REVIEW ARTICLE

The Use of Immunohistochemistry in the Diagnosis of

Metastatic Clear Cell Renal Cell Carcinoma
A Review of PAX-8, PAX-2, hKIM-1, RCCma, and CD10
Ankur R. Sangoi, MD,*w Jason Karamchandani, MD,* Jinah Kim, MD, PhD,*
Reetesh K. Pai, MD,* and Jesse K. McKenney, MD*
Downloaded from https://journals.lww.com/anatomicpathology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3ltH2fbMApE1gL6S/k+zqpFgJCkW638MJjqtQA8Jsg2s= on 12/29/2018

and specific for metastatic CC-RCC and should replace the

Abstract: The diagnosis of metastatic clear cell renal cell carcinoma
may be difficult in some cases, particularly in the small image-
guided biopsies that are becoming more common. As targeted
therapies for renal cell carcinoma are now standard treatment, the
recognition and diagnosis of renal cell carcinoma has become even
more critical. Many adjunctive immunohistochemical markers of
renal epithelial lineage such as CD10 and RCCma have been
proposed as aids in the diagnosis of metastatic renal cell carcinoma,
but low specificities often limit their utility. More recently described
markers (PAX-2, PAX-8, human kidney injury molecule-1,
hepatocyte nuclear factor-1-b, and carbonic anhydrase-IX) offer
the potential for greater sensitivity and specificity in this diagnostic
setting; however, knowledge of their expected staining in other
neoplasms and tissues is critical for appropriate use. In this review,
we discuss the most widely used immunohistochemical markers of
renal lineage with an emphasis on their sensitivity and specificity
for metastatic clear cell renal cell carcinoma. Subsequently, we
present a variety of organ-specific differential diagnostic scenarios
in which metastatic clear cell renal cell carcinoma might be
considered and we propose immunopanels for use in each situation.
Key Words: renal cell carcinoma, clear cell, metastatic, immunohis-
tochemistry, PAX-8, PAX-2, hKIM-1, RCCma, CD10
(Adv Anat Pathol 2010;17:377–393)
older standards such as CD10 and renal cell carcinoma
monoclonal antibody (RCCma).1,9 In this review, we discuss
the antibodies with the most utility in the diagnosis of CC-
RCC, review the nonrenal tissues known to express them, and
present the spectrum of differential diagnostic scenarios that
may be encountered.
IMMUNOHISTOCHEMICAL MARKERS
PAX-8
PAX-8, a member of the human paired boxed gene
family, was originally described as an important transcription
factor in the development of thyroid and renal tumors.10 Only
1 study has evaluated PAX-8 staining in a large series of
metastatic CC-RCCs, and reported high sensitivity (94%) and
overall specificity (88%).1 Most studies reporting immunohis-
tochemical expression of this marker have focused on
expression in renal, thyroid, and epithelial ovarian neo-
plasms11–16 with infrequent reactivity reported in urothelial
carcinoma.9,14,17 Two recent studies have investigated PAX-8
reactivity in pancreatic neuroendocrine tumors,18,19 and 1
study has documented frequent immunoreactivity in Merkel

C lear cell renal cell carcinoma (CC-RCC) remains one of

the great mimickers in surgical pathology (perhaps
second only to malignant melanoma). It can metastasize to
virtually any body site1–3 and can have significant morpho-
logic overlap with other nonrenal neoplasms and normal
tissues.4 CC-RCC also has the propensity to metastasize years
after the initial diagnosis, making its diagnostic consideration
more problematic.5 As advances in image-guided biopsies
make a wide variety of body sites more accessible, we have
encountered an increasing number of cases in which a
diagnosis of metastatic CC-RCC is being considered from
an extremely small tissue sample.6–8 In this setting, adjunctive
immunohistochemical studies often play a significant diag-
nostic role. Although there is a long history of using
immunohistochemistry for the diagnosis of metastatic CC-
RCC, several novel putative CC-RCC markers have become
available in the past few years. Recent studies propose that
these newer markers [PAX-8, PAX-2, and human kidney
injury molecule-1 (hKIM-1)] are significantly more sensitive
From the *Department of Pathology, Stanford University Medical
Center, Stanford; and wDepartment of Pathology, El Camino
Hospital, Mountain View, CA.
Reprints: Ankur R. Sangoi, MD, Department of Pathology, El Camino
Hospital, GC-33, Mountain View, CA 94040 (e-mail: asangoi2@
yahoo.com).
Copyright r 2010 by Lippincott Williams & Wilkins
cell carcinoma, thymoma, and medulloblastoma/medullo-
myoblastoma.9
Nuclear immunoreactivity is considered positive PAX-
8 staining, but staining intensity may vary substantially
between cases (Fig. 1B). Interpretative caution should be
used in small biopsy samples as admixed B lymphocytes
show strong PAX-8 reactivity.9
PAX-2
Similar to PAX-8, PAX-2 is also a member of the
human paired boxed gene family and a renal cell-lineage
transcription factor. Both markers share coexpression in
embryonal and renal tissues.10,14 Although reactivity for both
markers in RCC was originally reported more than decade
ago,10,20 PAX-2 has been more frequently studied as a
putative marker of CC-RCC, including metastatic tu-
mors.21–30 Of the few studies reporting PAX-2 reactivity in
metastatic CC-RCC, results show moderate sensitivity (47%
to 85%) and high overall specificity (90% to 97%).1,21,22,30
Nonrenal neoplasms with well-documented PAX-2
immunoreactivity include tumors of müllerian origin (eg,
uterine carcinomas, ovarian surface epithelial neoplasms, and
endocervical carcinomas),9,11,30–34 parathyroid tumors,9,21
epididymal tumors,21 and lobular breast carcinoma.9,32 One
study has also reported PAX-2 staining in testicular yolk sac

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Sangoi et al Adv Anat Pathol  Volume 17, Number 6, November 2010

A B

C D

E F

G H

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Adv Anat Pathol  Volume 17, Number 6, November 2010
tumors and Merkel cell carcinoma.9 Variable PAX-2 reactivity
has been described in some soft tissue sarcomas.9
Nuclear immunoreactivity is considered positive PAX-
2 staining (Fig. 1C). Interpretative caution should be used
in small biopsy samples as admixed B-lymphocytes show
strong PAX-2 reactivity.9 Although both PAX-2 and PAX-
8 are useful markers of CC-RCC (primary and metastatic),
it is our experience that PAX-8 has superior performance,
given the generally stronger staining pattern for PAX-8 and
the increasingly lower sensitivity of PAX-2 in our clinical
diagnostic immunohistochemistry laboratory. Although
using a more concentrated dilution of anti-PAX-2 will
increase sensitivity to a level comparable with PAX-8, we
have earlier shown that in certain instances this reduces
specificity for metastatic CC-RCC, particularly in the
distinction from lesions of the adrenal cortex.35
Human Kidney Injury Molecule-1
Although most studies of hKIM-1 are in the medical
renal literature given its association with proximal tubular
injury/ischemia, hKIM-1 has been recently reported as a
diagnostic marker of CC-RCC and ovarian clear cell
carcinoma.9,36,37 Variable reactivity with this marker has also
been reported in hepatocellular carcinoma (HCC), colonic
adenocarcinoma, urothelial carcinoma, and germ cell tu-
mors.9,36–39 The 2 studies specifically investigating hKIM-1
reactivity in metastatic CC-RCC show good sensitivity (78%
to 92%) and high overall specificity (86% to 98%).1,37
Membranous and/or cytoplasmic reactivity is considered
positive hKIM-1 staining (Fig. 1D). Although the studies
reporting hKIM-1 expression were not from a commercially
available source, this is currently under development and
should be available in the near future (personal communica-
tion, J.V. Bonventre, MD, PhD, Boston, MA). Some
antibodies that share significant homology with hKIM-1 are
available (TIM-1; R&D Systems, Minneapolis, MN and anti-
rat KIM-1; Immunology Consultants Laboratory, Newberg,
OR), but are not yet fully evaluated in a diagnostic setting.
Renal Cell Carcinoma Monoclonal Antibody
RCCma, which is reactive to a proximal nephrogenic
renal antigen, was first described as a highly sensitive (84%)
and specific (83%) marker of metastatic RCC over 30 years
ago.40 The initial description suggested poor diagnostic speci-
ficity with documented reactivity in 78% of mammary carci-
nomas, 100% of parathyroid tumors, and 50% of germ cell
tumors.40 Several more recent studies have also highlighted
specificity problems by showing RCCma staining in a variety
of tumors.21,41 Overall specificities for metastatic RCC (either
CC-RCC or unspecified type) with anti-RCCma range from
48% to 100%, and sensitivities range from 27% to 90%.21,41–43
Membranous and/or cytoplasmic reactivity is considered
positive RCCma staining (Fig. 1E). In our opinion, for most
differential diagnostic scenarios PAX-8, PAX-2, and hKIM-1
should replace RCCma in routine diagnostic practice.
FIGURE 1. Patterns of immunoreactivity in clear cell renal cell carcinoma. A, Hematoxylin and eosin-stained section; B, PAX-8: nuclear
reactivity; C, PAX-2: nuclear reactivity; D, human kidney injury molecule-1: membranous and cytoplasmic staining; E, renal cell
carcinoma monoclonal antibody: membranous and cytoplasmic staining; F, CD10: membranous and cytoplasmic staining; G, carbonic
anhydrase-IX: predominantly membranous reactivity; and H, hepatocyte nuclear factor-1-b: nuclear reactivity.
r 2010 Lippincott Williams & Wilkins
Immunohistochemistry in Metastatic RCC
CD10
Since the initial description of CD10 as a proximal
nephron marker over 20 years ago,44 CD10 immunoreactivity
in CC-RCC has been well established.45,46 Some studies have
reported sensitivities for metastatic CC-RCC ranging from
83% to 100%43,47; however, the fact that CD10 immunor-
eactivity is seen in a wide variety of nonrenal neoplasms has
been extensively reviewed and recognized.45,46,48–50
Cytoplasmic and/or membranous reactivity is consid-
ered positive CD10 staining (Fig. 1F). As in the statement
for RCCma, it is our opinion that with few exceptions,
PAX-8, PAX-2, and hKIM-1 should replace CD10 in
routine diagnostic practice.
Carbonic Anhydrase-IX and Hepatocyte Nuclear
Factor-1-b
Although the antibody carbonic anhydrase-IX (regulated
by hypoxia-inducible factor-1) has been described as a sensitive
marker for CC-RCC (Fig. 1G), its expression is well recognized
in a wide variety of other common nonrenal neoplasms,
particularly in areas associated with ischemia or necrosis.51,52
Hepatocyte nuclear factor-1-b, originally reported
as a marker of ovarian clear cell carcinoma,53 has since
been described with immunoreactivity in many nonrenal
neoplasms with a clear cell phenotype in addition to CC-
RCC (Fig. 1H).54–57 As such, these markers are not as
thoroughly studied at present time, and may lack diagnostic
specificity in cases where metastatic CC-RCC is in the
differential diagnosis, particularly in small biopsy samples.
DIFFERENTIAL DIAGNOSTIC SCENARIOS
Metastatic Clear Cell Renal Cell Carcinoma in
Carcinoma of Unknown Primary (General
Comments)
Given modern imaging techniques, the possibility of a
radiographically undetectable, occult primary RCC that has
given rise to metastatic disease is extremely improbable. In
some patients with multicystic kidneys, either from auto-
somal-dominant disease or dialysis, it is possible that some
imaging studies may be inconclusive. However, in most cases,
abdominal computed tomography studies that include the
kidneys offer the most specific test for excluding a primary
renal carcinoma. Using immunohistochemistry for diagnos-
ing CC-RCC in the absence of a renal mass or lesion is ill-
advised. In most situations, the use of immunohistochemistry
is for the pathologic confirmation of metastatic CC-RCC in
the setting of a suspicious renal mass or in a patient with prior
history of CC-RCC. In rare instances, immunostains may be
used to exclude the possibility that a tumor might be un-
related to a synchronous renal mass or previously treated CC-
RCC. It should be remembered that metastatic RCC may pre-
sent many years after nephrectomy. The diagnostic work-up in
various differential diagnostic scenarios is presented in the
following sections. To facilitate the use of renal epithelial
markers in the work-up of carcinomas of uncertain primary, we
provide a summary of lesions with known immunoreactivity
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Sangoi et al Adv Anat Pathol  Volume 17, Number 6, November 2010

