Original Research. Immunohistochemical panel for differentiating renal cell carcinoma with clear and papillary features. Hanan AlSaeid Alshenawy

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1 Originl Reserh Journl of Moleulr Pthophysiology DOI: /jmp Immunohistohemil pnel for differentiting renl ell rinom with ler nd ppillry fetures Hnn AlSeid Alshenwy Deprtment of Pthology, Fulty of Mediine, Tnt University, Tnt, Egypt. Address for orrespondene: Hnn Al-Seid Al-Shenwy, Deprtment of Pthology, Fulty of Mediine, Tnt University, 25 Hmdy Gdo Street, Tnt, Egypt. Tel.: / , E-mil: Hnn_ Reeived: August 21, 2014 Aepted: Otoer 17, 2014 Pulished: Novemer 01, 2014 ABSTRACT Aim: Renl ell rinom (RCC) in whih ler ells with ppillry rhiteture is present is diffiult dignosti hllenge. The most ommon type, ler ell RCC, only rrely hs ppillry rhiteture. The seond most ommon one, ppillry RCC (PRCC), only rrely ontins ler ells. However, two reently desried less-ommon types, ler ell ppillry nd Xp11 trnslotion RCC hrteristilly feture oth ppillry rhiteture nd ells with ler ytoplsm. Aurte dignosis hs oth prognosti nd therpeuti implitions. This study ims to highlight the helpful ytomorphologi nd immunohistohemil (IHC) fetures of eh of these entities to enle reproduile lssifition. Mterils nd Methods: Sixty RCC ses with ler ells nd ppillry rhiteture were seleted nd lssified ording to The Interntionl Soiety of Urologil Pthology (ISUP) Vnouver lssifition of renl neoplsi nd grded ording to The ISUP grding system for RCC then stined for ytokertin 7 (CK7), roni nhydrse IX (CA IX), α-methylyl-oenzyme remse (AMACR) nd trnsription ftor E3 (TFE3). Results: the hrteristi immunoprofile of ler RCC is CK7, AMACR, CA IX + nd TFE3, PRCC is CK7 +, AMACR +, CA IX nd TFE3, while for ler ell PRCC it is CK7 +, AMACR, CA IX + nd TFE3 nd lstly Xp11 trnslotion RCC is CK7, AMACR +, CAIX- nd TFE3 +. Conlusions: IHC stining for CA IX, CK7, AMACR nd TFE3 omprises onise pnel for distinguishing RCC with ppillry nd ler pttern. KEY WORDS: α-methylyl-oenzyme remse, roni nhydrse IX, retine kinse 7, renl ell rinom, trnsription ftor E3 INTRODUCTION Renl epithelil tumors re renl neoplsms rising from renl tuules nd n e lssified into mny mjor tegories sed on morphology [1]. Different tumor type ppers to hve different outome. With inresed understnding of the pthogenesis of eh type of tumors, new trget therpy my e developed [2]. Primry renl ell rinoms (RCCs) with oth ppillry rhiteture nd ells with ler ytoplsm my e diffiult dignosti hllenge. The most ommon RCC, ler RCC (CRCC), whih represent out 75% of the ses, my sometimes hve ppillry rhiteture. The seond most ommon RCC, ppillry RCC (PRCC) whih represent out 15%, my lso ontin ler ells [3]. However, 2 reently desried ut less-ommon RCCs, ler ell PRCC (CPRCC) nd Xp11 trnslotion RCC, hrteristilly feture oth ppillry rhiteture nd ells with ler ytoplsm. Aurte dignosis of these distint entities hs prognosti nd therpeuti implitions [4]. Immunohistohemil (IHC) mrkers my e needed to estlish the orret dignosis [5]. CPRCC is reently reognized renl neoplsm, omposed of n dmixture of ysti, glndulr, nd ppillry omponents, ll lined y ells with ler ytoplsm, usully of low nuler grde. The nulei re hrteristilly loted wy from the sement memrne to show pino-key-like pttern [3]. The outome dt re limited; however, the ville dt suggest tht this type of