy, symptoms, location,number o! sites and completeresection o! metastases, tumorthrombus, nuclear grade, histologictumor necrosis

%ur$i$al Algorithm

9LA, Leibo$ichet al (10b) +mmunotherapy All Lymph node status, constitutionalsymptoms, metastasis location,sarcomatoid !eatures, T%H le$el

%ur$i$al Algorithm

%@, otDer et al (18)

+mmunotherapy All Anemia, abnormal correctedcalcium le$el, reducedper!ormance status

%ur$i$al Algorithm

ulti/institutional,scudier et al(15)

+mmunotherapy All etastasis at or #ithin 1 yr o!nephrectomy, anemia, abnormalcorrected calcium le$el, ele$atedLH, number o! metastatic sites,prior radiotherapy

%ur$i$al Algorithm

le$eland linic,houeiri et al(15)

V*/targetedtherapy

lear cell etastasis at or #ithin 1 yr o!nephrectomy, abnormal correctedcalcium le$el, reducedper!ormance status, high plateletcount, high neutrophil count

%ur$i$al Algorithm

ulti/institutional,otDer et al

%unitinibtreated

lear cell etastasis at or #ithin 71 mo o!nephrectomy, anemia, abnormalcorrected calcium le$el, ele$ated

4rogression 'omogram



.;

(1B) LH, number o! metastatic sites,ele$ated al=aline phosphatase,thrombocytosis, lo# per!ormancestatus

@eio, @eio 9ni$ersity %chool o! edicine, To=yo, -apanE LH, lactate dehydrogenaseE %@, emorial %loan/@etteringancer enterE %%+*', ayo linic %tage, %iDe, *rade and 'ecrosis %coreE T%H, thyroid/stimulating hormoneE 9LA,

9ni$ersity o! ali!ornia, Los AngelesE 9+%%, 9LA +ntegrated %taging %ystemE V*(R), $ascular endothelial gro#th !actor (receptor).

1nother signi*icant prognostic *actor *or RCC is tumor si8e, &hich has prove' to be an

in'epen'ent prognostic *actor *or both organ)con*ine' an' invasive RCC 0=attan et al'

)--12 =onta3 and Camp/ell' )--+2 Lane and =attan' )--84, #iuliani and colleagues 01-4

reported 6?year survival rates of 8.* for patients (ith tumor diameter less than 6 cm' 6-*

for tumors /et(een 6 and 1- cm' and -* for tumors more than 1- cm in diameter, To a large

e5tent' this is due to a strong correlation /et(een tumor size and pathologic tumor stage' /utseveral studies have su/seBuently demonstrated that tumor size can function as an

independent prognostic factor 0#uinan et al' 16/2 =attan et al' )--12 &or/ellini et al' )--62

Crispen et al' )--8/2 Gguyen and #ill' )--4, Larger tumors are more li3ely to e5hi/it clear

cell histology and high nuclear grade' and /oth of these factors correlate (ith a compromised

prognosis 0"ran3 et al' )--+/2 Lane et al' )--;a2 Thompson et al' )--4, A revie( of 1;;1

patients (ith organ?confined RCC sho(ed 1-?year cancer?specific survival rates of -* to

6*' 8-* to 86*' and ;6* for patients (ith pT1a' pT1/' and pT) tumor' respectively

0%atard et al' )--.a4, Many other studies have also sho(n a particularly favora/le prognosis

for the unilateral pT1a tumors that are no( /eing discovered (ith increased freBuency, !n

series from the Cleveland Clinic and the Mayo Clinic' such tumors (ere associated (ith

greater than 6* 6?year cancer?specific survival rates' (hether they (ere managed (ithnephron?sparing surgery or radical nephrectomy 0$utler et al' 1.2 Lerner et al' 1>2

Cheville et al' )--12 #ill et al' )--;2 Lane and #ill' )--;2 Crispen et al' )--8/4,