for PAX-2, PAX-8, and hKIM-1 in Table 1. It cannot be 3%.1,58 Although differentiating metastatic CC-RCC from
overemphasized that immunohistochemistry is an adjunct to primary adrenal cortical lesions (including adrenal rests,
the morphologic appearance and the clinical setting. Unusual adrenal cortical hyperplasias, and adrenal cortical adenomas/
immunophenotypes and expression in unexpected tissues and carcinomas) can be made on clinical grounds in many in-
neoplasms invariably occur over time with more frequent use stances, steroid-inactive adrenal cortical lesions and cases
and additional study; therefore, these immunohistochemical with significant morphologic overlap (eg, cytologically bland
stains should always be interpreted within the morphologic metastatic CC-RCC, adrenal cortical lesion with marked
and clinical context. nuclear pleomorphism) can make this distinction challen-
ging.1,59,60 An antibody panel including pankeratin/epithelial
membrane antigen (EMA; reactive in metastatic CC-RCC)
Metastatic Clear Cell Renal Cell Carcinoma and calretinin/inhibin/MelanA (reactive in adrenal cortical
Versus Adrenal Tumors lesions) has been traditionally used in making this distinction.
These immunohistochemical markers are not entirely specific,
Adrenal Cortical Lesions particularly if used in isolation or without a minimum
The frequency of metastatic CC-RCC to the adrenal diagnostic staining intensity threshold.1 Adrenal cortical
gland among reported organ sites from 2 large series is 2% to markers may show some weak cytoplasmic staining in CC-
RCC. The addition of the nuclear marker steroidogenic
factor-1 (also known as adrenal 4 binding protein) to a dia-
TABLE 1. Summary of Lesions With Known Immunoreactivity for gnostic panel offers improved specificity for adrenal cortical
PAX-2, PAX-8, and hKIM-1
lesions (100%) and may also obviate issues of nonspecific
Nonrenal Tumor With cytoplasmic staining.1 Adrenal cortical lesions have not been
Immunoreactivity PAX-2 PAX-8 hKIM-1 reported to express PAX-2, PAX-8, or hKIM-11,36,37;
Breast however, we have noted that nuclear PAX-2 expression
Lobular carcinoma (+) ( ) ( ) may be seen with more concentrated antibody dilutions.35
Central nervous system
Pheochromocytoma
Medulloblastoma ( ) (++) ( )
Medullomyoblastoma ( ) (+++) ( )
Although the distinction of metastatic CC-RCC from
Endocrine pheochromocytoma can be made clinically in most instances,
Thyroid follicular/papillary tumor ( ) (++) ( ) not all patients present symptomatically.13,61 Moreover, the
Parathyroid hyperplasia/tumor (++) (+++) ( ) so-called “clear cell variant” (lipid degeneration) of pheochro-
Gastrointestinal mocytoma may show significant morphologic overlap
Colorectal adenocarcinoma ( ) ( ) (+) with metastatic CC-RCC.62,63 As such, an antibody panel
Hepatocellular carcinoma (+) (+) (+) including PAX-2, PAX-8, or hKIM-1 (reactive in meta-
Neuroendocrine tumor (pancreatic/ ( ) (+++) ( ) static CC-RCC) and chromogranin (reactive in pheochro-
duodenal) mocytoma) may be useful in certain cases. Chromogranin
Pancreatic solid-pseudopapillary tumor ( ) (+) ( ) is recommended over synaptophysin based on occasional
Gynecologic tract synaptophysin reactivity in metastatic CC-RCC (up to
Ovarian clear-cell carcinoma (++) (+++) (+++) 2%, even with >2+ diagnostic staining threshold).1
Uterine clear-cell carcinoma (++) (+++) (+++)
Endocervical adenocarcinoma (++) (++) ( )
Uterine serous carcinoma (++) (+++) (+) Summary: CC-RCC Versus Adrenal Tumor
Ovarian/peritoneal serous tumors (++) (+++) ( )
Useful Panel Versus Metastatic
Endometrioid adenocarcinoma (++) (+++) ( )
Diagnosis CC-RCC
Hematopoietic
B-cell lymphoma (small and large cell) (+) (++) ( ) Adrenal cortical lesion (+): Calretinin*, inhibin*, melanA*, SF-1
Thymoma ( ) (++) ( ) ( ): EMA, PAX-2, PAX-8, hKIM-1
Male reproductive tract Pheochromocytoma (+): Chromogranin
Seminoma ( ) (+) ( ) ( ): EMA, PAX-2, PAX-8, hKIM-1
Yolk sac tumor (++) (+) (+)
Epididymal clear-cell papillary (+++) NA NA *>2+ diagnostic staining intensity/extent thresholds should be maintained.
CC-RCC indicates clear cell renal cell carcinoma; EMA, epithelial
cystadenoma membrane antigen; hKIM-1, human kidney injury molecule-1; SF-1,
Soft tissue sarcoma steroidogenic factor-1.
Clear-cell sarcoma ( ) (+) ( )
Malignant fibrous histiocytoma ( ) (+) ( )
Monophasic synovial sarcoma ( ) (+) ( ) Metastatic Clear Cell Renal Cell Carcinoma
Skin Versus Breast Tumors
Merkel cell carcinoma (++) (+++) ( )
Urinary tract
Given the cyclical histologic changes in the breast64
Clear-cell adenocarcinoma (+) (+++) NA
and various types of mammary clear cells (including
Nephrogenic adenoma (+++) (+++) NA sebaceous, apocrine, endocrine, myoepithelial, glycogen-
Urothelial carcinoma (bladder) ( ) (+) (+) rich, lipid-rich, and mucin-rich),65 it is not surprising that
Urothelial carcinoma (renal pelvis) (+) (++) (+) metastatic CC-RCC may show morphologic overlap with a
primary breast tumor. Most studies using “putative RCC”
hKIM-1 indicates human kidney injury molecule-1; NA, data not markers in breast pathology have focused on differentiating
currently available.
=no staining; +=weak/focal staining; ++=moderately strong/
mammary carcinoma from ovarian or thyroid neoplasms
diffuse staining; +++=strong/diffuse staining. using PAX-8. Although most studies have reported no
expression of PAX-8 in mammary carcinomas,11,33 weak

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Adv Anat Pathol  Volume 17, Number 6, November 2010 Immunohistochemistry in Metastatic RCC

nuclear immunoreactivity has been reported in a small

subset of cases.9 Similarly, PAX-2 immunoreactivity in
breast tumors (particularly lobular carcinoma) is well
described.9,32,66 To date, expression of hKIM-1 has not
been described in breast carcinoma.9,36,37 In addition,
immunoreactivity for the most used breast-lineage markers
mammaglobin, gross cystic disease fluid protein-15, and
GATA3 has not been reported in CC-RCC.67,68
Given their potential for cytoplasmic clearing and infre-
quent immunoreactivity with typical breast markers, differ-
entiating myoepithelial breast lesions from metastatic
CC-RCC can be problematic in a subset of cases. Almost no
data is available for expression of newer RCC markers in
mammary myoepithelial lesions; therefore, myoepithelial
markers are presently the most specific antibodies in this
diagnostic scenario.
Summary: CC-RCC Versus Breast Tumors
Diagnosis Useful Panel Versus Metastatic CC-RCC
Ductal and lobular (+): Mammaglobin, GCDFP-15, GATA3
carcinoma ( ): hKIM-1, PAX-8 (rare weak staining)
Myoepithelial (+): p63, SMA, S-100 protein, calponin,
lesions smooth muscle myosin heavy chain
CC-RCC indicates clear cell renal cell carcinoma; GCDFP-15, gross
cystic disease fluid protein-15; hKIM-1, human kidney injury molecule-1;
SMA, smooth muscle actin.
Metastatic Clear Cell Renal Cell Carcinoma
Versus Lung Tumors
The lungs are the most common site of CC-RCC
metastasis, comprising from 21% to 54% of metastases.1,2,58
Clear cell change can occur in primary bronchogenic squamous
cell carcinoma, adenocarcinoma, or neuroendocrine tumors.69,70
Of the studies reporting hKIM-1 immunoreactivity in nonrenal
tumors,9,36,37 focal, weak hKIM-1 has been reported in only 1
lung adenocarcinoma.9 PAX-2 and PAX-8 staining have not
been reported in lung tumors,9,21 whereas thyroid transcription
factor-1 immunoreactivity has not been reported in RCC.71,72
Importantly, the putative lung marker Napsin A can be
expressed in up to one-third of CC-RCCs and should not be
used in this setting.71
Other lung neoplasms that may show prominent clear
cell phenotypes overlapping with CC-RCC include salivary-
type tumors (most notably acinic cell carcinoma and muco-
epidermoid carcinoma), clear cell (sugar) tumor, and clear cell
mesothelioma.70 Only limited data for hKIM-1, PAX-2, and
PAX-8 expression is available in these rarer lung tumors.9
Summary: CC-RCC Versus Lung Tumors
Useful Panel Versus
Diagnosis Metastatic CC-RCC
Adenocarcinoma with (+): TTF-1, SP-A (limited data)
clear cell change ( ): hKIM-1*, PAX-2, PAX-8
Squamous cell (+): p63, CK5/6
carcinoma
with clear cell change ( ): hKIM-1, PAX-2, PAX-8
Acinic cell carcinoma (+): a-1-antichymotrypsin, amylase
( ): hKIM-1, PAX-2, PAX-8
(limited data for all 3 markers)
(continued)
Useful Panel Versus
Diagnosis Metastatic CC-RCC
Clear cell (sugar) tumor (+): HMB45, MelanA, SMA
( ): hKIM-1, PAX-2, PAX-8
(limited data for all 3 markers)
Clear cell mesothelioma (+): Calretinin, CK5/6, WT-1
( ): hKIM-1, PAX-2, PAX-8
(limited data for all 3 markers)
*Rare reported case of positivity in lung adenocarcinoma.
CC-RCC indicates clear cell renal cell carcinoma; CK, cytokeratin;
hKIM-1, human kidney injury molecule-1; SMA, smooth muscle actin;
SP-A, surfactant apoprotein A; TTF-1, thyroid transcription factor-1.
Metastatic Clear Cell Renal Cell Carcinoma
Versus Gynecologic Tract Tumors
Using immunohistochemistry to distinguish metastatic
CC-RCC from neoplasms of the gynecologic tract is
problematic. In this differential diagnostic category, the novel
CC-RCC markers PAX-8, PAX-2, and hKIM-1 may not be
as useful as the more traditional markers. Both ovarian and
uterine clear cell carcinomas show strong immunoreactivity
with hKIM-1, PAX-2, and PAX-89,16,21,30–33,37,39; however,
CD10 is reportedly negative in most gynecologic carcino-
mas.49,73,74 Similarly, Aries-Stella change shows PAX-8
immunoreactivity without staining for CD10.49,75
Other gynecologic tumors containing clear cells, which
may show morphologic overlap with metastatic CC-RCC,
include vaginal and cervical clear cell adenocarcinomas;
similarly, CD10 is also reportedly negative in these carcinomas
and has been reported as useful in this distinction.49 A detailed
study of the newer CC-RCC markers in these tumors has not
been performed. Trophoblastic tumors, which often show a
clear cell phenotype, are frequently positive for CD10 and
should prompt additional serologic and immunohistochemical
work-up (eg, b-human chorionic gonadotrophin).49
Summary: CC-RCC Versus Gynecologic Tract Tumors
Useful Panel Versus Metastatic
Diagnosis CC-RCC
Ovarian clear cell carcinoma (+): p53*, CK7*, WT-1
(V): ER
( ): CD10, RCCma*
Uterine clear cell carcinoma (+): p53*, CK7*
(V): ER
( ): CD10, RCCma*
*Not entirely specific.
CC-RCC indicates clear cell renal cell carcinoma; CK, cytokeratin;
ER, estrogen receptor; RCCma, renal cell carcinoma monoclonal antibody;
V, variable.
Metastatic Clear Cell Renal Cell Carcinoma
Versus Male Reproductive Tract Tumors
Testis
Of germ cell tumors, seminoma and yolk sac tumors
have the most histologic overlap with CC-RCC. Seminoma
shows no immunohistochemical reactivity with the markers
hKIM-1 or PAX-2,9 but infrequent staining is reported for