tumor usully hve good prognosis. Originlly they were disovered in kground of end-stge renl disese (ESRD) nd quired ysti kidney disese [6]. Xp11 trnslotion RCC initilly desried in hildren nd young dults. Reently, the term MiTF/trnsription ftor E3 (TFE3) fmily trnslotion-ssoited rinom hs een proposed for tumors tht hve trnslotions involving TFE3. TFE3 is trnsription ftor tht elong to the sme fmily of trnsription ftors tht will overexpress nuler TFE3. These IHC findings re importnt given the ourrene of these tumors in the dult popultion, s they morphologilly overlp with CCRCC nd PRCC. In the literture, these tumors do not pper to respond to immunotherpy [7]. Outome dt of this entity re still premture, nd good long-term follow-up dt re neessry. Pulished outome series in dults show poor prognosis [4]. J Mol Pthophysiol Apr-Jun 2014 Vol 3 Issue 2 23

2 Alshenwy: Renl ell rinom with ler nd ppillry fet The tretment prdigm for renl tumors is hnging, nd these hnges re in prt driven y tumor lssifition. Trditionlly, RCC hs een onsidered surgil disese. In some ses, surgery with its ssoited omplitions nd negtive impt on longterm renl funtion my e very hrmful nd hene follow up fter hemordiotherpy my e used in low-grde smll tumors [8]. CKs re fmily of intermedite filments tht hrterize epithelil differentition, There hve een onfliting results on the expression of ytokertin 7 (CK7) in renl epithelil tumors in the literture s some uthors reognized its role in the differentition of non-ler ell RCC from CRCC [9]. The most useful positive IHC stin in supporting dignosis of PRCC is α-methylyl-oenzyme remse (AMACR). It is now reognized tht AMACR n show positivity in tumors from mny different orgns nd in severl different types of renl tumors. However, AMACR stining hs onfliting results in CPRCC s it is often negtive [10] ut in other studies it is folly or, rrely, diffusely positive [6]. Croni nhydrse IX (CA IX) protein is thought to ply role in the regultion of ell prolifertion nd my e involved in onogenesis nd tumor progression. Previous immunoiohemil studies reveled tht CA IX expression my e useful dignosti iomrker in RCC sulssifition. Clinil tumor trgeting studies with monolonl ntiody to CA IX hve shown tht CA IX shows promise s mrker for seleting ptients with dvned disese who would enefit from ertin speifi systemi gents, speifilly interleukin-2 [7,11]. This work ims to highlight the helpful ytomorphologi nd IHC fetures of eh of these entities to enle reproduile lssifition. We exmined the expression of four mrkers in series of the four mjor renl ell tumors with ler nd ppillry rhiteture. In this study, we evluted the expression of CA IX, AMACR, CK7 nd TFE3 for differentil dignosis nd sulssifition. MATERIALS AND METHODS Cse Seletion nd Histopthologil Study A retrospetive study ws performed on RCC ses seleted from Jnury 1, 2010 to April 30, A totl of 250 ses of RCC were removed y nephretomy either prtil or rdil nd rought to the Deprtment of Pthology, University of Tnt. Representtive tissue setions from the surgil speimens were fixed in 10% uffered formlin nd emedded in prffin. For routine mirosopy, 4μ-thik setions were stined with hemtoxylin nd eosin. The linil sheets for ll ses were reviewed. The ses were lssified ording to The Interntionl Soiety of Urologil Pthology (ISUP) Vnouver lssifition of renl neoplsi [12]. Tumors tht fulfill