








































Tissue-Based Immunohistochemical Markers for 
Diagnosis and Classification of Renal Cell Carcinoma
Liang G. Qu,1,2 Vaisnavi Thirugnanasundralingam,3 Damien Bolton,1,2  
Antonio Finelli,4 Nathan Lawrentschuk2,3,5,6

1 Department of Urology, Austin Health, Heidelberg, Australia, 2 Department of Surgery, University of Melbourne, Australia, 3 Department of Urology, Royal Melbourne 
Hospital, Melbourne, Australia, 4 Division of Surgical Oncology, Princess Margaret Hospital, University Health Network, University of Toronto, Canada, 5 Department of 
Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia, 6 EJ Whitten Prostate Cancer Research Centre, Epworth Healthcare, Melbourne, Australia

Abstract

The development and description of renal cell carcinoma (RCC) subtypes has led to an increase in demand for tissue 
biomarkers. This has implications not only in informing diagnosis, but also in guiding treatment selection and in 
prognostication. Although historically, many immunohistochemical (IHC) stains have been widely characterized for 
RCC subtypes, challenges may arise in interpreting these results. These may include variations in tumor classification, 
specimen collection and processing, and IHC techniques. In light of the reclassification of RCC subtypes in 2016, 
there remains a requirement for a comprehensive outline of tissue biomarkers that may be used to differentiate 
between RCC subtypes and distinguish these from other non-renal neoplasms. In this review, concise summaries of 
the commonest RCC subtypes, including clear cell, papillary, and chromophobe RCC, have been provided. Important 
differences have been highlighted between chromophobe RCC and renal oncocytomas. An overview of the current 
landscape of tissue biomarkers in other RCC subtypes has also been explored, revealing the variable staining results 
reported for some markers, whilst highlighting the essential markers for diagnosis in other subtypes.

Introduction

Classifying renal cell carcinoma (RCC) into its various subtypes relies on a range of diagnostic techniques. These 
involve the analysis of anatomical, morphological, immunohistochemical (IHC), and molecular characteristics. 
IHC tissue biomarkers have maintained a useful role in aiding the diagnosis and subtyping of RCC [1]. In addition, 
tissue biomarkers may aid in the differentiation of non-renal neoplasms or metastatic disease. Its other uses include 
prognostication, as well as guidance of treatment selection [2,3].

Advances have been made in IHC staining for RCC classification; however, challenges arise in the subtyping of RCC. 
Substantial staining heterogeneity exists across and within tumor subtypes [4]. Variations in processing may lead 
to inconsistencies in reported immunoreactivity or staining patterns [4]. Ongoing revision of the classification of 
renal cell tumors (Table 1) by the World Health Organization and International Society of Urological Pathology 
creates difficulty in interpreting older literature [5,6]. There is increasing demand for smaller volume samples 
to be analyzed, as diagnostic biopsies are performed more frequently. Although some of the described markers 
may not yet be commonly encountered in daily clinical practice, IHC staining remains useful in indicating 
the presence or absence of such markers, and in relaying quantitative information such as staining extent.  

Key Words Competing Interests Article Information

Tissue-based markers, immunohistochemistry, 
renal cell carcinoma, cancer subtyping.

None declared. Received on June 23, 2020 
Accepted on August 3, 2020

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This review provides an update on the current landscape 
of tissue biomarkers for the diagnosis and classification 
of common RCC subtypes. 

Clear Cell RCC
Clear cell RCC (ccRCC) is responsible for approximately 
75% of diagnosed RCCs [5]. Its staining profile has been 
widely characterized; however, markers are still being 
described that may aid differentiation of ccRCC from 
other subtypes (Table 2). Carbonic anhydrase 9 (CAIX), 
a transmembrane protein responsible for CO2 transfer, 
stains along membranous non-necrotic areas [7,8].  
A transmembrane mucin protein, epithelial membrane 
antigen (EMA), may also be present in up to 85% of 
specimens [9,10]. Human kidney injury molecule-1 
(hKIM-1) is a type 1 transmembrane glycoprotein 
found in injured proximal tubules [11]. This marker can 
be expressed in ccRCCs but may also be found in other 
clear cell carcinomas of the ovaries or endometrium.