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Sangoi et al
PAX-833; PAX-2 (and rarely PAX-8) may show reactivity in
yolk sac tumors and should therefore be used cautiously.9
The marker hKIM-1 can be useful in the differentiation of
CC-RCC from germ cell tumors, and the newer germ cell
markers OCT3/4 (seminoma) and SALL-4 (seminoma and
yolk sac tumor) seem relatively specific. In the category of
sex-cord stromal testicular tumors, both Leydig and Sertoli
cell tumors can show lipid accumulation imparting a clear cell
phenotype.76 Immunoreactivity for typical sex-cord stromal
markers (steroidogenic factor-1 and inhibin) with negative
staining for hKIM-1, PAX-2, and PAX-8 are useful.
Finally, papillary cystadenoma of the epididymis
presents a unique dilemma as it has both morphologic
(clear cell phenotype) and clinical [von Hippel-Lindau
(VHL) disease association with potential for concomitant
RCC] overlap with metastatic CC-RCC. A cytokeratin
(CK)7-positive, CD10-negative phenotype in clear cell
papillary cystadenoma is reported as useful in this
distinction77,78; however, we have anecdotally encountered
a similar tumor in the ovary showing reactivity for CD10
(personal observation). Importantly, PAX-2 (and prob-
ably PAX-8) is not useful in this scenario as it character-
istically has strong expression in clear cell papillary
cystadenoma.21 The expression of hKIM-1 in the epididy-
mis is not known.
Prostate
In the prostate, the most common malignant morpho-
logic mimic of metastatic CC-RCC is prostatic acinar
adenocarcinoma with clear cell change, particularly those of
transition zone origin, with posthormonal therapy, or with a
diffuse Gleason pattern 5 sheet-like growth.76 Although
unlikely to be problematic in most cases, clear cell cribriform
hyperplasia and adenosis (atypical adenomatous hyperplasia)
are some of the most frequently encountered benign lesions
with clear cytoplasm.76,79 These benign and malignant
morphologic mimics of metastatic CC-RCC show negative
immunoreactivity with hKIM-1, PAX-2, and PAX-8 and
positive immunoreactivity for prostate-specific acid, prostate-
specific acid phosphatase, and p63 (p63 staining in basal cells
of benign mimics). A recent study has proposed NKX3.1 as a
useful prostatic epithelial marker.80 PAX-2 staining has been
reported in rare benign prostatic secretory cells within the
central zone, but PAX-8 has not been fully evaluated.81
Summary: CC-RCC Versus Male Genital Tract Tumors
Useful Panel Versus Metastatic
Diagnosis CC-RCC
Testis (+): OCT3/4, SALL4
Seminoma ( ): hKIM-1, PAX-2, PAX-8*
Yolk sac tumor (+): SALL4
( ): hKIM-1
Sex-cord stromal tumor (+): SF-1, inhibin
with clear cells
( ): hKIM-1, PAX-2, PAX-8
Clear cell papillary (+): CK7*
cystadenoma
( ): CD10
Prostate (+): PSA, PSAP, NKX3.1
Prostatic ( ): hKIM-1, PAX-2, PAX-8
adenocarcinoma
Clear cell cribriform (+): PSA, PSAP, p63 (basal cells)
hyperplasia, adenosis
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Adv Anat Pathol  Volume 17, Number 6, November 2010
(continued)
Useful Panel Versus Metastatic
Diagnosis CC-RCC
( ): hKIM-1, PAX-2, PAX-8
*Not entirely specific.
CC-RCC indicates clear cell renal cell carcinoma; CK, cytokeratin;
hKIM-1, human kidney injury molecule-1; PSA, prostate-specific acid;
PSAP, prostate-specific acid phosphatase; SF-1, steroidogenic factor-1.
Metastatic Clear Cell Renal Cell Carcinoma
Versus Other Urinary Tract Tumors
In the setting of metastatic RCC to the urinary bladder,
isolated bladder metastasis in the absence of multiple organ
involvement is extremely rare.82 As such, differentiating meta-
static CC-RCC from a primary vesical urothelial carcinoma
with clear cell features (so-called “glyocogen-rich” variant)
should strongly rely on clinical findings given the infrequent,
but reported immunohistochemical overlap with both
hKIM-1 and PAX-8 in both of these tumors.9,14,17,83 PAX-2
may have utility in this distinction, but has not been fully
studied. We have encountered a small number of invasive
urothelial carcinomas of the renal pelvis showing PAX-8 and
PAX-2 immunoreactivity (15 and 10%, respectively, unpub-
lished data), although others have reported infrequent
staining.84
Clear cell adenocarcinoma of the urinary bladder or
urethra is another tumor showing both morphologic
and immunophenotypic overlap with metastatic CC-RCC,
as both express of CD10, PAX-2, and PAX-8.85,86 Diffuse
strong staining with CK7 and cancer antigen-125 have
been reported in clear cell adenocarcinoma,74,85–88 which
would be uncommon in metastatic CC-RCC. Nevertheless,
clinical (female sex predilection and lack of prior/concur-
rent renal mass) and other morphologic features such as
associated endometriosis and/or papillary, tubulocystic,
and hobnail patterns may be the most useful information in
differentiating clear cell adenocarcinoma from metastatic
CC-RCC.
The solid, clear cell pattern of nephrogenic adenoma
(ie, the diffuse pattern) may arise anywhere along the urinary
tract (including the prostatic urethra) and can be a very close
mimic of metastatic CC-RCC, particularly in a patient with
an uncertain history of renal neoplasia. Given the proposed
renal tubular histogenesis of a subset of nephrogenic adeno-
mas, it is not surprising that they show immunohistochemical
overlap with metastatic CC-RCC with reported positivity for
CD10, PAX-2, and PAX-8.85,86,89–91 To our knowledge,
hKIM-1 expression in nephrogenic adenoma has not been
evaluated. As such, reliance on an admixture of more typical
morphologic patterns of nephrogenic adenoma (ie, papillary,
tubulocystic, hobnail, and thickened basement membrane)
may be the most reliable tool in the distinction from metastatic
CC-RCC.
Ureteral von Brunn nests frequently show clear cell
change, and anecdotally we have seen several CC-RCCs over-
staged in radical cystectomy specimens based on this finding.
Spread of RCC along the ureter would be highly unusual.
Immunohistochemistry is typically not needed for this distin-
ction, but von Brunn nests maintain the typical urothelial
phenotype.
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Adv Anat Pathol  Volume 17, Number 6, November 2010
Summary: CC-RCC Versus Urinary Tract Tumors
Useful Panel Versus
Diagnosis Metastatic CC-RCC
Urothelial carcinoma (+): p63, uroplakin, CK20,
with clear cells CK7*
(“glycogen-rich” ( ): PAX-2, hKIM-1*
variant)
Clear cell (+): CK7, CA125
adenocarcinoma
Nephrogenic None (reliance on background
adenoma morphologic patterns
of nephrogenic adenoma)
*Not entirely specific.
CA-125 indicates cancer antigen-125; CC-RCC, clear cell renal cell
carcinoma; CK, cytokeratin; hKIM-1, human kidney injury molecule-1.
Metastatic Clear Cell Renal Cell Carcinoma
Versus Mediastinal Tumors
Clear cell thymic carcinomas, lymphomas with clear
cell phenotype, and germ cell tumors are the 3 most
common neoplasms of the anterior mediastinum showing
morphologic overlap with metastatic CC-RCC.63,92,93
Germ cell tumors have already been discussed in the male
reproductive tract section and will not be repeated here.
Given the immunohistochemical overlap between hemato-
poietic tumors (lymphomas and thymomas) and renal
neoplasms using markers of the PAX gene family (notably
PAX-2, PAX-5, and PAX-8),9,30,94 these markers may not
be a useful tool in differentiation. Rather, a reliance on
hKIM-1 and lineage-specific markers (CD5 for thymic
tumors and CD20/CD45/CD3/CD43 for lymphomas) are
helpful.
Of the posterior mediastinal tumors, neurogenic
tumors (in particular paraganglioma) may show the most
morphologic overlap with metastatic CC-RCC, and will be
discussed in the soft tissue tumor section.
Summary: CC-RCC Versus Mediastinal Tumors
Diagnosis Useful Panel Versus Metastatic CC-RCC
Thymic clear cell (+): CD5; CD1a in thymic lymphocytes,
carcinoma S100 in interdigitating reticulum cells
( ): hKIM-1
Lymphoma with (+): CD20, CD45, CD43 (CD15/CD30
clear cells for Hodgkin lymphoma)
( ): hKIM-1
CC-RCC indicates clear cell renal cell carcinoma; hKIM-1, human
kidney injury molecule-1.
Metastatic Clear Cell Renal Cell Carcinoma
Versus Head and Neck Tumors
Thyroid
Although the frequency of thyroid metastasis from
CC-RCC among reported organ sites from a single large
series is low (1%),1 it is important to recognize that several
thyroid lesions, both benign (follicular adenoma) and
malignant (follicular and papillary carcinoma), can be
comprised of clear cells mimicking metastatic CC-RCC.63,95
Moreover, acknowledgment of the role of the PAX-8 gene
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Immunohistochemistry in Metastatic RCC
in thyroid development is critical in appreciating immuno-
histochemical overlap in both thyroid tumors and meta-
static CC-RCC.1,9–12,15,96 Immunoreactivity for PAX-2 in
thyroid tumors is predominantly negative (1 case with weak
staining reported),9,97 whereas hKIM-1 is reportedly
negative in thyroid lesions.9,36,37
Parathyroid
Similar to the thyroid, both benign (parathyroid
adenoma, particularly “water-clear cell” variant) and malig-
nant (parathyroid carcinoma) parathyroid neoplasms can
show morphologic overlap with metastatic CC-RCC.63
Although clear cell hyperplasia may also show features
reminiscent of metastatic CC-RCC, involvement of multiple
glands is a helpful clinical aid in this distinction. Although
both PAX-2 and PAX-8 show immunoreactivity in both the
normal and neoplastic parathyroid,9,21,30 hKIM-1 staining
has not been reported in the parathyroid gland.9
Salivary Gland
Metastatic CC-RCC can show morphologic overlap
with several categories of primary salivary gland tumors,
particularly (hyalinizing) clear cell carcinoma, epithelial-
myoepithelial carcinoma, and myoepithelioma/myoepithe-
lial carcinoma, as well as clear cell variants of mucoepi-
dermoid carcinoma, acinic cell carcinoma, oncocytoma/
oncocytic carcinoma, and sebaceous adenoma/carcino-
ma.98–100 Tumors with a myoepithelial component can be
differentiated from metastatic CC-RCC using myoepithelial
immunohistochemical markers (eg, calponin and p63).98–101
Many of these tumors can be differentiated from metastatic
CC-RCC using traditional histochemistry [periodic-acid
Schiff-diastase (PAS-D) in acinic cell carcinoma and mucin
stain in mucoepidermoid carcinoma).95 Although very few
cases have been evaluated, immunoreactivity for PAX-2,
PAX-8, and hKIM-1 is negative to date in salivary gland
tumors.
Oropharynx
Squamous cell carcinoma may occasionally have abun-
dant intracytoplasmic glycogen imparting a clear cell
appearance. Typical markers of squamous cell carcinoma,
such as CK5/6, high molecular weight CK, and p63 are
characteristically expressed. No PAX-2, PAX-8, or hKIM-1
expression has been reported in squamous cell carcinoma.9,21
Odontogenic
Clear cell odontogenic carcinoma is a rare carcinoma
of the mandible and maxilla, which can closely mimic the
histology of metastatic CC-RCC, but is most commonly
found in older women. There is very limited immunohis-
tochemical data available for these tumors. Close clinical
correlation is critical to exclude a metastatic lesion.
Rare clear cell variants of calcifying epithelial odonto-
genic tumors (Pindborg tumors) are described. Although
most are located in the mandible or maxilla, rare peripheral
lesions may be seen in the anterior gingiva. There is very
limited immunohistochemical information available for
these tumors, but they have been shown to express p63
and CK5/6, which would aid in the distinction from
metastatic CC-RCC.102 In addition, calcifying epithelial
odontogenic tumor is associated with extensive amyloid
deposition that can be highlighted by Congo red stains.
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Sangoi et al Adv Anat Pathol  Volume 17, Number 6, November 2010

Ameloblastoma, which typically presents as a mass one of the few known tumors, along with lung, colon, and
lesion in the mandible or maxilla, may have pronounced breast carcinomas, known to metastasize to the pan-
clear cell or granular features that might mimic metastatic creas,5,103–108 with an estimated frequency of metastasis
CC-RCC. Extraosseous or peripheral ameloblastomas among reported organ sites of 1%.1,58 Metastatic CC-RCC
may also involve the gingiva or buccal mucosa. The can closely mimic a primary pancreatic neoplasm, as many
immunophenotype of ameloblastoma is similar to the are also known to exhibit clear cell change. Pancreatic
Pindborg tumor with CK5/6 and p63 expression.102 Little ductal adenocarcinoma can exhibit a clear cell or foamy
to no data is available regarding staining with renal gland appearance.109–112 Although primary clear cell or
markers. Recognition of other more typical patterns foamy gland adenocarcinoma of the pancreas typically
of ameloblastoma is most helpful in the distinction from maintains a tubular architecture and is often associated
a metastatic carcinoma. with areas of conventional ductal adenocarcinoma, cases
with a predominantly solid growth pattern have been
reported.111 clear cell and foamy gland ductal adenocarci-
noma of the pancreas are positive for CK7, carcinoem-
Summary: CC-RCC Versus Head and Neck Tumors bryonic antigen, and MUC1 by immunohistochemistry,
Useful Panel Versus which are not typically immunoreactive in CC-RCC.109,111
Diagnosis Metastatic CC-RCC Both clear cell and foamy gland ductal adenocarcinoma
show cytoplasmic mucin positivity with mucicarmine and
Thyroid tumors with (+): TTF-1, thyroglobulin PAS-D, which is not seen in CC-RCC.109,112 PAX-8
clear cells
reactivity has been reported in a small subset of pancreatic
( ): hKIM-1, PAX-2
Parathyroid tumors (+): PTH, chromogranin ductal adenocarcinomas and thus may not be useful in
with clear cells ( ): hKIM-1 distinguishing these 2 entities.113,114
Salivary gland Clear cell change in well-differentiated neuroendocrine
Epithelial- (+): Calponin and p63 tumors of the pancreas has also been recognized, particu-
myoepithelial (myoepithelial marker) larly in patients with VHL syndrome, and can also be
carcinoma, ( ): PAX-2, PAX-8, hKIM-1 confused for CC-RCC.115 Strong and diffuse expression for
myoepithelioma/ immunohistochemical neuroendocrine markers synapto-
myoepithelial
physin and chromogranin in clear cell neuroendocrine
carcinoma,
oncocytoma/ tumors should allow distinction from CC-RCC. PAX-8 and
oncocytic CD10 immunohistochemistry are not helpful as both
carcinoma characteristically label both pancreatic neuroendocrine
tumors and CC-RCC.18,19,116
Acinic cell (+): a-1-antichymotrypsin, Clear cell solid-pseudopapillary neoplasms of the
carcinoma amylase, PAS-D pancreas have also been reported,117 although their
( ): PAX-2, PAX-8, hKIM-1 distinction from CC-RCC is usually not problematic given
(Hyalinizing) clear (+): PAS the characteristic nuclear localization of b-catenin in solid-
cell carcinoma ( ): PAX-2 (limited data)
pseudopapillary neoplasm.118,119 CD10 and PAX-8 are not
Mucoepidermoid (+): Mucin stain; squamous/ helpful in the distinction of solid-pseudopapillary neoplasm
carcinoma intermediate cell presence from CC-RCC, as both tumors can be positive for these
( ): PAX-2, PAX-8, hKIM-1 markers.18 Finally, serous adenomas of the pancreas
Oropharynx characteristically have clear cytoplasm with abundant
Squamous cell (+): CK5/6, p63 PAS-positive cytoplasmic glycogen which is diastase-
carcinoma ( ): PAX-2, PAX-8, hKIM-1 sensitive, similar to CC-RCC. Serous adenomas of the
pancreas lack the cytologic atypia typical of CC-RCC and
Odontogenic are characterized by perfectly round nuclei, which are
Clear cell Very limited data
uniformly euchromatic. Immunohistochemical analysis is
odontogenic (radiographic correlation
carcinoma is essential) rarely needed to distinguish these entities and caution
Calcifying clear (+): CK5/6, p63, Congo red should be used as serous adenomas of the pancreas may
cell odontogenic show immunoreactivity for RCCma.21 Two studies have
carcinoma shown an absence of PAX-2 expression in pancreatic serous
Ameloblastoma (+): CK5/6, p63 neoplasms.18,120
CC-RCC indicates clear cell renal cell carcinoma; CK, cytokeratin;
hKIM-1, human kidney injury molecule-1; PAS-D, periodic-acid
Schiff-diastase; PTH, parathyroid hormone; TTF-1, thyroid transcription Gastrointestinal Tract
factor-1. A small subset of gastric and gastroesophageal
junction adenocarcinomas have been described as clear cell
adenocarcinoma with most exhibiting a tubulopapillary
growth pattern.121–123 Clear cell carcinomas of the stomach
Metastatic Clear Cell Renal Cell Carcinoma can be intermixed with areas with a hepatoid morphology
Versus Clear Cell Pancreaticobiliary Tract, and can also be associated with a-fetoprotein produc-
tion.123,124 Similar to CC-RCC, the cytoplasmic clearing of
Gastrointestinal Tract, and Liver Tumors
these tumors is because of the accumulation of glycogen
Pancreaticobiliary Tract and thus will stain with PAS but not after diastase
Metastatic carcinoma to the pancreas from another digestion. These tumors are positive for CK7 and
primary site is extremely uncommon; however, CC-RCC is carcinoembryonic antigen, and a subset may also be