the morphologil riteri of ler nd ppillry renl ell neoplsms were seleted. They were 60 ses. Only the seleted ses were ssessed for size, lterlity, multifolity, presene of ssoited ESRD. Then they ssessed histologilly for the presene of rnhed tuulr strutures, sunuler vuoles, ini, thin-wlled sinusoid-like vessels, seretory ells with nulei ligned t the pil end of the ells, ysti omponents, hrter of the stroml omprtment, presene of tumor pseudopsule, nd lifition. The seleted rinoms were lter reevluted for morphologi hrteristis of those tumors tht qulify them in either one of the following tegories; CRCC, PRCC, CCPRCC or Xp11 trnslotion RCC. Speifilly, the riteri used for lssifition of tumor s CCPRCC inluded the following: (1) Diffuse ytoplsmi lrity; (2) ppillry, tuulr or ysti rhiteture; nd (3) hrteristi liner rrngement of the nulei wy from the sement memrne [10]. Xp11 trnslotion RCC ses were onfirmed y TFE3 immunostining positivity. The ISUP grding system for RCC grding system ws pplied to ess the nuleolr grdes [13]. The tumors were stged ording to the 2010 UICC/AJCC onsensus guidelines [14]. IHC Study nd Evlution IHC stining ws performed using the following ntiodies: CK7 (OV-TL 12/30, 1:100, DAKO, Glostrup, Denmrk), CA IX (dilution 1:200, mouse monolonl, Lei), AMACR (13H4, 1:100; DAKO, Glostrup, Denmrk) nd TFE3 (1:1500, Snt Cruz Biotehnology Inv., Snt Cruz, CA, USA). Evlution of the IHC stining ws performed y light mirosopy using 10 ojetive lens with the seletive use of ojetive lens for onfirmtion. The interprettion of immunoretivity ws performed in semiquntittive mnner y nlyzing the extent of the stining positivity of the tumor ells. Immunostining of >10% of tumor ells ws required for soring s positive se. The interprettion sore ws s follows: 0 or negtive 10% tumor ell positivity; +1 or wek = 11-25% tumor ell positivity; +2 or moderte = 26-50% tumor ell positivity; nd +3 or strong >50% tumor ell positivity [6]. Cytoplsmi nd/or memrnous expression of CK7 nd AMACR were onsidered positive. Only distint memrnous stining for CA IX nd distint nuler stining for TFE3 were onsidered positive [15]. Sttistil Anlysis The liniopthologil nd IHC fetures were tested for their ssoition with the histologil sutype using Student s t-test for ontinuous vriles nd the Chi-squre test (or Fisher s ext test) for qulittive vriles. All sttistil nlyses were performed using the SPSS 13.0 softwre (SPSS In., Chigo, IL, USA). Sttistil signifine ws onsidered when P RESULTS Cliniopthologi Findings of the Seleted Cses The liniopthologi findings re listed in Tle 1. The seleted ses were omprised of 60 ses; 40 men nd 20 women (men to women rtio, 2:1) with men ge of 54 yers (rnge, yers). A definite positive history of hemodilysis 24 J Mol Pthophysiol Apr-Jun 2014 Vol 3 Issue 2

3 Alshenwy: Renl ell rinom with ler nd ppillry fet Tle 1: The liniopthologil vriles of the seleted ses Cliniopthologil vrile Numer of ses Size <7 m 45 More thn 7 m 15 Lterlity Right 30 Left 24 Bilterl 6 Multifolity Yes 8 No 52 ESRD Yes 14 No 46 Grde Grde I 24 Grde II 21 Grde III 15 Stge Stge I 38 Stge II 15 Stge III 7 Stge IV 0 Histologil types CRCC 28 PRCC 15 CPRCC 8 Xp11 trnslotion RCC 9 CRCC: Cler renl ell rinoms, PRCC: Ppillry renl ell rinoms, CPRCC: Cler-ell ppillry renl ell rinoms, ESRD: End-stge renl disese ws found in 14 ses ESRD with durtion rnging from 1 to 24 yers. The ISUP