Cy tokeratin (CK) staining in ccRCC may vary 
depending on the antibody used and the specific CK 
studied. Immunoreactivity in 60% of ccRCC specimens 
may be achieved for CK8 using CAM 5.2 antibody [12]. 
ccRCC does not typically stain for CK7 [8]. CK19 
antibody may result in infrequent immunoreactivity in 
20% of specimens [13]. Broad spectrum CK (pan-
c y tokerat i n) may be detec ted usi ng A E1/A E3 
antibodies [14]. ccRCCs are not immunoreactive to 
34βE12, an antibody for high molecular weight CK 
(HMWCK) [13]. Vimentin, an intermediate filament 
protein found in mesenchymal cells, may be detected in 
87% of specimens [15,16]. Lectins, carbohydrate-binding 
proteins, may also be used as markers in RCC. 

TABLE 1.

 The WHO/ISUP classification of renal cell tumors, 2016

The classification of renal cell tumors as described by 
World Health Organization and International Society 
for Urological Pathology, in 2016.

Renal Cell Tumors

Clear cell RCC

Multilocular cystic renal neoplasm of low malignant potential

Papillary RCC

Hereditary leiomyomatosis and renal cell carcinoma-associated RCC

Chromophobe RCC

Collecting duct carcinoma

Renal medullary carcinoma

Microphthalmia-associated transcription family translocation RCC

Succinate dehydrogenase-deficient RCC

Mucinous tubular and spindle cell carcinoma

Tubulocystic RCC

Acquired cystic disease-associated RCC

Clear cell papillary RCC

RCC, unclassified

Papillary adenoma

Renal oncocytoma

Previously, galectin-1 (51%) and galectin-3 (78%) have 
been detected in ccRCC [17].

It is important to note that a number of mark ers 
produce negative immunoreactivity in ccRCC. Alpha-
methylacyl coenzyme A racemase (AMACR), an enzyme 
found in peroxisomes and mitochondria involved in 
fatty acid oxidation, does not typically stain in ccRCC 
tissue [8]. There is usually minimal immunoreactivity 
for parvalbumin, a calcium-binding albumin protein, 
and similar negative staining for claudin 7, 8, and  
CD117 [16,18-21]. E-cadherin is also ty pically not 
expressed, although may be detectable in tumors of 
higher grade [10,22,23]. Kidney-specif ic cadherin 
(Ksp-cadherin), detectable in the distal convoluted 
tubules, can be expressed in moderate intensity in 
some specimens (30%) [20]. BRCA1-associated protein 
1 (BAP1), a protein with deubiquitinase properties, 
expresses nuclear staining in up to 81% of ccRCCs; 
wherein a loss of expression may be associated with 
higher grade of disease [24].

Sensitive but non-specific markers may prove useful 
in confirming RCCs, especially in determining the 
origin of metastatic deposits. RCC marker (RCCM), an 

Abbreviations 

AMACR  alpha-methylacyl coenzyme A racemase
BAP1 BRCA1-associated protein 1
CAIX carbonic anhydrase 9
ccRCC clear cell RCC
CD10 cluster differential marker 10
chRCC chromophobe RCC
CK cytokeratin
EMA epithelial membrane antigen
hKIM-1 human kidney injury molecule-1
HMWCK high molecular weight CK
IHC immunohistochemical
MiT  microphthalmia-associated transcription
RCC renal cell carcinoma
RCCM RCC marker
RO renal oncocytoma

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antibody directed at the brush border of the proximal 
tubule, is present in 85% of ccRCC specimens [25]. 
However, it may also be detected in 27% of non-renal 
carcinoma specimens, including Müllerian-derived 
tumors with clear cell morphology, rendering it a  
non-specific marker for RCC [26]. Similarly, cluster 
differential marker 10 (CD10), is expressed in 94% of 
ccRCC specimens but may be detectable in many non-
renal tumors [27].

ccRCC may appear similar to chromophobe RCC 
(chRCC) because of their shared clear and eosinophilic 
morphology. To minimize the number of markers used 
to differentiate tumor subtypes, a suggested panel of 
IHC markers should include vimentin, RCCM, CAIX, 
Ksp-cadherin, CD117, and parvalbumin.