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Adv Anat Pathol  Volume 17, Number 6, November 2010 Immunohistochemistry in Metastatic RCC

positive for SALL4, unlike CC-RCC.121,124 Epithelioid

gastrointestinal stromal tumor (GIST) can also be con- (continued)
sidered in the differential diagnosis of CC-RCC, as both Useful Panel Versus
may have a “rhabdoid” or clear appearance.125 Distinction Diagnosis Metastatic CC-RCC
from CC-RCC is often not difficult histologically, and
ancillary immunohistochemical studies for CD117 and Clear cell (+): CK19, CK7*
DOG1 can help to confirm the diagnosis of GIST.126–128 cholangio- ( ): CD10, PAX-8
Of note, a small number of GISTs can show focal carcinoma
immunoreactivity for CK8 and CK18 and such staining
*Not entirely specific.
should not be interpreted as being indicative of carcino- CC-RCC indicates clear cell renal cell carcinoma; CEA, carcinoem-
ma.129 Renal markers are not well studied in GISTs. bryonic antigen; CK, cytokeratin; EMA, epithelial membrane antigen;
hKIM-1, human kidney injury molecule-1; RCCma, renal cell carcinoma
monoclonal antibody.
Liver
The frequency of metastatic CC-RCC to the liver
among reported organ sites ranges from 3% to 10%.1,2,58 Metastatic Clear Cell Renal Cell Carcinoma
The differential diagnosis for hepatic neoplasms with clear Versus Cutaneous Tumors
cell morphology includes metastatic CC-RCC, clear cell Metastatic carcinoma to the skin is a relatively common
HCC, and clear cell cholangiocarcinomas.125 Hepar-1 and finding and cutaneous metastasis of RCC may occur in 3% to
arginase-1 are sensitive markers of hepatic differentiation 11% of cases.1,58,137–139 Dermal tumors composed entirely of
and can typically distinguish HCC from CC-RCC.130–132 clear cells, however, are not common and typically show
Glypican-3 is also a useful marker for HCC and is only adnexal differentiation. Therefore, the main morphologic
rarely seen in RCC, most commonly in the chromophobe differential diagnosis of cutaneous metastatic CC-RCC
subtype.133 Recent data also suggests that PAX-2 and includes dermal adnexal neoplasms with clear cell change
PAX-8 may be useful in distinguishing CC-HCC from CC- and other metastatic clear cell carcinomas. As metastatic
RCC, as only a small subset of HCC will exhibit cutaneous adenocarcinomas typically maintain their char-
immunoreactivity for these markers.36,134 Importantly, acteristic primary immunohistochemical patterns, this discus-
RCCma is not specific for CC-RCC in this setting as it sion will be limited to other entities.
often is positive in HCCs with clear cell change.21 Adnexal lesions may show eccrine, follicular, or
Intrahepatic clear cell cholangiocarcinoma is a rare entity sebaceous differentiation. Clear cell adnexal lesions that
with few cases reported in the literature.135,136 Clear cell show eccrine differentiation include hidradenoma, syringo-
cholangiocarcinomas typically maintain a tubular architec- ma, eccrine carcinoma, syringoid carcinoma, and porocar-
ture and are positive for CK7 and CK19, but negative for cinoma.140–147 The clear cell adnexal lesions with follicular
CD10 and PAX-8.9 differentiation include trichilemmoma and trichilemmal
carcinoma. Neoplasms with sebaceous differentiation, such
as sebaceous adenoma, sebaceoma, and sebaceous carcino-
Summary: CC-RCC Versus Gastrointestinal/Pancreaticobiliary/ ma, contain distinctive EMA-positive intracytoplasmic
Hepatic Tumors vacuoles with lipid droplets.148–150 Primary adnexal lesions
Useful Panel Versus
are p63 positive, in contrast to metastatic carcinomas,
Diagnosis Metastatic CC-RCC
including CC-RCC.151–154 Recently, it was reported that
combined expression of podoplanin (D2-40) and p63
Pancreatobiliary tract permits the distinction between primary cutaneous tumors
Clear cell or (+): CK7, CEA, MUC1, mucin and metastatic adenocarcinomas.155,156 In addition, adnex-
foamy gland histochemistry al carcinomas lack expression of PAX-8.157
pancreatic ( ): RCCma* Occasionally, melanocytic lesions (balloon cell nevi and
adenocarcinoma melanoma) may also mimic metastatic CC-RCC. Expression
Clear cell well- (+): Synaptophysin, chromogranin
differentiated ( ): hKIM-1, PAX-2 (limited data) of S-100 protein or other melanocytic immunohistochemical
neuroendocrine markers is useful to assist in this distinction.
tumor Recently, a clear cell dermal tumor present on the
Clear cell solid- (+): Nuclear b-catenin lower extremities of adults has been described and termed
pseudopapillary “distinctive dermal clear cell mesenchymal neoplasms.”158
neoplasm These lesions morphologically mimic CC-RCC; however,
Gastrointestinal tract the lesional cells express NKI-C3 and did not show
Gastric clear cell (+): CK7, CEA
( ): hKIM-1, PAX-8, and PAX-2 reactivity with any melanocytic or keratinocytic markers
carcinoma
(limited data for all 3 markers) tested.158 Dermal-based perivascular epithelioid cell tumors
Clear cell well- (+): synaptophysin, chromogranin may also have cytoplasmic clearing that could potentially
differentiated ( ): hKIM-1, PAX-2 (limited data) mimic CC-RCC.159 The expression of smooth muscle actin
neuroendocrine and melanocytic markers in perivascular epithelioid cell
tumor tumors should aid in this distinction.
Gastrointestinal (+): CD117, DOG-1 Other entities, such as Paget disease, extramammary
stromal tumor, ( ): CK AE1/AE3 (some positive
Paget disease, clear cell squamous cell carcinoma in situ,
epithelioid type with CK8 and 18)
Liver melanoma in situ, tricholemmal carcinoma, and sebaceous
Clear cell (+): Hepar-1, arginase-1, Glypican-3 carcinoma may also show clear cell change; however, the
hepatocellular ( ): EMA* intraepidermal location/component of these lesions typi-
carcinoma cally allows distinction.