grding system ws s follows: 24 were Grde I, 21 were Grde II nd 15 were Grde III. The tumors pthologi stge ws s follows; 38 ses were Stge I, 15 were Stge II, 7 were Stge III nd no ses were Stge IV. Overll, of the 60 ses, 28 (47%) were CRCC, 15 (25%) PRCC, 8 (13%) CPRCC nd 9 (15%) Xp11 trnslotion RCC were identified. The ses were lssified ording to the pulished dt into these tegories ording to some vriles summrized in Tle 2. CRCC is usully hrterized y optilly ler ytoplsm nd very well-defined ytoplsmi memrne. The ells re rrnged in nests, lveolr rhitetures, strnds nd ppille, or ysts. The strom ontins very typil nd prominent pillry network. Hemorrhge nd nerosis re frequent [Figure 1]. Ppillry rhiteture is the hrteristi histology of renl tumors in PRCC. The delite firo vsulr stlks lined y smll ells with low-grde nulei nd snt ytoplsms [Figure 2]. Psmmom odies nd ler ells re ommon. CPRCC were well irumsried with well-defined, thin, firous psule nd were omposed histologilly of mixture of ysts nd ppille. Tuulr/inr fetures were lso ommon. Even in the predominntly ysti res, the lining ells frequently showed ppillry infoldings. The tumors were omposed of uoidl or olumnr ells with ler ytoplsm, Tle 2: Mirosopi finding in the seleted ses Histologil fetures CRCC PRCC CPRCC Xp11 trnslotion Cler ells Yes Yes Yes Yes Seretory ells with nulei No No Yes No ligned t the pil end of the ells Sunuler vuoles No No Yes No True ppille No Yes Yes Yes Tuules No No Yes Yes Cysts Yes Yes Yes Yes Aini Yes No Yes Yes Biologi ggressiveness Yes Yes No Yes Cpsule No Yes Yes No Psmmom odies No Yes No No Leiomyomtous stroml omponents Yes No Yes Yes Thin wlled sinusoid-like vessels Yes No No No CRCC: Cler renl ell rinoms, PRCC: Ppillry renl ell rinoms, CPRCC: Cler-ell ppillry renl ell rinoms d Figure 1: A se of ler renl ell rinoms Grde I showing ler ells with fint ppillry strutures (H nd E, 100, ) showing positive memrnous stining for roni nhydrse IX ( 400, ) nd week positivity for oth ytokertin 7 ( 200, ) nd α-methylyl-oenzyme A remse ( 400, d) smll hyperhromti, round or ovl nulei, nd inonspiuous nuleoli. A onspiuous nuler positioning wy from the sement memrne with sunuler vuoles ws noted in ll ses exmined [Figure 3]. The ysts, tuules, nd ini ontined pink seretion. Renl psulr nd vsulr invsion, mitoses, tumor nerosis, nd stroml ggregtes of mrophges were not oserved. The stroml omponent formed vrily thik nds of firous tissue dmixed with strnds of leiomyomtous tissue inside the tumors Renl rinoms with Xp11.2 trnslotion hve hrteristi morphology; they re omposed of very lrge ler ells tht form nests, lveoli, nd ppille [Figure 4] ompnied y J Mol Pthophysiol Apr-Jun 2014 Vol 3 Issue 2 25

4 Alshenwy: Renl ell rinom with ler nd ppillry fet Figure 2: A se of ppillry renl ell rinoms Grde II showing prominent ppille with osionl ler ells (H nd E, 100, ). It expresses strong memrnous positivity for ytokertin 7 ( 200, ). α-methylyl-oenzyme A remse demonstrtes ytoplsmi grnulr positivity ( 200, ) Figure 3: A se of ell ppillry renl ell rinoms Grde I show ler ells with low grde nulei show hrteristi liner polriztion wy from the sement memrne (H n E 200, ), it demonstrtes positive ytoplsmi stining for ytokertin 7 ( 200, ), roni nhydrse-ix diffusely expressed in memrnous distriution in up-shped distriution ( 400, ) Figure 4: A se of Xp11 trnslotion Grde II shows ler ells