Papillary RCC
Papillary RCC (pRCC) is the second most common 
RCC subtype, representing 15% of diagnosed RCCs [5]. 
pRCCs demonstrate diffuse immunoreactivity to AE1/
AE3 antibody and CAM 5.2 antibody, no reactivity to 
34βE12, and strong membranous staining for CK7 [28]. 
Roughly 90% of pRCCs will express some CK19 on 
staining [13]. Other markers that are immunoreactive 
include AMACR, vimentin, RCCM, EMA, hKIM-1 and 
CD10 [11,25,27,29-31].

E-cadherin expression has been inconsistently 
described, likely because of variations in tumor grade or 
type, and in technique and processing [22]. Specimens 
were more likely to express E-cadherin if they were 
higher grade or if they were type 2 pRCC [22]. pRCCs 
do not express Ksp-cadherin [20]. Importantly, pRCC 

TABLE 2.

  Summary of immunohistochemical markers for common renal cell tumor subtypes A summary of the commonly 
described immunohistochemical markers and their expression is listed for clear cell RCC, papillary RCC, 
chromophobe RCC, and renal oncocytoma.

Immunohistochemical marker ccRCC pRCC chRCC Renal oncocytoma

Pan-cytokeratin 
(AE1/AE3)

+ + + variable

CK7 −
Type 1: + 
Type 2: −

+ −

CK8/CK18 
(CAM 5.2)

+ + + +

CK19 − + − −

HMWCK (34βE12) − − − −

EMA + + + +

E-cadherin − variable + +

Ksp-cadherin − − + +

CAIX + − − −

AMACR − + − −

Vimentin + + − −

Parvalbumin − variable + +

c-Kit/CD117 − − + +

CD10 + + − −

RCCM + + − −

hKIM-1 + + − −

Caveolin-1 + + + −

S100A1 + + − +

+ ≥ 50% staining; − < 50% staining.

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usually do not stain for CAIX, though some specimens 
may be weakly immunoreactive near necrotic areas [8].  
There is variable staining for parvalbumin but typically 
negative staining for CD117 [16,19,32]. Reported data for 
membranous staining of claudin 7 range from 28% to 
78% of pRCCs [33,34]. Claudin 8 does not stain well in 
pRCCs in roughly 14% of specimens [34]. Up to 83% may 
express galectin-1, whilst less than 6% of pRCC stain for 
galectin-3 [17]. BAP1 is reported to be expressed across 
all pRCC specimens [24].

To assist with classifying a RCC with papillary features, 
a marker panel should consist of CK7, AMACR, CD10, 
RCCM, TFE3, and CD57 [30,35].

Chromophobe RCC
Chromophobe RCC (chRCC) represents up to 11% of 
diagnosed RCCs [7]. chRCC specimens are typically 
immunoreactive to CAM 5.2 antibody, AE1/AE3 
antibody, as well as CK7 [7]. chRCC do not usually 
express CK19 or HMWCK [13].

Ty pic a l ly, ch RCC s sta i n posit ive for EM A, 
E-cadherin, and Ksp-cadherin [10,20,22,36]. chRCCs 
are immunoreactive for parvalbumin and CD117 in 
most specimens [16,37]. chRCCs may also demonstrate 
immunoreactivity for tight junction proteins, claudin 7 
(91%), and less frequently, claudin 8 (27%) [21,34]. These 
tumor subtypes highly express galectin-1 (100%), as 
well as galectin-3 (63%) [17]. BAP1 may be expressed in 
up to 77% of specimens [24]. Rh family C glycoprotein 
(RHCG) as a membranous stain, is homogeneously 
expressed across chRCC specimens [38]. It is also 
expressed in renal oncocytomas, although staining 
patterns may differ in comparison [38]. Long non-
coding RNA LINC01187 has also been studied. chRCC 
specimens demonstrate widespread expression of 
LINC01187 using RNA in situ hybridization, although 
this may also be identified in renal oncocytomas [38].

chRCCs do not express vimentin, although specimens 
may stain positive in sarcomatoid areas [7,15,39]. CAIX, 
hKIM-1, CD10, RCCM and AMACR are also not 
typically expressed in chRCCs [7,11,27,29].