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Sangoi et al
Summary: CC-RCC Versus Cutaneous Tumors
Diagnosis Useful Panel Versus Metastatic CC-RCC
Adnexal tumor (+): p63 and podoplanin (D2-40)
( ): PAX-8
Balloon cell nevi (+): S-100 protein, HMB-45, MelanA
and melanoma ( ): PAX-2, PAX-8, hKIM-1 (limited data
for all 3 markers)
CC-RCC indicates clear cell renal cell carcinoma; hKIM-1, human
kidney injury molecule-1.
Metastatic Clear Cell Renal Cell Carcinoma
Versus Bone Tumors
Metastatic Carcinoma
As metastatic carcinoma is the most common malig-
nant bone lesion in adult patients, a variety of other
carcinoma types may be encountered. Studies have reported
that 9% to 25% of metastatic CC-RCC lesions involve
bone.1,2,58 The comments for carcinoma of unknown pri-
mary are relevant here.
Primary Bone Tumors
Chordoma typically arises at the base of skull or in the
sacrum, but may be seen anywhere in bone along the
midline. In very rare instances, chordomas may be found in
nonaxial locations (so-called true peripheral chordo-
mas).160–162 Although peripheral chordomas are extraordi-
narily rare, they are described in multiple locations with the
tibia representing the most common site.161
Chordoma can closely mimic RCC given its poten-
tially nested or solid growth and typically clear cytoplasm.
Recent studies have identified brachyury, a transcription
factor involved in notochord development, that is expressed
strongly in chordomas by immunohistochemistry.163 The
use of this antibody has made the distinction of chordoma
from CC-RCC much easier. A recent study of a large
number of metastatic CC-RCCs has documented that they
do not show immunoreactivity for brachyury.164 Rare
chordomas may show focal PAX-8 immunoreactivity, but
usually not as strongly or as diffusely as CC-RCC.164
Similarly, rare chordoma cases may also have RCCma
expression,21 but CD10 expression is not typical.165
Clear cell chondrosarcoma typically occurs in the
epiphyseal region of long tubular bones, typically in
patients in their third or fourth decade of life; however,
they have been reported in a wide spectrum of patient ages
and in varying bones.166,167 Although these sarcomas have
abundant clear cytoplasm, they generally have other features
that are distinct from CC-RCC such as heterogeneous
osteoid matrix, very well-delineated cell borders with
surrounding eosinophlic material, or osteoclast-type giant
cells. However, in a small biopsy, the presence of delicate
capillaries forming a lobular architecture may closely mimic
metastatic CC-RCC. To our knowledge, PAX-8, PAX-2,
and hKIM-1 have not been studied in clear cell chondro-
sarcoma; therefore, the distinction is currently based
predominantly on the morphologic features and the
clinical/radiographic setting.
Occasional high-grade osteosarcomas may have abun-
dant clear cytoplasm.168 Although osteosarcomas may be
seen in any bone, they are most common in the metaphysis
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Adv Anat Pathol  Volume 17, Number 6, November 2010
of long tubular bones, predominantly in adolescents and
young adults. As with chondrosarcomas, the renal markers
have not been well studied in osteosarcomas. Diagnosis
depends on the clinical setting, the radiographic appear-
ance, and the identification of irregular osteoid production
by the neoplastic cells.
Adamantinoma may mimic metastatic carcinoma
because it contains epithelial elements. It arises in the
cortex of the tibia and fibula, and is commonly associated
with a fibrous stromal component.169 Although not typical,
adamantinomas may show clear cell change that could
create diagnostic confusion on a small biopsy. We have
seen biopsies misinterpreted as metastatic carcinoma
because of biopsy crush artifact and positive CK stains.
Very few published immunohistochemical studies of
adamantinomas are available; however, distinction from
CC-RCC is typically not difficult as the radiographic
appearance is usually quite distinct.
Summary: CC-RCC Versus Bone Tumors
Diagnosis Useful Panel Versus Metastatic CC-RCC
Chordoma (+): Brachyury
( ): PAX-2, CD10
CC-RCC indicates clear cell renal cell carcinoma.
Metastatic Clear Cell Renal Cell Carcinoma
Versus Soft Tissue Tumors
Paragangliomas may mimic CC-RCC because of the
nested architecture with surrounding well-formed vascular
septae. These tumors typically express the neuroendocrine
markers synaptophysin, chromogranin, and microtubule-
associated protein-2 (MAP2).13 They may also show S-100
protein reactivity in the sustentacular cell component
surrounding the nests. An absence of CK immunoreactivity
also helps to exclude an epithelial process. PAX-2 is
reportedly negative in paraganglioma, but RCCma staining
may be observed.21
Clear cell sarcoma (melanoma of soft parts) also
commonly has a nested pattern that may potentially mimic
CC-RCC.170,171 Most cases have a distinctive spindled
morphology with dense fibrous septa creating a nested
architecture, but nested epithelioid patterns that mimic
carcinoma are also seen. Despite the name, clear cell
sarcoma more commonly has eosinophilic cytoplasm.
Many cases also have admixed multinucleated giant cells.
Immunohistochemically, clear cell sarcoma has a melano-
cytic phenotype with expression of S-100 protein, HMB-45,
melanA, and other markers. In addition, clear cell sarcoma
harbors an EWS translocation that can be identified with
break-apart fluorescence in-situ hybridization (FISH)
probes.172 Renal epithelial markers are not well studied in
clear cell sarcoma, but we have seen cases with weak
immunoreactivity for PAX-8.9
Alveolar soft part sarcoma often mimics the eosino-
philic pattern of CC-RCC because of the characteristic
sinusoidal vascular spaces that divide the tumor into
nests.173 PAS-D stains characteristically show large intra-
cytoplasmic crystals in alveolar soft part sarcoma.174
Diffuse nuclear overexpression for TFE3 is considered
diagnostic of alveolar soft part sarcoma, but the antibody
can be technically challenging to use.175 On account of this
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Adv Anat Pathol  Volume 17, Number 6, November 2010
issue, some laboratories have developed a FISH test for
documentation of a TFE3 rearrangement.176,177 CD10
expression has been reported in alveolar soft part sarco-
ma,178 but other renal lineage markers have not been well
studied. Although not the focus of this review, the
possibility of a TFE3/microphthalmia-associated transcrip-
tion factor translocation RCC should be carefully con-
sidered when diagnosing alveolar soft part sarcoma as they
may have the same translocation. This is particularly
important in the presence of a renal mass.179
Many other sarcomas may have focal areas with
cytoplasmic clearing that could potentially mimic a
carcinoma on a small biopsy. Ewing/primitive neuroecto-
dermal tumor (PNET) and rhabdomyosarcoma are 2
sarcomas that occasionally have abundant clear cytoplasm.
Ewing/PNETs with abundant intracytoplasmic glycogen
maintain their typical strong membranous immunoreactiv-
ity with CD99. A subset of cases may show CK reactivity,
but the diagnosis of Ewing/PNET can usually be confirmed
by testing with EWS break-apart FISH probes.180 Rhab-
domyosarcoma may similarly have intracytoplasmic glyco-
gen in some cases imparting a clear cell appearance, but
documentation of myogenin and/or MyoD1 expression aids
in this diagnosis.181–183 The epithelioid variant of pleo-
morphic liposarcoma may closely resemble a carcinoma,
usually RCC or adrenal cortical carcinoma.184 The expres-
sion of CK and EMA in these epithelioid areas further
complicates the distinction from carcinoma.184,185 Imaging
correlation (ie, exclusion of a renal or adrenal mass) may be
essential in tumors that do not show areas of more
conventional pleomorphic liposarcoma.
In a large study of the renal epithelial markers, PAX-2,
PAX-8, and hKIM-1 in nonrenal neoplasms and tissues, a
few soft tissue sarcomas were evaluated. One pleomorphic
undifferentiated sarcoma and 1 monophasic synovial
sarcoma showed weak immunoreactivity for PAX-8, but
no expression of PAX-2 or hKIM-1 was observed.9 Given
the very limited immunoreactivity data available for the
broad spectrum of sarcomas, caution should be used in the
distinction of sarcomatoid RCC from a soft tissue sarcoma
until the novel renal epithelial markers are more fully
evaluated. Any immunophenotypic findings must be closely
correlated with the clinical and radiographic context.
Summary: CC-RCC Versus Soft Tissue Tumors
Useful Panel Versus
Diagnosis Metastatic CC-RCC
Paraganglioma (+): Synaptophysin, chromogranin, S-100,
MAP-2
( ): Cytokeratin, PAX-2, PAX-8
(limited data)
Clear cell sarcoma (+): S-100, HMB-45, MelanA, EWS
of soft parts by FISH
( ): Cytokeratin, PAX-2, hKIM-1
Alveolar soft part (+): TFE3, PAS-D, TFE3 by FISH
sarcoma
( ): Cytokeratin
Ewing/PNET (+): CD99, EWS by FISH
Rhabdomyosarcoma (+): Desmin, myogenin, MyoD1
CC-RCC indicates clear cell renal cell carcinoma; FISH, fluorescence in-
situ hybridization; hKIM-1, human kidney injury molecule-1; MAP-2,
microtubule-associated protein-2; PAS-D, periodic-acid Schiff-diastase;
PNET, primitive neuroectodermal tumor.
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Immunohistochemistry in Metastatic RCC
Metastatic Clear Cell Renal Cell Carcinoma
Versus Central Nervous System Tumors
Many neoplasms of the central nervous system (CNS),
such as oligodendroglioma, hemangioblastoma, germino-
ma, and neurocytoma are composed of cells with clear
cytoplasm. Others tumors have morphologic variants
featuring prominent clear cells such as clear cell meningio-
ma and clear cell ependymoma.
Oligodendrogliomas are composed of monomorphic
cells with round nuclei and delicate chromatin that frequently
show perinuclear clearing.186,187 This perinuclear clearing is a
processing artifact, and is not seen on frozen section.188
Unlike metastatic CC-RCC, oligodendrogliomas typically
lack a pushing border, and frequently show an infiltrative
growth pattern. FISH will often identify 1p/19q co-dele-
tion.189 Glial fibrillary acid protein is positive in gliofibrillary
oligodendroglial cells.190,191 MAP-2 and SOX10 are consis-
tently positive in oligodendrogliomas,192,193 and Olig2 is also
frequently expressed in oligodendrogliomas.194 CKs are not
expressed in oligodendrogliomas,194 although crossreactivity
is possible with other intermediate filaments.195 EMA is also
not expressed in oligodendrogliomas.194
Hemangioblastomas are partially composed of stromal
cells featuring clear, lipidized, and occasionally glycogenated
vacuoles.187 The clear cell appearance of these stromal cells
frequently raises the possibility of metastatic CC-RCC in the
differential diagnosis. This consideration is of particular
importance as approximately 25% to 30% of these tumors
are associated with an inherited mutation of the VHL gene on
3p25 to 26, and these patients are also prone to developing
renal tumors.196 To complicate matters, true collision metastatic
CC-RCC to hemangioblastoma has been described.197–199
Although necrosis and mitoses are frequently present in
metastatic CC-RCC, these features are typically absent in
hemangioblastomas; however, the stromal cells of hemangio-
blastoma can show marked atypia.188 When interpreting
immunohistochemical stains, it is important to evaluate only
the clear stromal cells. A number of immunohistochemical
stains, most prominently inhibin-a200 and D2-40,201,202 have
recently been touted as useful in distinguishing hemangioblas-
toma from RCC. These reports have been followed by
publications describing discordant results.28,203 Most recently,
PAX-2 negativity, along with inhibin-a positivity has been
reported to help to distinguish between these entities.28
Primary germinoma of the CNS is morphologically
identical to its counterpart in the testis and ovary.
Germinomas in the CNS have a predilection for the midline,
particularly the pineal and pituitary/suprasellar regions.187 In
the CNS, germinomas can be accompanied by vigorous
lymphocytic and occasionally granulomatous inflammation.
CK immunoreactivity in germinomas is typically weak and
patchy,204,205 but diffuse strong CK staining may represent a
component of embryonal carcinoma.190 The use of markers
such as placental-like alkaline phosphatase and CD117 has
generally been supplanted by the newer makers OCT3/4 and
SALL4,206–208 which show nuclear staining and have
increased specificity when compared with their predecessors.
In other anatomic sites, PAX-8 expression has been reported
in a subset of seminomas (germinomas), but PAX-2 and
hKIM-1 have been negative.
Central neurocytoma is a rare tumor composed of a
monotonous uniform population of small round cells
featuring mild perinuclear clearing. It typically occurs in
www.anatomicpathology.com | 387
Sangoi et al
the supratentorial ventricular system of young adults (in
contrast to RCC, which typically affects older patients).
Unlike metastatic RCC, mitotic activity and necrosis are
not generally present, although these features can be seen in
atypical neurocytomas.209,210 Central neurocytomas typi-
cally show nuclear Neu-N staining,211 and strong cytoplas-
mic staining for MAP-2212,213 and synaptophysin.188
Clear cell meningioma is a rare variant of meningioma
that typically features sheet-like growth pattern, and often
lacks obvious meningothelial differentiation, whorl forma-
tion, and psammoma bodies. The tumor cells are clear as a
consequence of glycogen-rich cytoplasm, and are thus PAS
positive.187 Although earlier reported to be most commonly
encountered in the cauda equina,187 a recent large series
showed a predilection for these tumors to arise in the dura
overlying the frontal lobes and posterior fossa.214 Nearly
half of the 18 clear cell meningiomas in this study showed
expression of carbonic anhydrase-IX, and more than a