!ther important prognostic *actors *or RCC inclu'e nuclear gra'e, histologic subt#pe

an' s#mptomatic presentation. &everal grading systems for RCC have /een proposed on

the /asis of nuclear size and morphology and presence or a/sence of nucleoli, 7nfortunately'

intero/server varia/ility is common in the assignment of nuclear grade2 there is no ideal

classification system that can overcome the su/Fectivity of this e5ercise, Gevertheless' almost

all the proposed grading systems have provided prognostic information for RCC' and nuclear

grade has proved in most cases to /e an independent prognostic factor (hen su/Fected to

multivariate analysis 0#oldstein' 1;2 "icarra et al' )--12 =attan et al' )--12 Iisman et al')--1/2 Lohse et al' )--)' )--62 True' )--)2 =onta3 and Camp/ell' )--+2 %atard et al' )--.c2

Lang et al' )--62 Lane and =attan' )--82 "icarra et al' )--4,

"uhrmanJs classification system has /een the most generally adopted grading system for

RCC, !n "uhrman and colleaguesN original report 018)4 the 5)#ear survival rates *or

gra'es $ to 4 &ere 4/, +4/, +$/, an' $(/, respectivel#, an' nuclear gra'e prove' to

be the most signi*icant prognostic *actor *or organ)con*ine' tumors in this series.

&u/seBuent reports have demonstrated correlations /et(een "uhrmanJs nuclear grade and

tumor stage' tumor size' venous tumor throm/i' and lymph node and systemic metastases

0$retheau et al' 162 Lang et al' )--62 Lohse et al' )--62 "icarra et al' )--4, &ignificant

differences have /een consistently o/served /et(een lo(?grade 0grades 1)4 and high?grade

0grade +.4 tumors (ith some difficulty distinguishing the intermediate grades, $ased on



.8

these studies' some have recommended changing to a three?tiered system' /ut this remains a

matter of investigation 0Medeiros et al' 1;2 Lang et al' )--62 Lane and =attan' )--82 Ihou

)--4, !n addition' although significant differences according to nuclear grade have /een

reported in series that have included patients (ith all types of RCC or clear cell RCC alone'

the relevance of the "uhrman classification system to evaluation of other su/types of RCC is

not entirely clear, %apillary RCC may /e /etter su/grouped into type 1 and type )' andoncocytic neoplasms may /e /etter classified as chromopho/e RCC' hy/rid oncolytic tumors'

and oncocytomas' although (hether these provide /etter prognostic information a/out cancer

recurrence has not /een determined 0see %athology4,

3istologic subt#pe also carries prognostic signi*icance, although, again, primaril# at the

en's o* the spectrum. The presence of sarcomatoid differentiation or collecting duct' renal

medullary' or unclassified histologic su/type denotes a poor prognosis 0Carter et al' 1)2

<avis et al' 16/2 Chao et al' )--)/2 Escudier et al' )--)a2 Mian et al' )--)2 %olasci3 et al'

)--)2 MeFean et al' )--+2 Cheville et al' )--.2 Ganus et al' )--.2 To3uda et al' )-->2

=o/ayashi et al' )--82 Ihou )--4, &everal studies no( suggest that clear cell RCC may

have a (orse prognosis on average compared (ith papillary or chromopho/e RCC' althoughthere are clearly poorly differentiated tumors in each of these su/categories that can /e lethal

0Moch et al' )---2 Amin et al' )--)2 Lau et al' )--)2 Cheville et al' )--+2 =reFci et al' )--+2

$ec3 et al' )--.2 %atard et al' )--62 Lane and =attan' )--82 Crispen et al' )--8/2 <allNOglio

et al' )--82 Lam et al' )--82 Margulis et al' )--82 =latte et al' )--8/2 Rothman et al' )--4,

"inally' several su/types of RCC are predicta/ly indolent' including multiloculated cystic

clear cell RCC and mucinous tu/ular and spindle cell carcinoma,

7or patients &ith clinicall# locali8e' 'isease, mo'e o* presentation :inci'ental vs.

s#mptomatic; can be combine' &ith other pre'ictive elements to better strati*# patients

a*ter primar# surgical management 0=attan et al' )--12 %atard et al' )--.a2 &or/ellini et al'