Renal Oncocytoma
Renal oncocy tomas (ROs) remain challenging to 
diagnose because they share morphological and IHC 
features with chRCC. The IHC profile of ROs consist of 
variable immunoreactivity to AE1/AE3 antibody (49%) 
and CK19 (40%), while no expression is demonstrated 
for HMWCK [13]. ROs may stain for CAM 5.2 
antibody [40].

ROs can also be immunoreactive for parvalbumin, 
CD117, E-cadherin, and sometimes EMA (52%) 
[10,16,36,37]. They may express Ksp-cadherin in up 
to 76% of specimens [20]. There can be membranous 
staining for claudin 7 in 55% and mixed pattern 
expression of claudin 8 in 92% of specimens [21,33,34]. It 
is important to note that ROs stain negative for vimentin, 
AMACR, CAIX, CD10, and RCCM [27,29,30,39,41]. 
Limited staining has been reported for hKIM-111.

Several markers to distinguish between ROs and 
chRCCs have been investigated. ROs typically stain 
negative for Hale’s colloidal iron stain; however, 
variability in processing and technique has affected 
the interpretability and reproducibility of this staining 
technique [10]. CK7 staining may demonstrate focal 
positivity in ROs, which is in contrast to the diffuse 
staining observed in chRCCs [39]. S100A1, a calcium-
binding protein, demonstrates consistent and diffuse 
cytoplasmic staining in ROs compared with chRCC, 
in which the positive staining rate for S100A1 is 
considerably lower [42]. Caveolin-1, a scaffolding protein, 
which was originally described as demonstrating 
expression in chRCC and not in ROs, has since been 
reported with variable expression and staining pattern, 
likely due to inconsistencies among subtypes [39,43-45].

Additional markers are currently being explored. 
Amylase α1A, a salivar y-ty pe digestive enzyme, 
produces 100% staining in RO specimens, compared 
with only 13% of chRCCs [46]. Wnt-5a, involved in 
tumor development, similarly produces 100% staining 
in RO specimens while only 16% of chRCCs may stain 
positive [47]. FXYD2, a marker coding for a subunit 
of a distal tubule Na/K ATPase, stains in 17% of ROs, 
compared with 96% in chRCCs [48]. Ankyrin-repeated 
protein with a proline-rich region, a muscle protein, was 
present in 86% of ROs, compared with 0% in chRCC 
specimens [49]. CD63, a glycoprotein investigated 
for differential staining patterns, produces apical/
polar staining in 94% of ROs, which is in contrast 
to the diffuse staining pattern observed in 96% of 
chRCCs [50]. Transforming growth factor β1, a cytokine, 
demonstrates predominantly cytoplasmic staining in 
ROs, while producing membranous staining in chRCC 
specimens [51].

Other novel markers include FOXI1, a transcription 
factor identified in intercalated cells (positive in 
ROs) [52], ELA, a ligand of apelin receptor (positive in 
ROs) [52], caspase 3, a protease involved in apoptosis 
(positive in chRCCs) [53], nuclear expression of leptin 
(in ROs) [54], loss of RB1 (in chRCCs) [55], and nuclear 
staining of tyrosine kinase ERBB4 [55].

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Other RCC Subtypes
In clear cell papillary RCC (ccpRCC), there is diffuse 
positive cytoplasmic immunoreactivity for CK7. In 
addition, there can be a diffuse membranous expression 
of CAIX as in ccRCC; however, a unique “cup-like” 
pattern may be identified on basolateral tumor cells [8]. 
AMACR is not usually expressed in ccpRCC. There 
can be variable expression for HMWCK using 34βE12 
antibody [7]. In contrast to ccRCCs, this subtype is 
negative for CD10 and positive for CK7. Unlike pRCC, 
this subtype is negative for AMACR and CD10.