quarter of clear cell meningiomas were positive for CD10,
although both of these stains were positive in fewer than
50% of cells. None of the tumors in their series were
RCCma positive.214 EMA is unhelpful in distinguishing
clear cell meningioma from metastatic CC-RCC, as this can
be positive in both entities.188
Clear cell ependymoma is a rare variant of ependymoma
that occurs most commonly in the supratentorial region in
children.215 These tumors are composed of a monomorphic
population of cells with the classic nuclear morphology of
ependymal cells (ovoid nuclei with finely stippled chromatin),
and moderate amounts of clear cytoplasm. Perivascular
pseudorosettes are present, but these may be focal. These
tumors are glial fibrillary acid protein positive and show the
classic “dot-like” EMA positivity of ependymoma.186
Unfortunately, at present, the newer renal epithelial
markers are not adequately studied in the CNS.
Summary: CC-RCC Versus Central Nervous System Tumors
Useful Panel Versus
Diagnosis Metastatic CC-RCC
Oligodendroglioma (+): MAP-2, Olig2, Sox10,
1p/19q deletion, GFAP (variable)*
( ): Cytokeratin, EMA
Hemangioblastoma (+): S100, inhibin-a (variable),
(stromal cells) D2-40 (variable)
( ): PAX-2, cytokeratin
Germinoma (+): OCT3/4, SALL4
( ): hKIM-1, PAX-2
Neurocytoma (+): Neu-N, MAP-2, synaptophysin
( ): Cytokeratin
Clear cell ( ): RCCma
meningioma
Clear cell (+): GFAP, EMA (dot-like)
ependymoma ( ): Cytokeratin
*Stains gliofibrillary oligodendrocytes.
CC-RCC indicates clear cell renal cell carcinoma; EMA, epithelial
membrane antigen; GFAP, glial fibrillary acid protein; hKIM-1, human
kidney injury molecule-1; MAP-2, microtubule-associated protein-2;
RCCma, renal cell carcinoma monoclonal antibody.
REFERENCES
1. McKenney JK, Fujiwara M, Higgins JP, et al. Comparison of
putative renal cell carcinoma immunohistochemical markers
in primary adrenal cortical lesions and metastatic renal cell
388 | www.anatomicpathology.com
Adv Anat Pathol  Volume 17, Number 6, November 2010
carcinoma: a tissue microarray study of 246 Cases. Mod
Pathol. 2009;22(suppl 1):182A.
2. Hoffmann NE, Gillett MD, Cheville JC, et al. Differences in
organ system of distant metastasis by renal cell carcinoma
subtype. J Urol. 2008;179:474–477.
3. Renshaw AA, Richie JP. Subtypes of renal cell carcinoma.
Different onset and sites of metastatic disease. Am J Clin
Pathol. 1999;111:539–543.
4. Nappi O, Mills SE, Swanson PE, et al. Clear cell tumors of
unknown nature and origin: a systematic approach to
diagnosis. Semin Diagn Pathol. 1997;14:164–174.
5. Kassabian A, Stein J, Jabbour N, et al. Renal cell carcinoma
metastatic to the pancreas: a single-institution series and
review of the literature. Urology. 2000;56:211–215.
6. Hughes JH, Jensen CS, Donnelly AD, et al. The role of fine-
needle aspiration cytology in the evaluation of metastatic
clear cell tumors. Cancer. 1999;87:380–389.
7. Jhala NC, Jhala D, Eloubeidi MA, et al. Endoscopic
ultrasound-guided fine-needle aspiration biopsy of the adre-
nal glands: analysis of 24 patients. Cancer. 2004;102:308–314.
8. Sahni VA, Silverman SG. Biopsy of renal masses: when and
why. Cancer Imaging. 2009;9:44–55.
9. Sangoi AR, West RB, Bonventre JV, et al. Exploring the
specificity of putative renal cell carcinoma markers in non-
renal tissues and neoplasms from various organ systems: a
tissue microarray study of 501 cases. Mod Pathol. 2010;
23(suppl 1):216A.
10. Poleev A, Fickenscher H, Mundlos S, et al. PAX8, a human
paired box gene: isolation and expression in developing
thyroid, kidney and Wilms’ tumors. Development. 1992;116:
611–623.
11. Nonaka D, Tang Y, Chiriboga L, et al. Diagnostic utility of
thyroid transcription factors Pax8 and TTF-2 (FoxE1) in
thyroid epithelial neoplasms. Mod Pathol. 2008;21:192–200.
12. Puglisi F, Cesselli D, Damante G, et al. Expression of Pax-8,
p53 and bcl-2 in human benign and malignant thyroid
diseases. Anticancer Res. 2000;20:311–316.
13. Sangoi AR, McKenney JK. A tissue microarray-based
comparative analysis of novel and traditional immunohisto-
chemical markers in the distinction between adrenal cortical
lesions and pheochromocytoma. Am J Surg Pathol. 2010;34:
423–432.
14. Tong GX, Yu WM, Beaubier NT, et al. Expression of PAX8
in normal and neoplastic renal tissues: an immunohistochem-
ical study. Mod Pathol. 2009;22:1218–1227.
15. Zhang P, Zuo H, Nakamura Y, et al. Immunohistochemical
analysis of thyroid-specific transcription factors in thyroid
tumors. Pathol Int. 2006;56:240–245.
16. Bowen NJ, Logani S, Dickerson EB, et al. Emerging roles for
PAX8 in ovarian cancer and endosalpingeal development.
Gynecol Oncol. 2007;104:331–337.
17. Pellizzari L, Puppin C, Mariuzzi L, et al. PAX8 expression in
human bladder cancer. Oncol Rep. 2006;16:1015–1020.
18. Sangoi AR, Ohgami RS, Pai RK, et al. PAX-8 expression
reliably distinguishes pancreatic well-differentiated neuroen-
docrine tumors from ileal and pulmonary well-differentiated
neuroendocrine tumors and pancreatic acinar cell carcinoma.
Mod Pathol. 2010. In press.
19. Long KB, Srivastava A, Hirsch MS, et al. PAX8 Expression
in well-differentiated pancreatic endocrine tumors: correlation
with clinicopathologic features and comparison with gastro-
intestinal and pulmonary carcinoid tumors. Am J Surg
Pathol. 2010;34:723–729.
20. Gnarra JR, Dressler GR. Expression of Pax-2 in human renal
cell carcinoma and growth inhibition by antisense oligonu-
cleotides. Cancer Res. 1995;55:4092–4098.
21. Gokden N, Gokden M, Phan DC, et al. The utility of PAX-2
in distinguishing metastatic clear cell renal cell carcinoma
from its morphologic mimics: an immunohistochemical study
with comparison to renal cell carcinoma marker. Am J Surg
Pathol. 2008;32:1462–1467.
r 2010 Lippincott Williams & Wilkins
Adv Anat Pathol  Volume 17, Number 6, November 2010
22. Gokden N, Kemp SA, Gokden M. The utility of Pax-2 as an
immunohistochemical marker for renal cell carcinoma in
cytopathology. Diagn Cytopathol. 2008;36:473–477.
23. Gupta R, Balzer B, Picken M, et al. Diagnostic implications
of transcription factor Pax 2 protein and transmembrane
enzyme complex carbonic anhydrase IX immunoreactivity in
adult renal epithelial neoplasms. Am J Surg Pathol. 2009;33:
241–247.
24. Luu VD, Boysen G, Struckmann K, et al. Loss of VHL and
hypoxia provokes PAX2 up-regulation in clear cell renal cell
carcinoma. Clin Cancer Res. 2009;15:3297–3304.
25. Mazal PR, Stichenwirth M, Koller A, et al. Expression of
aquaporins and PAX-2 compared to CD10 and cytokeratin 7
in renal neoplasms: a tissue microarray study. Mod Pathol.
2005;18:535–540.
26. Memeo L, Jhang J, Assaad AM, et al. Immunohistochemical
analysis for cytokeratin 7, KIT, and PAX2: value in the
differential diagnosis of chromophobe cell carcinoma. Am
J Clin Pathol. 2007;127:225–229.
27. Ozcan A, Zhai J, Hamilton C, et al. PAX-2 in the diagnosis of
primary renal tumors: immunohistochemical comparison
with renal cell carcinoma marker antigen and kidney-specific
cadherin. Am J Clin Pathol. 2009;131:393–404.
28. Rivera AL, Takei H, Zhai J, et al. Useful immunohistochem-
ical markers in differentiating hemangioblastoma versus
metastatic renal cell carcinoma. Neuropathology. 2010;
Mar 30 [Epub ahead of print].
29. Wasco MJ, Pu RT. Comparison of PAX-2, RCC antigen, and
antiphosphorylated H2AX antibody (gamma-H2AX) in
diagnosing metastatic renal cell carcinoma by fine-needle
aspiration. Diagn Cytopathol. 2008;36:568–573.
30. Zhai QJ, Ozcan A, Hamilton C, et al. PAX-2 expression in
non-neoplastic, primary neoplastic, and metastatic neoplastic
tissue: a comprehensive immunohistochemical study. Appl
Immunohistochem Mol Morphol. 2010;18:323–332.
31. Chivukula M, Dabbs DJ, O’Connor S, et al. PAX 2: a novel
Mullerian marker for serous papillary carcinomas to differ-
entiate from micropapillary breast carcinoma. Int J Gynecol
Pathol. 2009;28:570–578.
32. Muratovska A, Zhou C, He S, et al. Paired-Box genes are
frequently expressed in cancer and often required for cancer
cell survival. Oncogene. 2003;22:7989–7997.
33. Nonaka D, Chiriboga L, Soslow RA. Expression of
pax8 as a useful marker in distinguishing ovarian carcinomas
from mammary carcinomas. Am J Surg Pathol. 2008;32:
1566–1571.
34. Tong GX, Chiriboga L, Hamele-Bena D, et al. Expression
of PAX2 in papillary serous carcinoma of the ovary:
immunohistochemical evidence of fallopian tube or secondary
Mullerian system origin? Mod Pathol. 2007;20:856–863.
35. McKenney JK, Fujiwara M, Higgins JP, et al. A cautionary
note regarding the use of PAX-2 immunohistochemistry in
differentiating metastatic clear cell renal cell carcinoma from
adrenal cortical lesions: a tissue microarray study of 245
cases. Mod Pathol. 2009;22(suppl 1):823.
36. Han WK, Alinani A, Wu CL, et al. Human kidney injury
molecule-1 is a tissue and urinary tumor marker of renal cell
carcinoma. J Am Soc Nephrol. 2005;16:1126–1134.
37. Lin F, Zhang PL, Yang XJ, et al. Human kidney injury
molecule-1 (hKIM-1): a useful immunohistochemical marker
for diagnosing renal cell carcinoma and ovarian clear cell
carcinoma. Am J Surg Pathol. 2007;31:371–381.
38. Lin F, Shi J, Yang XJ, et al. A useful panel of immunohis-
tochemical markers in differentiating papillary renal cell
carcinoma from papillary urothelial carcinoma. Mod Pathol.
2008;21:166A.
39. Liu H, Prichard JW, Shi J, et al. The von hippel-lindau
gene product (pVHL) and kidney injury molecule-1 (KIM-1)
are useful diagnostic markers for identifying focal clear cell
carcinoma of the uterus. Mod Pathol. 2009;22:225A.
40. Yoshida SO, Imam A. Monoclonal antibody to a proximal
nephrogenic renal antigen: immunohistochemical analysis of
r 2010 Lippincott Williams & Wilkins
Immunohistochemistry in Metastatic RCC
formalin-fixed, paraffin-embedded human renal cell carcino-
mas. Cancer Res. 1989;49:1802–1809.
41. Bakshi N, Kunju LP, Giordano T, et al. Expression of renal
cell carcinoma antigen (RCC) in renal epithelial and nonrenal
tumors: diagnostic implications. Appl Immunohistochem Mol
Morphol. 2007;15:310–315.
42. McGregor DK, Khurana KK, Cao C, et al. Diagnosing
primary and metastatic renal cell carcinoma: the use of the
monoclonal antibody “renal cell carcinoma marker.” Am
J Surg Pathol. 2001;25:1485–1492.
43. Simsir A, Chhieng D, Wei XJ, et al. Utility of CD10 and
RCCma in the diagnosis of metastatic conventional renal-cell
adenocarcinoma by fine-needle aspiration biopsy. Diagn
Cytopathol. 2005;33:3–7.
44. Holm-Nielsen P, Pallesen G. Expression of segment-specific
antigens in the human nephron and in renal epithelial tumors.
APMIS Suppl. 1988;4:48–55.
45. Chu P, Arber DA. Paraffin-section detection of CD10 in 505
nonhematopoietic neoplasms. Frequent expression in renal
cell carcinoma and endometrial stromal sarcoma. Am J Clin
Pathol. 2000;113:374–382.
46. Pan CC, Chen PC, Tsay SH, et al. Differential immunopro-
files of hepatocellular carcinoma, renal cell carcinoma, and
adrenocortical carcinoma: a systemic immunohistochemical
survey using tissue array technique. Appl Immunohistochem
Mol Morphol. 2005;13:347–352.
47. Yang B, Ali SZ, Rosenthal DL. CD10 facilitates the diagnosis
of metastatic renal cell carcinoma from primary adrenal
cortical neoplasm in adrenal fine-needle aspiration. Diagn
Cytopathol. 2002;27:149–152.
48. Kristiansen G, Schluns K, Yongwei Y, et al. CD10 expression
in non-small cell lung cancer. Anal Cell Pathol. 2002;24:41–46.
49. Ordi J, Romagosa C, Tavassoli FA, et al. CD10 expression in
epithelial tissues and tumors of the gynecologic tract: a useful
marker in the diagnosis of mesonephric, trophoblastic, and
clear cell tumors. Am J Surg Pathol. 2003;27:178–186.
50. Perna AG, Smith MJ, Krishnan B, et al. CD10 is expressed in
cutaneous clear cell lesions of different histogenesis. J Cutan
Pathol. 2005;32:348–351.
51. Al-Ahmadie HA, Alden D, Qin LX, et al. Carbonic
anhydrase IX expression in clear cell renal cell carcinoma:
an immunohistochemical study comparing 2 antibodies. Am
J Surg Pathol. 2008;32:377–382.
52. Potter C, Harris AL. Hypoxia inducible carbonic anhydrase
IX, marker of tumour hypoxia, survival pathway and therapy
target. Cell Cycle. 2004;3:164–167.
53. Tsuchiya A, Sakamoto M, Yasuda J, et al. Expression
profiling in ovarian clear cell carcinoma: identification of
hepatocyte nuclear factor-1 beta as a molecular marker and a
possible molecular target for therapy of ovarian clear cell
carcinoma. Am J Pathol. 2003;163:2503–2512.
54. Cuff J, Huang S, Higgins JP, et al. CpG island methylation
within the TCF2 promoter may enable epigenetic modulation
of HNF1-beta and clear cell phenotype in ovarian clear cell
carcinoma. Mod Pathol. 2009;22:210A.
55. Illei PB, Epstein JI, Herawi M, et al. Hepatocyte nuclear
factor-1 beta expression in clear cell adenocarcinomas of the
bladder and urethra. Mod Pathol. 2010;23:197A.
56. Kim L, Liao J, Zhang M, et al. Clear cell carcinoma of the
pancreas: histopathologic features and a unique biomarker:
hepatocyte nuclear factor-1beta. Mod Pathol. 2008;21:
1075–1083.
57. Yamamoto S, Tsuda H, Aida S, et al. Immunohistochemical
detection of hepatocyte nuclear factor 1beta in ovarian and
endometrial clear-cell adenocarcinomas and nonneoplastic
endometrium. Hum Pathol. 2007;38:1074–1080.
58. Saitoh H. Distant metastasis of renal adenocarcinoma.
Cancer. 1981;48:1487–1491.
59. Duenschede F, Bittinger F, Heintz A, et al. Malignant and
unclear histological findings in incidentalomas. Eur Surg Res.
2008;40:235–238.
www.anatomicpathology.com | 389
Sangoi et al
60. Midorikawa S, Sanada H, Hashimoto S, et al. Analysis of
cortisol secretion in hormonally inactive adrenocortical
incidentalomas: study of in vitro steroid secretion and
immunohistochemical localization of steroidogenic enzymes.
Endocr J. 2001;48:167–174.
61. Anagnostis P, Efstathiadou Z, Polyzos SA, et al. Long term
follow-up of patients with adrenal incidentalomas—a single
center experience and review of the literature. Exp Clin
Endocrinol Diabetes. 2009; Oct 23 [Epub ahead of print].