nd ppillry rhiteture with high grde nulei (H nd E, 200, ), strongly expressing α-methylyl-oenzyme A remse in the ytoplsm ( 200, ), nd hrteristilly show nuler positivity for TFE3 ( 200, ) signifint differene etween the histologil type of RCC nd the tumor size s most of the ses of PRCC, Xp11.2 trnslotion RCC (12/15 nd 7/9 respetively) nd ll the ses of CPRCC were of smller size ( 7 m) while most of the lrge sized tumors were CRCC. Aout the lterlity, PRCC ws the most ommon ilterl RCC (5/15) s five ses out of the six ilterl ses were PRCC with sttistil differene. Furthermore, the multifolity ws only seen in PRCC (8/15) s ll the multifol ses were PRCC with strong sttistil differene. ESRD ws ssoited with most of CPRCC (6/8) nd some CRCC (6/28) with sttistil signifine. The grde ws orrelted signifintly with RCC types s it ws low in ll the ses of CPRCC (either Grde I or II). On the other hnd, more thn hlf of the Xp11 trnslotion RCC ses were of high grde (Grde III). The tumor stge ws lso low in most of the ses of CRCC, PRCC nd ll the ses of CPRCC with strong signifint differene. These dt were summrized in Tle 3. IHC Findings in the Studied Cses The IHC findings re listed in Tle 4. Correltion Study etween the Studied Cses nd Cliniopthologil Vriles The IHC profile of CRCC ws tht ll the ses show positive memrnous stining for CA IX (18/28 nd 10/28 were strongly positive [Figure 1] nd modertely positive onsequently), wheres they were negtive for oth CK7 nd AMACR, lthough oth my e weekly positive (2/28 [Figure 1] nd 5/28 were [Figure 1d] wek positive respetively), espeilly in higher-grde tumors. TFE3, mrker of Xp11 trnslotion RCC, is onsistently negtive. In orreltion etween the different pthologil types of RCC nd the liniopthologil vriles, it ws found tht there is PRCC ses show strong memrnous positivity for CK7 [Figure 2]. Stining with AMACR demonstrtes ytoplsmi n undne of psmmom odies. The ells re not very ohesive, whih uses lveolr imges nd pseudo ppille. 26 J Mol Pthophysiol Apr-Jun 2014 Vol 3 Issue 2

5 Tle 3: Correltion study etween the studied ses nd liniopthologil vriles Histologil type 7 m n=45 Alshenwy: Renl ell rinom with ler nd ppillry fet Size Lterlity Multifolity ESRD Grde Stge >7 m Right n=30 Left n=24 Bilterl n=6 Yes n=8 CRCC n= PRCC CPRCC n= Xp11.2 trnslotion RCC n=9 P vlue CRCC: Cler renl ell rinoms, PRCC: Ppillry renl ell rinoms, CPRCC: Cell ppillry renl ell rinoms, ESRD: End-stge renl disese No n=52 Yes n=14 No n=46 I n=24 II n=21 III I n=38 II III n=7 IV n=0 Tle 4: IHC profile of the studied ses Studied mrker CRCC n=28 PRCC CPRCC n=8 Xp11 trnslotion n=9 CK7 Negtive AMACR Negtive CA IX Negtive TFE3 Negtive CK7: Cytokertin 7, CA IX: Croni nhydrse IX, CRCC: Cler renl ell rinoms, PRCC: Ppillry renl ell rinoms, CPRCC: Cell ppillry renl ell rinoms, IHC: Immunohistohemil grnulr positivity in ll the ses [Figure 2]. The CA IX stining is either ompletely negtive (13/15) or my e wek positive ner res of nerosis (2/15). TFE3 is onsistently negtive. CPRCC displys unique IHC profile overlpping with CRCC nd PRCC. CPRCC shows positive ytoplsmi stining for CK7 in ll the ses [Figure 3]; similr to PRCC. AMACR, TFE3 were negtive in ll the ses exmined. The tumor ells lso expressed CA-IX diffusely in memrnous distriution (6/8 nd 2/8 were strongly nd modertely positive onsequently); the sene of stining long the luminl orders of the