)--62 =ara3ie(icz et al' )--;2 Lane and =attan' )--84, !n addition' patients (ith systemic

symptoms suggestive of metastatic spread have significantly poorer outcomes than those (ith

only local symptoms' such as hematuria or flan3 pain 0=attan et al' )--12 &or/ellini et al'

)--64,

<ozens of genes that may have prognostic or therapeutic significance for patients (ith RCC

have /een identified using high?throughput technologies 0Ta3ahashi et al' )--+2 Ihao et al'

)-->2 Lane et al' )--8/4, #ene e5pression profiling 0c<GA microarrays4 can Buantify the

levels of thousands of individual messenger RGA transcripts (ithin an individual tumor

sample, Alterations in gene e5pression can then /e correlated (ith the amount and location of

specific gene products 0proteins4 using immunohistochemical staining of cancer specimens0=im HL et al' )--.a2 Liu et al' )--.2 %ar3er et al' )--4, Construction of tissue microarrays

can facilitate the screening of hundreds of tumors' /ut interpretation of results can /e

challenging due to tumor heterogeneity and the selection of only a small amount of tissue for

analysis 0=im HL et al' )--.a2 Liu et al' )--.2 Lei/ovich et al' )--;4, "urthermore' (hen

evaluating the potential value of a ne( mar3er' it is important to consider its contri/ution

after accounting for other 3no(n prognostic factors 0#eorge and $u3o(s3i' )--;2

Tunuguntia and 9orda' )--84,

Several molecular marers appear to serve as in'epen'ent prognostic *actors *or RCC

an' have provi'e' important insights into tumor biolog# 0see Tumor $iology4 0$ui et al'

)--12 Han et al' )--+2 Crispen et al' )--8/2 Gogueira and =im' )--82 %ar3er et al' )--4,One such factor is CA?!' (hich is regulated /y the VHL gene and overe5pressed in most



.

clear cell RCCs 0$ui et al' )--+' )--.2 Lei/ovich et al' )--;4, Although initial studies

indicated that decreased e5pression of CA?! is independently associated (ith poorer

survival in patients (ith metastatic RCC 0$ui et al' )--+2 =im et al' )--64' this association

does not appear to apply for patients (ith localized disease 0=im et al' )--62 Lei/ovich et al'

)--;4, CA?! also may serve as a mar3er for response to systemic therapy' ma3ing CA?!

immunostaining of particular value for patients (ith advanced disease 0$ui et al' )--.2At3ins et al' )--62 Cho et al' )--;4, $;?H1 is a T?cell coregulatory molecule that is a strong

independent predictor of disease progression for RCC 0Thompson et al' )-->2 %ar3er et al'

)--4, This association holds even after accounting for other molecular factors and the maFor

clinical and pathologic predictors 0=ram/ec3 et al' )--;2 %ar3er et al' )--4, !ncreased

proliferative inde5 as assessed /y =i?>; has also /een correlated (ith reduced survival in

clear cell RCC 0$ui et al' )--.2 =latte et al' )--2 %ar3er et al' )--4, Although initial data

indicated that =i?>; e5pression (as a surrogate for histologic necrosis' more recent studies

have found =i?>; to /e an independent predictor and have incorporated it into predictive

algorithms 0Tollefson et al' )--;2 =latte et al' )--2 %ar3er et al' )--4, Other factors that

appear to /e useful include cell cycle regulators' such as the tumor suppressor TP43 0=im HL

et al' )--.a2 &hvarts et al' )--6/2 =latte et al' )--42 various gro(th factors and their receptors' including mem/ers of the E#" family 09aco/sen et al' )---2 Rivet et al' )--82

%hyoc et al' )--82 =latte et al' )--42 adhesion molecules2 and other factors' such as survivin

0%ar3er et al' )-->' )--2 $yun et al' )--;2 =ram/ec3 et al' )--;4,

Several investigators have no& 'evelope' tools that combine various prognostic *actors,

an' this has greatl# improve' our pre'ictive capacit# *or patients &ith RCC 0see Ta/le