62. Ramsay JA, Asa SL, van Nostrand AW, et al. Lipid
degeneration in pheochromocytomas mimicking adrenal
cortical tumors. Am J Surg Pathol. 1987;11:480–486.
63. Wick MR, Ritter JH, Humphrey PA, et al. Clear cell
neoplasms of the endocrine system and thymus. Semin Diagn
Pathol. 1997;14:183–202.
64. Vogel PM, Georgiade NG, Fetter BF, et al. The correlation of
histologic changes in the human breast with the menstrual
cycle. Am J Pathol. 1981;104:23–34.
65. Dina R, Eusebi V. Clear cell tumors of the breast. Semin
Diagn Pathol. 1997;14:175–182.
66. Silberstein GB, Dressler GR, Van Horn K. Expression of
the PAX2 oncogene in human breast cancer and its role in
progesterone-dependent mammary growth. Oncogene.
2002;21:1009–1016.
67. Bhargava R, Beriwal S, Dabbs DJ. Mammaglobin versus
GCDFP-15: an immunohistologic validation survey for
sensitivity and specificity. Am J Clin Pathol. 2007;127:
103–113.
68. Higgins JP, Kaygusuz G, Wang L, et al. Placental S100
(S100P) and GATA3: markers for transitional epithelium and
urothelial carcinoma discovered by complementary DNA
microarray. Am J Surg Pathol. 2007;31:673–680.
69. Gaffey MJ, Mills SE, Frierson HF Jr, et al. Pulmonary clear
cell carcinoid tumor: another entity in the differential
diagnosis of pulmonary clear cell neoplasia. Am J Surg
Pathol. 1998;22:1020–1025.
70. Gaffey MJ, Mills SE, Ritter JH. Clear cell tumors of the lower
respiratory tract. Semin Diagn Pathol. 1997;14:222–232.
71. Bishop JA, Sharma R, Illei PB. Napsin A and thyroid
transcription factor-1 expression in carcinomas of the lung,
breast, pancreas, colon, kidney, thyroid, and malignant
mesothelioma. Hum Pathol. 2010;41:20–25.
72. Reis-Filho JS, Carrilho C, Valenti C, et al. Is TTF1 a good
immunohistochemical marker to distinguish primary from
metastatic lung adenocarcinomas? Pathol Res Pract. 2000;
196:835–840.
73. Cameron RI, Ashe P, O’Rourke DM, et al. A panel of
immunohistochemical stains assists in the distinction between
ovarian and renal clear cell carcinoma. Int J Gynecol Pathol.
2003;22:272–276.
74. Vang R, Whitaker BP, Farhood AI, et al. Immunohisto-
chemical analysis of clear cell carcinoma of the gynecologic
tract. Int J Gynecol Pathol. 2001;20:252–259.
75. Aguilar CE, Silva EG. New antibodies for clear cell
carcinoma (Pax-8, HNF-a, vHL) are also positive in Arias-
Stella reaction. Mod Pathol. 2010;23:232A.
76. Humphrey PA. Clear cell neoplasms of the urinary tract and
male reproductive system. Semin Diagn Pathol. 1997;14:
240–252.
77. Aydin H, Young RH, Ronnett BM, et al. Clear cell papillary
cystadenoma of the epididymis and mesosalpinx: immuno-
histochemical differentiation from metastatic clear cell renal
cell carcinoma. Am J Surg Pathol. 2005;29:520–523.
78. Odrzywolski KJ, Mukhopadhyay S. Papillary cystadenoma
of the epididymis. Arch Pathol Lab Med. 2010;134:630–633.
79. Bostwick DG, Dundore PA. Clear Cell Proliferations of the
Prostate: Differential Diagnosis. New York: Chapman and
Hall Medical; 1997:39.
80. Gurel B, Ali TZ, Montgomery EA, et al. NKX3.1 as a arker
of prostatic origin in metastatic tumors. Am J Surg Pathol.
2010;34:1097–1105.
390 | www.anatomicpathology.com
Adv Anat Pathol  Volume 17, Number 6, November 2010
81. Quick CM, Gokden N, Sangoi AR, et al. The distribution of
PAX-2 immunoreactivity in the prostate gland, seminal
vesicle, and ejaculatory duct: comparison with prostatic
adenocarcinoma and discussion of prostatic zonal embry-
ogenesis. Hum Pathol. 2010;41:1145–1149.
82. Sim SJ, Ro JY, Ordonez NG, et al. Metastatic renal cell
carcinoma to the bladder: a clinicopathologic and immuno-
histochemical study. Mod Pathol. 1999;12:351–355.
83. Albadine R, Schultz L, Fajardo DA, et al. PAX-8 expression
in urothelial neoplasia—an immunohistochemical study of
236 cases. Mod Pathol. 2010;23:1474A.
84. Albadine R, Schultz L, Illei P, et al. PAX8 (+)/p63 ( )
immunostaining pattern in renal collecting duct carcinoma
(CDC): a useful immunoprofile in the differential diagnosis of
CDC versus urothelial carcinoma of upper urinary tract. Am
J Surg Pathol. 2010;34:965–969.
85. Herawi M, Drew PA, Pan CC, et al. Clear cell adenocarci-
noma of the bladder and urethra: cases diffusely mimicking
nephrogenic adenoma. Hum Pathol. 2010;41:594–601.
86. Tong GX, Weeden EM, Hamele-Bena D, et al. Expression of
PAX8 in nephrogenic adenoma and clear cell adenocarcino-
ma of the lower urinary tract: evidence of related histogenesis?
Am J Surg Pathol. 2008;32:1380–1387.
87. Oliva E, Amin MB, Jimenez R, et al. Clear cell carcinoma of
the urinary bladder: a report and comparison of four tumors
of mullerian origin and nine of probable urothelial origin with
discussion of histogenesis and diagnostic problems. Am J
Surg Pathol. 2002;26:190–197.
88. Sun K, Huan Y, Unger PD. Clear cell adenocarcinoma
of urinary bladder and urethra: another urinary tract lesion
immunoreactive for P504S. Arch Pathol Lab Med. 2008;132:
1417–1422.
89. Fromont G, Barcat L, Gaudin J, et al. Revisiting the
immunophenotype of nephrogenic adenoma. Am J Surg
Pathol. 2009;33:1654–1658.
90. Mazal PR, Schaufler R, Altenhuber-Muller R, et al. Deriva-
tion of nephrogenic adenomas from renal tubular cells
in kidney-transplant recipients. N Engl J Med. 2002;347:
653–659.
91. Tong GX, Melamed J, Mansukhani M, et al. PAX2: a reliable
marker for nephrogenic adenoma. Mod Pathol. 2006;19:
356–363.
92. McKenney JK, Heerema-McKenney A, Rouse RV. Extra-
gonadal germ cell tumors: a review with emphasis on
pathologic features, clinical prognostic variables, and differ-
ential diagnostic considerations. Adv Anat Pathol. 2007;14:
69–92.
93. Snover DC, Levine GD, Rosai J. Thymic carcinoma: five
distinctive histological variants. Am J Surg Pathol. 1982;6:
451–470.
94. Morgenstern DA, Hasan F, Gibson S, et al. PAX5 expression
in nonhematopoietic tissues. Reappraisal of previous studies.
Am J Clin Pathol. 2010;133:407–415.
95. Sindoni A, Rizzo M, Tuccari G, et al. Thyroid metastases
from renal cell carcinoma: review of the literature. Scienti-
ficWorldJournal. 2010;10:590–602.
96. Fabbro D, Di Loreto C, Beltrami CA, et al. Expression
of thyroid-specific transcription factors TTF-1 and PAX-8
in human thyroid neoplasms. Cancer Res. 1994;54:
4744–4749.
97. Liles N, Hamilton G, Shen SS, et al. PAX-8 is a sensitive
marker for thyroid differentiation. Comparison with PAX-2,
TTF-1, and thyroglobulin. Mod Pathol. 2010;23(suppl 1):
130A.
98. Maiorano E, Altini M, Favia G. Clear cell tumors of the
salivary glands, jaws, and oral mucosa. Semin Diagn Pathol.
1997;14:203–212.
99. Said-Al-Naief N, Klein MJ. Clear cell entities of the head and
neck: a selective review of clear cell tumors of the salivary
glands. Head Neck Pathol. 2008;2:111–115.
100. Wang B, Brandwein M, Gordon R, et al. Primary salivary
clear cell tumors–a diagnostic approach: a clinicopathologic
r 2010 Lippincott Williams & Wilkins
Adv Anat Pathol  Volume 17, Number 6, November 2010
and immunohistochemical study of 20 patients with clear cell
carcinoma, clear cell myoepithelial carcinoma, and epithelial-
myoepithelial carcinoma. Arch Pathol Lab Med. 2002;126:
676–685.
101. McHugh JB, Hoschar AP, Dvorakova M, et al. p63
immunohistochemistry differentiates salivary gland oncocy-
toma and oncocytic carcinoma from metastatic renal cell
carcinoma. Head Neck Pathol. 2007;1:123–131.
102. Gratzinger D, Salama ME, Poh CF, et al. Ameloblastoma,
calcifying epithelial odontogenic tumor, and glandular
odontogenic cyst show a distinctive immunophenotype with
some myoepithelial antigen expression. J Oral Pathol Med.
2008;37:177–184.
103. Ghavamian R, Klein KA, Stephens DH, et al. Renal cell
carcinoma metastatic to the pancreas: clinical and radiologi-
cal features. Mayo Clin Proc. 2000;75:581–585.
104. Robbins EG II, Franceschi D, Barkin JS. Solitary metastatic
tumors to the pancreas: a case report and review of the
literature. Am J Gastroenterol. 1996;91:2414–2417.
105. Sohn TA, Yeo CJ, Cameron JL, et al. Renal cell carcinoma
metastatic to the pancreas: results of surgical management.
J Gastrointest Surg. 2001;5:346–351.
106. Stankard CE, Karl RC. The treatment of isolated pancreatic
metastases from renal cell carcinoma: a surgical review. Am
J Gastroenterol. 1992;87:1658–1660.
107. Sweeney AD, Wu MF, Hilsenbeck SG, et al. Value of
pancreatic resection for cancer metastatic to the pancreas.
J Surg Res. 2009;156:189–198.
108. Z’Graggen K, Fernandez-del Castillo C, Rattner DW, et al.
Metastases to the pancreas and their surgical extirpation.
Arch Surg. 1998;133:413–447; discussion 418–419.
109. Adsay V, Logani S, Sarkar F, et al. Foamy gland pattern of
pancreatic ductal adenocarcinoma: a deceptively benign-
appearing variant. Am J Surg Pathol. 2000;24:493–504.
110. Kanai N, Nagaki S, Tanaka T. Clear cell carcinoma of the
pancreas. Acta Pathol Jpn. 1987;37:1521–1526.
111. Luttges J, Vogel I, Menke M, et al. Clear cell carcinoma of the
pancreas: an adenocarcinoma with ductal phenotype. Histo-
pathology. 1998;32:444–448.
112. Ray S, Lu Z, Rajendiran S. Clear cell ductal adenocarcinoma
of pancreas: a case report and review of the literature. Arch
Pathol Lab Med. 2004;128:693–696.
113. Laury AR, Hornick JL, Piao H, et al. PAX8 is highly sensitive
and specific for mullerian, renal, and thyroid neoplasms: a
study of 1500 epithelial tumors. Mod Pathol. 2010;23:388A.
114. Tacha D, Cheng L, Zhou D, et al. Expression of PAX8 in
normal and neoplastic tissues: a comprehensive IHC analysis.
Mod Pathol. 2010;23:222A.
115. Hoang MP, Hruban RH, Albores-Saavedra J. Clear cell
endocrine pancreatic tumor mimicking renal cell carcinoma: a
distinctive neoplasm of von Hippel-Lindau disease. Am J
Surg Pathol. 2001;25:602–609.
116. Salla C, Konstantinou P, Chatzipantelis P. CK19 and CD10
expression in pancreatic neuroendocrine tumors diagnosed by
endoscopic ultrasound-guided fine-needle aspiration cytology.
Cancer Cytopathol. 2009;117:516–521.
117. Albores-Saavedra J, Simpson KW, Bilello SJ. The clear cell
variant of solid pseudopapillary tumor of the pancreas: a
previously unrecognized pancreatic neoplasm. Am J Surg
Pathol. 2006;30:1237–1242.
118. Abraham SC, Klimstra DS, Wilentz RE, et al. Solid-
pseudopapillary tumors of the pancreas are genetically
distinct from pancreatic ductal adenocarcinomas and almost
always harbor beta-catenin mutations. Am J Pathol. 2002;
160:1361–1369.
119. Tiemann K, Heitling U, Kosmahl M, et al. Solid pseudopa-
pillary neoplasms of the pancreas show an interruption of the
Wnt-signaling pathway and express gene products of 11q.
Mod Pathol. 2007;20:955–960.
120. Molina CP, Kim M, Zhai J, et al. Differentiation of serous
cystic pancreatic neoplasms and metastatic renal cell
r 2010 Lippincott Williams & Wilkins
Immunohistochemistry in Metastatic RCC
carcinoma by immunohistochemistry. Mod Pathol. 2007;20:
287A.
121. Ghotli ZA, Serra S, Chetty R. Clear cell (glycogen rich)
gastric adenocarcinoma: a distinct tubulo-papillary variant
with a predilection for the cardia/gastro-oesophageal region.
Pathology. 2007;39:466–469.
122. Govender D, Ramdial PK, Clarke B, et al. Clear cell
(glycogen-rich) gastric adenocarcinoma. Ann Diagn Pathol.
2004;8:69–73.
123. Matsunou H, Konishi F, Jalal RE, et al. Alpha-fetoprotein-
producing gastric carcinoma with enteroblastic differentia-
tion. Cancer. 1994;73:534–540.
124. Ushiku T, Shinozaki A, Shibahara J, et al. SALL4 represents
fetal gut differentiation of gastric cancer, and is diagnostically
useful in distinguishing hepatoid gastric carcinoma from
hepatocellular carcinoma. Am J Surg Pathol. 2010;34:
533–540.
125. Ritter JH, Mills SE, Gaffey MJ, et al. Clear cell tumors of the
alimentary tract and abdominal cavity. Semin Diagn Pathol.
1997;14:213–219.
126. Espinosa I, Lee CH, Kim MK, et al. A novel monoclonal
antibody against DOG1 is a sensitive and specific marker for
gastrointestinal stromal tumors. Am J Surg Pathol. 2008;
32:210–218.
127. Liegl B, Hornick JL, Corless CL, et al. Monoclonal antibody
DOG1.1 shows higher sensitivity than KIT in the diagnosis of
gastrointestinal stromal tumors, including unusual subtypes.
Am J Surg Pathol. 2009;33:437–446.
128. Miettinen M, Wang ZF, Lasota J. DOG1 antibody in the
differential diagnosis of gastrointestinal stromal tumors:
a study of 1840 cases. Am J Surg Pathol. 2009;33:
1401–1408.
129. Miettinen M, Furlong M, Sarlomo-Rikala M, et al. Gastro-
intestinal stromal tumors, intramural leiomyomas, and
leiomyosarcomas in the rectum and anus: a clinicopathologic,
immunohistochemical, and molecular genetic study of 144
cases. Am J Surg Pathol. 2001;25:1121–1133.
130. Fan Z, van de Rijn M, Montgomery K, et al. Hep par 1
antibody stain for the differential diagnosis of hepato-
cellular carcinoma: 676 tumors tested using tissue microarrays
and conventional tissue sections. Mod Pathol. 2003;16:
137–144.
131. Lamps LW, Folpe AL. The diagnostic value of hepatocyte
paraffin antibody 1 in differentiating hepatocellular neo-
plasms from nonhepatic tumors: a review. Adv Anat Pathol.
2003;10:39–43.
132. Yan BC, Gong C, Song J, et al. Arginase-1: a new
immunohistochemical marker of hepatocytes and hepatocel-
lular neoplasms. Am J Surg Pathol. 2010;34:1147–1154.
133. Kandil DH, Cooper K. Glypican-3: a novel diagnostic marker
for hepatocellular carcinoma and more. Adv Anat Pathol.
2009;16:125–129.
134. Mattis AN, Browne LW, Kakar S, et al. Comparison of PAX-
2 and PAX-8 in distinguishing hepatocellular carcinomas with
clear-cell morphology from renla cell carcinomas. Mod
Pathol. 2010;23:365A.
135. Haas S, Gutgemann I, Wolff M, et al. Intrahepatic clear cell
cholangiocarcinoma: immunohistochemical aspects in a very
rare type of cholangiocarcinoma. Am J Surg Pathol. 2007;
31:902–906.
136. Toriyama E, Nanashima A, Hayashi H, et al. A case of
intrahepatic clear cell cholangiocarcinoma. World J Gastro-
enterol. 2010;16:2571–2576.
137. Cuckow P, Doyle P. Renal cell carcinoma presenting in the
skin. J R Soc Med. 1991;84:497–498.