tumor ells ws quite hrteristi (up-shped distriution) [Figure 3]. TFE3 is onsistently negtive. Renl rinoms with Xp11.2 trnslotion do not express, or only very wekly express CK7 nd CA IX (8/9 nd 7/9 were negtive for CK7 nd CA IX respetively) ut they express AMACR (6/9 [Figure 4] nd 3/9 were strongly nd modertely positive respetively). In ddition, this group of rinoms is hrterized y nuler positivity with the TFE3 trnsription ftor [Figure 4]. DISCUSSION The World Helth Orgniztion lssifition of renl tumors synthesizes morphologil, IHC, moleulr, nd linil dt to define distint entities tht re iologilly nd linilly relevnt. Although most epithelil renl tumors n e dignosed y morphology lone, the dignosis n e diffiult due to the overlp of histologil fetures. In these ses, differentilly expressed IHC mrkers n e of help [2]. In this study, we performed 4-ntiody pnel on RCC ses tht show oth ppillry nd ler ell rhiteture. The present study inluded 60 ses onsist of CRCC, PRCC, CPRCC nd Xp11.2 trnslotion RCC. Most of PRCC, Xp11.2 trnslotion RCC nd ll CPRCC ses were of smller size ( 7 m). PRCC ws found to e the most ommon ilterl nd multifol RCC. ESRD ws ssoited with most of CPRCC ut lso we oserved tht CPRCC n our in otherwise norml kidneys, nd this ws oserved in Prmik et l. study [10]. CRCC ws usully of ggressive rhiteture s it ws hrterized y tumor nerosis, mitoses, vsulr invsion, nd hrteristi network of smll, thin-wlled sinusoidlike lood vessels, so it ws usully presented with higher stge nd this ws seen in Brnnon et l. study [16]. PRCC usully hs ysti hnge nd ppillry rhiteture. Cler ell hnge n eome quite extensive in some tumors using morphologi onfusion. The ytoplsmi lering is typilly seen in ssoition with tumor nerosis, nd this ws similr to Aydin et l. study [17]. CPRCC were well-irumsried with well-defined firous psule nd were omposed of mixture of ysti, ppillry, tuulr, nd inr omponents. The nulei show hrteristi polriztion in liner rry wy from the sement memrne nd of low grde. The stroml omponent formed vrily thik nds of firoleiomyomtous tissue inside the tumors mong the epithelil omponent. These fetures were oserved in previous studies [10,18]. Xp11.2 trnslotion RCC hs distintive pttern whih is the presene of oth ler ells nd ppillry rhiteture. Nulei tend to e high grde, nd the ytoplsm my e ler to grnulr nd eosinophili. Numerous psmmomtous lifitions nd J Mol Pthophysiol Apr-Jun 2014 Vol 3 Issue 2 27

6 Alshenwy: Renl ell rinom with ler nd ppillry fet stroml hyline nodules re ommon. Most of our ses were of higher grdes, nd this ws similr to Goyl et l. [7]. The distintion etween CRCC, PRCC, CPRCC nd Xp11.2 trnslotion RCC is ritil euse of different ehvior, prognosis nd tretment [6]. In the present study, the grde ws low in ll the ses of CPRCC, nd the stge ws lso low in most of the ses of CRCC, PRCC nd ll the ses of CPRCC with strong signifint differene. On the sis of our results, it ppers tht CPRCC represents distint form of low grde RCC, the reognition of whih my e importnt for prognosis nd linil mngement no se of CPRCC hs ehved ggressively s in previous studies [19]. So IHC study to differentite diffiult ses my e needed to lssify them. CK7 is ommonly used mrker for RCC. Our results showed diffuse positivity for this mrker in memrnous pttern, onsistent with previous reports [20], onfirming its usefulness in differentiting oth