.14 0=attan et al' )--12 Iisman et al' )--1/2 "ran3 et al' )--)2 &or/ellini et al' )--62

Lane and =attan' )--84, "or instance' =attan and colleagues 0)--14 have com/ined manner

of presentation 0incidental vs, local or systemic symptoms4' tumor histology' tumor size' and

pathologic stage to develop a nomogram that predicts cancer?free survival after nephrectomy,

Tumor grade (as not included in this analysis /ecause its role for nonclear cell RCC has not

/een clearly defined, A su/seBuent analysis from this same group focused only on patients

(ith clear cell RCC and incorporated tumor grade' assessment of tumor necrosis' and

vascular invasion to further improve prognostication 0"ig, .1;4 0&or/ellini et al' )--64,

&uch nomograms provide an individual assessment of ris3 that clinicians can use during

patient counseling 0(((,nomograms,org 4, Although several predictive algorithms

incorporate histologic necrosis 0"ran3 et al' )--)2 &or/ellini et al' )--64' the utility of this

predictor has /een called into Buestion in some recent studies /ecause its assessment has not

/een standardized and it is not routinely reported at many centers 0!s/arn and =ara3ie(icz'

)--4,

http://www.expertconsultbook.com/expertconsult/b/linkTo?type=external&externalUrl=http%3A%2F%2Fwww.nomograms.org&eid=4-u1.0-B978-1-4160-6911-9..00049-9--s0025&isbn=978-1-4160-6911-9

http://www.expertconsultbook.com/expertconsult/b/linkTo?type=external&externalUrl=http%3A%2F%2Fwww.nomograms.org&eid=4-u1.0-B978-1-4160-6911-9..00049-9--s0025&isbn=978-1-4160-6911-9





61

1nother pre'ominant mo'el that provi'es in'ivi'uali8e' in*ormation *or patients &ith

clear cell RCC is the SS?E score, &hich incorporates $990 TEM stage, tumor si8e,

nuclear gra'e, an' presence o* tumor necrosis to pre'ict recurrence an' survival a*ter

ra'ical nephrectom# 0"ran3 et al' )--)4, Estimated cancer?specific survival according to the

&&!#G score (as /ased on data from more than 18-- patients and has su/seBuently /een

validated in several other datasets 0"icarra et al' )-->' )--2 "uFii et al' )--82 Iigeuner et al')-1-4, Thompson and colleagues 0)--;d4 have also developed a dynamic outcome prediction

model that provides patients (ith cancer?specific survival rates that improve as the disease?

free interval follo(ing surgery increases, Most recently' the group at Mayo Clinic has

developed a seBuential approach in (hich the predicted outcomes for patients at various ris3

of recurrence according to clinical and pathologic factors can /e further stratified /ased on

molecular data incorporated into a $io&core 0%ar3er et al' )--4, The e5pression of $;?H1'

survivin and =i?>; each added independent predictive a/ility after accounting for either the

7!&& or &&!#G score' especially for patients at intermediate or high ris3 of recurrence

0%ar3er et al' )--4,

TGM staging systems and prognostic algorithms have different purposes, The TGM stagingsystem is used to provide a universal language for communication /et(een clinicians and

patients and is /ased solely on the anatomic e5tent of cancer dissemination, 1 &ealth o*

literature no& supports the notion that algorithms that incorporate multiple pre'ictive

elements, such as nomograms an' arti*icial neural net&ors, outper*orm ris

assessment base' on e"pert opinion or simpler mo'els, such as classic staging s#stems

0<a(es et al' 182 Ross et al' )--)2 !s/arn and =ara3ie(icz' )--2 &hariat et al' )--4, The

'evelopment an' use o* these pre'ictive tools can help gui'e counseling an' *ollo&)up

o* patients &ith RCC an' i'enti*# patients more liel# to bene*it *rom speci*ic

interventions.

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Chapter 49 – Malignant Renal Tumors (Renal Cell Carcinoma)