138. Kouroupakis D, Patsea E, Sofras F, Renal cell carcinoma
metastases to the skin: a not so rare case? Br J Urol. 1995;
75:583–585.
139. Mueller TJ, Wu H, Greenberg RE, et al. Cutaneous
metastases from genitourinary malignancies. Urology. 2004;
63:1021–1026.
www.anatomicpathology.com | 391
Sangoi et al
140. Civatte J. Clear-cell tumors of the skin: a histopathologic
review. J Cutan Pathol. 1984;11:165–175.
141. Furue M, Hori Y, Nakabayashi Y. Clear-cell syringoma.
Association with diabetes mellitus. Am J Dermatopathol.
1984;6:131–138.
142. Kitamura K, Muraki R, Tamura N. Clear cell syringoma.
Cutis. 1983;32:169–172.
143. Ramos D, Monteagudo C, Carda C, et al. Clear cell syringoid
carcinoma: an ultrastructural and immunohistochemical
study. Am J Dermatopathol. 2000;22:60–64.
144. Requena L, Sarasa JL, Pique E, et al. Clear-cell porocarci-
noma: another cutaneous marker of diabetes mellitus. Am
J Dermatopathol. 1997;19:540–544.
145. Rutten A, Requena L, Requena C. Clear-cell porocarcinoma
in situ: a cytologic variant of porocarcinoma in situ. Am
J Dermatopathol. 2002;24:67–71.
146. Suster S. Clear cell tumors of the skin. Semin Diagn Pathol.
1996;13:40–59.
147. Wong TY, Suster S, Nogita T, et al. Clear cell eccrine
carcinomas of the skin: a clinicopathologic study of nine
patients. Cancer. 1994;73:1631–1643.
148. Heyderman E, Graham RM, Chapman DV, et al. Epithelial
markers in primary skin cancer: an immunoperoxidase study
of the distribution of epithelial membrane antigen (EMA) and
carcinoembryonic antigen (CEA) in 65 primary skin carcino-
mas. Histopathology. 1984;8:423–434.
149. Latham JA, Redfern CP, Thody AJ, et al. Immunohisto-
chemical markers of human sebaceous gland differentiation.
J Histochem Cytochem. 1989;37:729–734.
150. Noda Y, Horike H, Watanabe Y, et al. Immunohistochemical
identification of epithelial membrane antigen in sweat gland
tumors by the use of a monoclonal antibody. Pathol Res
Pract. 1987;182:797–804.
151. Ivan D, Diwan AH, Lazar AJ, et al. The usefulness of p63
detection for differentiating primary from metastatic skin
adenocarcinomas. J Cutan Pathol. 2008;35:880–881.
152. Ivan D, Hafeez Diwan A, Prieto VG. Expression of p63 in
primary cutaneous adnexal neoplasms and adenocarcinoma
metastatic to the skin. Mod Pathol. 2005;18:137–142.
153. Ivan D, Nash JW, Prieto VG, et al. Use of p63 expression in
distinguishing primary and metastatic cutaneous adnexal
neoplasms from metastatic adenocarcinoma to skin. J Cutan
Pathol. 2007;34:474–480.
154. Qureshi HS, Ormsby AH, Lee MW, et al. The diagnostic
utility of p63, CK5/6, CK 7, and CK 20 in distinguishing
primary cutaneous adnexal neoplasms from metastatic
carcinomas. J Cutan Pathol. 2004;31:145–152.
155. Liang H, Wu H, Giorgadze TA, et al. Podoplanin is a highly
sensitive and specific marker to distinguish primary skin
adnexal carcinomas from adenocarcinomas metastatic to
skin. Am J Surg Pathol. 2007;31:304–310.
156. Plaza JA, Ortega PF, Stockman DL, et al. Value of p63
and podoplanin (D2-40) immunoreactivity in the distinction
between primary cutaneous tumors and adenocarcinomas
metastatic to the skin: a clinicopathologic and immuno-
histochemical study of 79 cases. J Cutan Pathol. 2010;37:
403–410.
157. Fujiwara M, Taube J, Sharma M, et al. PAX8 discriminates
ovarian metastases from adnexal tumors and other cutaneous
metastases. J Cutan Pathol. 2010;37:938–943.
158. Lazar AJF, Fletcher CDM. Distinctive dermal clear cell
mesenchymal neoplasm; clinicopathologic analysis of five
cases. Am J Dermatopathol. 2004;26:273–279.
159. Liegl B, Hornick JL, Fletcher CD. Primary cutaneous
PEComa: distinctive clear cell lesions of skin. Am J Surg
Pathol. 2008;32:608–614.
160. Nielsen GP, Mangham DC, Grimer RJ, et al. Chordoma
periphericum: a case report. Am J Surg Pathol. 2001;25:
263–267.
161. O’Donnell P, Tirabosco R, Vujovic S, et al. Diagnosing an
extra-axial chordoma of the proximal tibia with the help of
392 | www.anatomicpathology.com
Adv Anat Pathol  Volume 17, Number 6, November 2010
brachyury, a molecule required for notochordal differentia-
tion. Skeletal Radiol. 2007;36:59–65.
162. Tirabosco R, Mangham DC, Rosenberg AE, et al. Brachyury
expression in extra-axial skeletal and soft tissue chordomas: a
marker that distinguishes chordoma from mixed tumor/
myoepithelioma/parachordoma in soft tissue. Am J Surg
Pathol. 2008;32:572–580.
163. Vujovic S, Henderson S, Presneau N, et al. Brachyury, a
crucial regulator of notochordal development, is a novel
biomarker for chordomas. J Pathol. 2006;209:157–165.
164. Sangoi AR, Karamchandani J, Lane B, et al. Specificity of
brachyury in the distinction of chordoma from clear cell renal
cell carcinoma and germ cell tumors: a study of 305 cases.
Mod Pathol. 2010. In press.
165. Al-Adnani M, Cannon SR, Flanagan AM. Chordomas do
not express CD10 and renal cell carcinoma (RCC) antigen:
an immunohistochemical study. Histopathology. 2005;47:
535–537.
166. Bjornsson J, Unni KK, Dahlin DC, et al. Clear cell
chondrosarcoma of bone. Observations in 47 cases. Am
J Surg Pathol. 1984;8:223–230.
167. Collins MS, Koyama T, Swee RG, et al. Clear cell
chondrosarcoma: radiographic, computed tomographic, and
magnetic resonance findings in 34 patients with pathologic
correlation. Skeletal Radiol. 2003;32:687–694.
168. Povysil C, Matejovsky Z, Zidkova H. Osteosarcoma with a
clear-cell component. Virchows Arch A Pathol Anat Histo-
pathol. 1988;412:273–279.
169. Keeney GL, Unni KK, Beabout JW, et al. Adamantinoma of
long bones: a clinicopathologic study of 85 cases. Cancer.
1989;64:730–737.
170. Chung EB, Enzinger FM. Malignant melanoma of soft parts:
a reassessment of clear cell sarcoma. Am J Surg Pathol. 1983;
7:405–413.
171. Enzinger FM. Clear-cell sarcoma of tendons and apo-
neuroses: an analysis of 21 cases. Cancer. 1965;18:1163–1174.
172. Curry CV, Dishop MK, Hicks MJ, et al. Clear cell sarcoma of
soft tissue: diagnostic utility of fluorescence in situ hybridiza-
tion and reverse transcriptase polymerase chain reaction.
J Cutan Pathol. 2008;35:411–417.
173. Lieberman PH, Brennan MF, Kimmel M, et al. Alveolar soft-
part sarcoma: a clinico-pathologic study of half a century.
Cancer. 1989;63:1–13.
174. Ladanyi M, Antonescu CR, Drobnjak M, et al. The
precrystalline cytoplasmic granules of alveolar soft part
sarcoma contain monocarboxylate transporter 1 and
CD147. Am J Pathol. 2002;160:1215–1221.
175. Argani P, Lal P, Hutchinson B, et al. Aberrant nuclear
immunoreactivity for TFE3 in neoplasms with TFE3 gene
fusions: a sensitive and specific immunohistochemical assay.
Am J Surg Pathol. 2003;27:750–761.
176. Ladanyi M, Lui MY, Antonescu CR, et al. The
der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma
fuses the TFE3 transcription factor gene to ASPL, a novel
gene at 17q25. Oncogene. 2001;20:48–57.
177. Zhong M, De Angelo P, Osborne L, et al. Dual-color, break-
apart FISH assay on paraffin-embedded tissues as an adjunct
to diagnosis of Xp11 translocation renal cell carcinoma and
alveolar soft part sarcoma. Am J Surg Pathol. 2010;34:
757–766.
178. Kasashima S, Minato H, Kobayashi M, et al. Alveolar soft
part sarcoma of the endometrium with expression of CD10
and hormone receptors. APMIS. 2007;115:861–865.
179. Argani P, Antonescu CR, Illei PB, et al. Primary renal
neoplasms with the ASPL-TFE3 gene fusion of alveolar soft
part sarcoma: a distinctive tumor entity previously included
among renal cell carcinomas of children and adolescents. Am
J Pathol. 2001;159:179–192.
180. Folpe AL, Goldblum JR, Rubin BP, et al. Morphologic and
immunophenotypic diversity in Ewing family tumors: a study
of 66 genetically confirmed cases. Am J Surg Pathol. 2005;
29:1025–1033.
r 2010 Lippincott Williams & Wilkins
Adv Anat Pathol  Volume 17, Number 6, November 2010
181. Cui S, Hano H, Harada T, et al. Evaluation of new
monoclonal anti-MyoD1 and anti-myogenin antibodies
for the diagnosis of rhabdomyosarcoma. Pathol Int. 1999;
49:62–68.
182. Folpe AL. MyoD1 and myogenin expression in human
neoplasia: a review and update. Adv Anat Pathol. 2002;9:
198–203.
183. Kumar S, Perlman E, Harris CA, et al. Myogenin is a specific
marker for rhabdomyosarcoma: an immunohistochemical
study in paraffin-embedded tissues. Mod Pathol. 2000;13:
988–993.
184. Miettinen M, Enzinger FM. Epithelioid variant of pleo-
morphic liposarcoma: a study of 12 cases of a distinctive
variant of high-grade liposarcoma. Mod Pathol. 1999;12:
722–728.
185. Gebhard S, Coindre JM, Michels JJ, et al. Pleomorphic
liposarcoma: clinicopathologic, immunohistochemical, and
follow-up analysis of 63 cases: a study from the French
Federation of Cancer Centers Sarcoma Group. Am J Surg
Pathol. 2002;26:601–616.
186. Burger PC, Scheithauer BW; American Registry of Pathol-
ogy, Armed Forces Institute of Pathology (US). Tumors of the
Central Nervous System. Washington, DC: American Registry
of Pathology in collaboration with the Armed Forces Institute
of Pathology; 2007:596.
187. Burger PC, Scheithauer BW, Vogel FS. Surgical Pathology of
the Nervous System and its Coverings. 4th ed. New York:
Churchill Livingstone; 2002:657.
188. Vogel H. Nervous System. Cambridge, New York: Cambridge
University Press; 2009:501.
189. Perry A. Oligodendroglial neoplasms: current concepts,
misconceptions, and folklore. Adv Anat Pathol. 2001;8:
183–199.
190. Greenfield JG, Love S, Louis DN, et al. Greenfield’s
neuropathology. 8th ed. London: Hodder Arnold; 2008.
191. Herpers MJ, Budka H. Glial fibrillary acidic protein (GFAP)
in oligodendroglial tumors: gliofibrillary oligodendroglioma
and transitional oligoastrocytoma as subtypes of oligoden-
droglioma. Acta Neuropathol. 1984;64:265–272.
192. Bannykh SI, Stolt CC, Kim J, et al. Oligodendroglial-specific
transcriptional factor SOX10 is ubiquitously expressed in
human gliomas. J Neurooncol. 2006;76:115–127.
193. Blumcke I, Becker AJ, Normann S, et al. Distinct expression
pattern of microtubule-associated protein-2 in human oligo-
dendrogliomas and glial precursor cells. J Neuropathol Exp
Neurol. 2001;60:984–993.
194. Ikota H, Kinjo S, Yokoo H, et al. Systematic immunohisto-
chemical profiling of 378 brain tumors with 37 antibodies
using tissue microarray technology. Acta Neuropathol.
2006;111:475–482.
195. Kriho VK, Yang HY, Moskal JR, et al. Keratin expression in
astrocytomas: an immunofluorescent and biochemical reas-
sessment. Virchows Arch. 1997;431:139–147.
196. Hussein MR. Central nervous system capillary haemangio-
blastoma: the pathologist’s viewpoint. Int J Exp Pathol.
2007;88:311–324.
197. Altinoz MA, Santaguida C, Guiot MC, et al. Spinal
hemangioblastoma containing metastatic renal cell carcinoma
in von Hippel-Lindau disease: case report and review of the
literature. J Neurosurg Spine. 2005;3:495–500.
r 2010 Lippincott Williams & Wilkins
Immunohistochemistry in Metastatic RCC
198. Hamazaki S, Nakashima H, Matsumoto K, et al. Metastasis
of renal cell carcinoma to central nervous system hemangio-
blastoma in two patients with von Hippel-Lindau disease.
Pathol Int. 2001;51:948–953.
199. Polydorides AD, Rosenblum MK, Edgar MA. Metastatic
renal cell carcinoma to hemangioblastoma in von Hippel-
Lindau disease. Arch Pathol Lab Med. 2007;131:641–645.
200. Hoang MP, Amirkhan RH. Inhibin alpha distinguishes
hemangioblastoma from clear cell renal cell carcinoma. Am
J Surg Pathol. 2003;27:1152–1156.
201. Kalof AN, Cooper K. D2-40 immunohistochemistry–so far!
Adv Anat Pathol. 2009;16:62–64.
202. Roy S, Chu A, Trojanowski JQ, et al. D2-40, a novel
monoclonal antibody against the M2A antigen as a marker to
distinguish hemangioblastomas from renal cell carcinomas.
Acta Neuropathol. 2005;109:497–502.
203. Jung SM, Kuo TT. Immunoreactivity of CD10 and inhibin
alpha in differentiating hemangioblastoma of central nervous
system from metastatic clear cell renal cell carcinoma. Mod
Pathol. 2005;18:788–794.
204. Felix I, Becker LE. Intracranial germ cell tumors in children:
an immunohistochemical and electron microscopic study.
Pediatr Neurosurg. 1990;16:156–162.
205. Ho DM, Liu HC. Primary intracranial germ cell tumor.
Pathologic study of 51 patients. Cancer. 1992;70:1577–1584.
206. Edgar MA, Rosenblum MK. The differential diagnosis of
central nervous system tumors: a critical examination of some
recent immunohistochemical applications. Arch Pathol Lab
Med. 2008;132:500–509.
207. Mei K, Liu A, Allan RW, et al. Diagnostic utility of SALL4
in primary germ cell tumors of the central nervous system: a
study of 77 cases. Mod Pathol. 2009;22:1628–1636.
208. Takei H, Bhattacharjee MB, Rivera A, et al. New immuno-
histochemical markers in the evaluation of central nervous
system tumors: a review of 7 selected adult and pediatric brain
tumors. Arch Pathol Lab Med. 2007;131:234–241.
209. Kuchiki H, Kayama T, Sakurada K, et al. Two cases of
atypical central neurocytomas. Brain Tumor Pathol. 2002;
19:105–110.
210. Soylemezoglu F, Scheithauer BW, Esteve J, et al. Atypical
central neurocytoma. J Neuropathol Exp Neurol. 1997;56:
551–556.
211. Soylemezoglu F, Onder S, Tezel GG, et al. Neuronal nuclear
antigen (NeuN): a new tool in the diagnosis of central
neurocytoma. Pathol Res Pract. 2003;199:463–468.
212. Hessler RB, Lopes MB, Frankfurter A, et al. Cytoskeletal
immunohistochemistry of central neurocytomas. Am J Surg
Pathol. 1992;16:1031–1038.
213. Liu Y, Saad RS, Shen SS, et al. Diagnostic value of
microtubule-associated protein-2 (MAP-2) for neuroendo-
crine neoplasms. Adv Anat Pathol. 2003;10:101–106.
214. Prayson RA, Chamberlain WA, Angelov L. Clear cell
meningioma: a clinicopathologic study of 18 tumors and
examination of the use of CD10, CA9, and RCC antibodies to
distinguish between clear cell meningioma and metastatic
clear cell renal cell carcinoma. Appl Immunohistochem Mol
Morphol. 2010;18:422–428.
215. Fouladi M, Helton K, Dalton J, et al. Clear cell ependymoma:
a clinicopathologic and radiographic analysis of 10 patients.
Cancer. 2003;98:2232–2244.
www.anatomicpathology.com | 393