PRCC nd CPRCC from CRCC nd Xp11trnslotion RCC whih is onsistently negtive in oth. AMACR is mitohondril enzyme, whih medites the oxidtion of rnhed-hin lipids. In this study, it hs een shown tht this mrker is usully positive in PRCC nd Xp11 trnslotion RCC with diffuse strong ytoplsmi stining pttern. Our study showed tht AMACR ws usully negtive or weekly positive in CRCC wheres CPRCC ws negtive for this mrker, onsistent with prior reports [2,3]. CA IX is hypoxi-indued protein nd is predominntly reported to e positive in CRCC [2,21]. In this study, CPRCC is lrgely positive for this mrker, result tht onurs with previous oservtions [11]. CA IX is useful for the differentition of CRCC nd CPRCC from PRCC with ler ell hnges. CRCC nd CPRCC re usully positive for this mrker, wheres the PRCC is either ompletely negtive or my e weekly positive ner res of nerosis. However, the pttern of expression of CA IX in CPRCC differs from tht seen in CRCC in tht most ell in CPRCC lk leling on the luminl spet. This pttern of stining ws not oserved in ny of the CRCCs evluted in this study, nd this ws in greeing with Rohn et l., [15] nd Tikoo nd Reuter [22]. Xp11 trnslotion RCC dignosis is supported y TFE3 positivity. In summry, The hrteristi immunoprofile of CRCC is CK7, AMACR, CA IX + nd TFE3, for PRCC it is CK7 +, AMACR +, CA IX nd TFE3, while for CPRCC it is CK7 +, AMACR, CA IX + nd TFE3 nd lstly Xp11trnslotion RCC is CK7, AMACR +, CA IX nd TFE3 +. To onlude, IHC stining for CA IX, CK7, AMACR nd TFE3 omprises onise pnel for distinguishing RCC with ppillry nd ler pttern. Our mrker pnel is ler dvnement in terms of immunohistohemistry pplition for RCC sutype differentition when ppillry nd ler ells re the predominnt rhiteture s this is very ruil for further prognosis nd trgeted therpy euse of the different ehvior of eh type. REFERENCES 1. Deng FM, Melmed J. Histologi vrints of renl ell rinom: Does tumor type influene outome? Urol Clin North Am 2012;39:119-32, v. 2. Bing Z, Ll P, Lu S, Zioer A, Tomszewski JE. Role of roni nhydrse IX, -methylyl oenzyme remse, ytokertin 7, nd gletin-3 in the evlution of renl neoplsms: A tissue mirorry immunohistohemil study. Ann Dign Pthol 2013;17: Willimson SR, Ele JN, Cheng L, Grignon DJ. Cler ell ppillry renl ell rinom: Differentil dignosis nd extended immunohistohemil profile. Mod Pthol 2013;26: Hillry R, Guido M, Pedrm A. renl ell rinom with ler ell nd ppillry fetures. Arh Pthol L Med 2012;136: Wlter B, Hrtmnn A, Hofstädter F, Junker K, Moh H, Bertz S, et l. 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7 Alshenwy: Renl ell rinom with ler nd ppillry fet immunohistohemistry in dignosing renl neoplsms: When is it relly useful? Arh Pthol L Med 2012;136: Al-Ahmdie HA, Alden D, Fine SW, Gopln A, Touijer KA, Russo P, et l. Role of immunohistohemistry in the evlution of needle ore iopsies in dult renl ortil tumors: An ex vivo study. Am J Surg Pthol 2011;35: Tikoo SK, Reuter VE. Differentil dignosis of renl tumors with ppillry rhiteture. Adv Ant Pthol 2011;18: GESDAV; liensee GESDAV. This is n open ess rtile liensed under the terms of the Cretive Commons Attriution Non-Commeril Liense ( whih permits unrestrited, non-ommeril use, distriution nd reprodution in ny medium, provided the work is properly ited. Soure of Support: Nil, Conflit of Interest: None delred. J Mol Pthophysiol Apr-Jun 2014 Vol 3 Issue 2 29