Microphthalmia-associated transcription (MiT) 
family translocation carcinomas warrant careful 
discrimination from their morphologically similar 
counterparts, namely ccRCC and pRCC, because of 
the differences in disease outcome, prognosis, and 
management [56]. MiT family translocation carcinomas 
do not express CKs or EMA but do express CD10 and 
RCCM. Although the primary diagnostic modality is a 
fluorescence in situ hybridization assay, IHC markers 
may be used to distinguish MiT family translocation 
RCCs [57]. Translocation RCCs involving chromosome 
Xp11.2 are negative for CK7 and CAIX, but positive 
for AMACR [29]. A specific IHC marker, TFE3, may 
be used to identify this transcription factor that is 
overexpressed in this particular translocation [8]. A 
similar translocation-related marker, TFEB, may be 
used to distinguish cells affected by a translocation at 
chromosome 6p21 [58]. In relation to both chromosomal 
loci, an additional marker, cathepsin-K, may also be 
overexpressed and detectable in both Xp11.2 and 6p21 
translocation tumors. Cathepsin-K is expressed in 
TFEB translocation RCCs, and in up to 60% of TFE3 
RCCs [59,60]. IHC markers can be used as a supportive 
aid to diagnosis, but must be cautiously supplemented by 
other diagnostic tools, because of the occurrence of false 
positive and false negative results [61].

Acquired cystic disease-associated RCCs are slow-
growing tumors that occur within cysts. These tumors 
can occur multi-focally and bilaterally [14,62]. Their 
diagnosis can of ten be made according to their 
characteristic morphological features; however, IHC 
markers may assist with diagnosis. This particular 
subtype of RCC is often immunoreactive to AMACR, 
AE1/AE3 antibody, CAM 5.2 antibody, vimentin, CD10, 
and RCCM. They have been reported to demonstrate 
variable expression for CAIX and CK7 [62,63].

Tubulocystic RCCs, although similar to pRCCs 
morphologically, may be distinguished using IHC 
markers. These tumors stain positive for CK7, CD10, 
PAX2, PAX8, and diffusely for AMACR [29]. In a study of  
3 tubulocystic RCC specimens, all 3 cases stained 
positive for CK19, as well as vimentin, while being 
negative for HMWCK [15].

IHC markers for succinate dehydrogenase-deficient 
RCCs have been characterized in limited reports. These 
tumors have variable CK expression but have positivity 
for PAX8, EMA, and Ksp-cadherin. Typically, these 
tumors stain negative for vimentin, CD117, RCCM, and 
CAIX [64,65]. These tumors require a loss of the SDHB 
gene, which codes a subunit for succinate dehydrogenase 
enzyme [64]. A negative stain for SDHB can be useful to 
confirm this diagnosis.

It is important to differentiate collecting duct 
carcinomas from urothelial carcinomas. These tumors 
stain positive for CK5/6, CK7, CK8, CK19, as well as for 
HMWCK [15] and are immunoreactive for vimentin, 
PAX2, and PAX8 [10,15]. They usually stain negative for 
CD10. In addition to PAX8, urothelial markers p63 and 
GATA3 may be used to rule out a urothelial tumor [30].

Renal medullary carcinoma is closely related to 
collecting duct carcinomas and may be identified in 
individuals with sickle cell trait or anemia [66,67].  
This subtype demonstrates immunoreactivity for CK7 
and AE1/AE3 antibody but not to 34βE12 [15]. There is 
variable EMA expression. These tumors stain positive for 
PAX2 and PAX8. SMARCB1, a nuclear transcriptional 
regulator, can be used to distinguish renal medullary 
carcinoma from collecting duct carcinoma [68]. Another 
transcription factor, OCT3/4, can be used as a marker  
to distinguish this tumor from urothelial or collecting 
duct carcinomas [69].

Multilocular cystic renal cell neoplasms of low 
malignant potential demonstrate IHC features that 
are identical to those found in low-grade ccRCCs. This 
subtype is immunoreactive to CAM 5.2 antibody, EMA, 
CK7, CAIX, and PAX2 [70,71]. Variable expression has 
been reported for CD10 [70,71].

Histologically, hereditary leiomyomatosis renal cell 
carcinoma-associated RCC (HLRCC) was historically 
reported as being similar to type 2 pRCC or collecting 
duct carcinomas. In these tumors, there can be positive 
staining for CK7, CAM 5.2 antibody, and CD10. The 
stroma is negative for CD117. Loss of the fumarate 
hydratase gene is specific for HLRCC [72]. Because 
of increasing fumarate, IHC staining may result 
from accumulating S-(2-succinyl cysteine) (S2C), 
where strong nuclear and cytoplasmic expression has 
been described. S2C can, however, be found in type  
2 pRCCs [72].

Mucinous tubular and spindle cell carcinoma 
(MTSCC) displays several IHC similarities to pRCC, 
despite being genetically dissimilar. These tumors are 
immunoreactive for AMACR, CK7, PAX2, E-cadherin 
and EMA, but stain negative for RCCM, 34βE12, and 
CD117 [15,73,74]. There can be variable staining for 
vimentin [15]. MTSCC differs from pRCC, with a lower 

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level of staining for CD10 (15% versus 100%) [73]. Reports 
have also described the in situ hybridization expression 
of VSTM2A. VSTM2A is expressed in moderate to high 
levels in MSTCC, with a reported diagnostic area under 
receiver operating characteristics curve of 99.2% [75].

Other Tissue Markers
Other useful markers may help distinguish RCC from 
non-renal cell tumor origins. PAX2 and PAX8 are 
transcription factors implicated in kidney and Müllerian 
organ development [30,76]. PAX2 and PAX8 are usually 
expressed and found diffusely in normal kidney tissue; 
however, they are also present in up to 90% of renal 
neoplasms. PAX2 differs from PAX8 in that it is not 
usually expressed in ROs or chRCCs. In addition, 
urothelial carcinomas do not express PAX2 or PAX8, 
thereby demonstrating their utility in determining 
tumor origin [77].

GATA3, an endothelial cell transcription factor, is a 
marker for urothelial carcinoma that consistently stains 
negative in RCC specimens [78]. CA-125, a marker 
classically associated with ovarian cancer, may also 
be used as a negative marker for RCCs, distinguishing 
them from other tumors of clear cell morphology [26]. 
CK20 is a useful negative marker for ruling out renal 
cell neoplasms [30]. Most RCCs typically stain negative 
for CK20, with the exception of previously reported 
eosinophilic solid cystic RCCs [79]. These may be useful 
in ruling out other CK20+ tumors, such as urothelial, 
ovarian, or colorectal carcinomas. Other markers useful 
in work-up for ruling out non-renal neoplasms include 
RCCM, CD10, vimentin and CKs.

Add it iona l t is sue-ba sed ma rkers a re bei ng 
investigated, as guided by the recent advances in the 
study of RCC genomic alterations. Commonly reported 

altered genes for ccRCC include VHL, PBRM1, and 
SETD2 [80]. pRCC may demonstrate MET mutation, 
while chRCC may exhibit TP53 or PTEN mutations [81]. 
Some genomic alterations may also aid differentiation of 
chRCC and RO [81]. Although genomic alterations have 
largely been studied using next-generation sequencing 
techniques, some have been adapted to IHC. VHL,  
a tumor suppressor gene, is commonly inactivated in 
both hereditary and sporadic ccRCCs [82]. The IHC 
detection of its gene product is expressed in up to 90% 
of primary renal tumors and 86% of metastatic RCC 
specimens [83]. However, it may also be identified 
in non-renal tumors such as clear cell carcinomas 
of the ovary or uterus [83]. PBRM1 has also been 
studied as an IHC marker; however, its application 
is mainly to aid prognostication. A loss of PBRM1 
expression is associated with late tumor stage and poor 
differentiation [84]. Similarly, IHC SETD2 expression 
has been identified in metastatic RCC, and demonstrates 
utility in determining likely prognostic outcomes [85]. 
Future studies should continue to investigate the 
adaptation of altered gene products to the field of 
diagnostic tissue markers.

Conclusion
The characterization of RCC subtypes using tissue 
biomarkers must undergo ongoing review as new 
markers and techniques are developed and described. 
IHC staining remains a useful method to subtype 
RCCs and to distinguish them from non-renal tumors, 
especially in small tissue volume specimens, such as 
in metastatic tissue biopsies. More study is required 
to further characterize the subtypes of RCC to further 
delineate them and improve the accuracy of diagnosis, 
treatment, and prognostication. 

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