The American Journal of Surgical Pathology 24(1): 4–18, 2000
, Philadelphia
Clear Cell Sarcoma of the Kidney
A Review of 351 Cases From the National Wilms Tumor
Study Group Pathology Center
Pedram Argani, M.D., Elizabeth J. Perlman, M.D.,
Norman E. Breslow, Ph.D., Nancy G. Browning, M.S.,
Daniel M. Green, M.D., Giulio J. D’Angio, M.D., and
J. Bruce Beckwith, M.D.
We reviewed 351 cases of clear cell sarcoma of the kidney
(CCSK), including 182 cases entered on National Wilms Tu-
mor Study Group (NWTSG) trials 1–4 for which clinical fol-
low-up information was available. Tumors were restaged using
NWTS 5 criteria. Mean age at diagnosis in the NWTS group
was 36 months with a range of 2 months to 14 years. The male
to female ratio was 2:1. Typical gross features included large
size (mean diameter 11.3 cm), a mucoid texture, foci of necro-
sis, and prominent cyst formation. Nine major histologic pat-
terns were identified (classic, myxoid, sclerosing, cellular, epi-
thelioid, palisading, spindle, storiform, and anaplastic); virtu-
ally all tumors contained multiple patterns that blended with
one another. Immunohistochemical stains were performed on
45 cases; only vimentin was consistently immunoreactive. Con-
sistently negative results with other antibodies helped exclude
other tumors in the differential diagnosis; all CCSKs were cy-
tokeratin-negative, including epithelioid tumors that mimicked
Wilms tumor, and MIC2-negative, including cellular tumors
that mimicked primitive neuroectodermal tumor. The p53 gene
product was rarely overexpressed in non-anaplastic CCSKs, but
strikingly overexpressed in two of three anaplastic CCSKs.
Overall survival was 69%. Multivariate analysis revealed four
independent prognostic factors for survival: treatment with
doxorubicin, stage, age at diagnosis, and tumor necrosis. Of
note, stage 1 patients had a remarkable 98% survival rate. No
other histologic or clinical variable independently correlated
with survival.
Key Words: Clear cell sarcoma—Kidney—Childhood cancer.
Am J Surg Pathol 24(1): 4–18, 2000.
From the Department of Pathology, The Johns Hopkins Hospital,
Baltimore, Maryland (P.A., E.J.P.); the Department of Biostatistics,
University of Washington, Seattle, Washington (N.E.B.); the Depart-
ment of Pathology and Human Anatomy, Loma Linda University,
Loma Linda, California (N.G.B., J.B.B.); the Department of Pediatrics,
Roswell Park Cancer Institute, Buffalo, New York (D.M.G.); and the
Department of Radiation Oncology, Hospital of the University of
Pennsylvania, Philadelphia, Pennsylvania, U.S.A. (G.J.D.).
Address correspondence and reprint requests to Pedram Argani, MD,
The Johns Hopkins Hospital, Pathology Building, Room 612, 600
North Wolfe St., Baltimore, MD 21287, U.S.A.
4
© 2000 Lippincott Williams & Wilkins, Inc.
Clear cell sarcoma of the kidney (CCSK), an uncom-
mon renal neoplasm of childhood, nonetheless represents
one of the most common “unfavorable histology” tumors
entered on National Wilms Tumor Study Group
(NWTSG) clinical protocols. Approximately 20 new
cases of CCSK are diagnosed each year in the United
States.3 CCSK was initially recognized as a distinct clin-
icopathologic entity by Kidd in 1970, who noted its pro-
pensity to metastasize to bone.15 The distinctive histo-
pathologic features of CCSK were reported simulta-
neously in 1978 by Morgan and Kidd,22 Marsden and
Lawler,19 and Beckwith and Palmer.5 These reports con-
firmed the propensity to metastasize to bone, the poor
clinical outcome, and the sarcomatous, nonepithelial na-
ture of the tumor. The tremendous morphologic diversity
that CCSK can show, ranging from epithelioid to spindle
cell patterns, has been emphasized in later writings.4,23
Since its initial description, several small series of
CCSK have been published. Early studies emphasized
that even low-stage tumors had a poor prognosis, adding
to the tumor’s fearsome reputation.30,32 Subsequently,
results from the first three NWTS trials suggested that
the addition of doxorubicin (Adriamycin) to vincristine
and dactinomycin improved the 6-year relapse-free sur-
vival for patients with CCSK, although the difference did
not reach statistical significance.10 Nonetheless, all pa-
tients with CCSK on NWTS trial 5 are now treated with
doxorubicin regardless of stage. While this approach has
decreased the importance of accurate staging, the essen-
tial role of doxorubicin in therapy emphasizes the need
for pathologists to accurately identify CCSK. Failure to
recognize a tumor as a CCSK could deprive a child of
optimal chemotherapy.
Immunohistochemical studies have been performed
with the hope of establishing a unique profile that dis-
 CLEAR CELL SARCOMA OF THE KIDNEY
tinguishes CCSK from other lesions in the differential
diagnosis. These have generally shown that CCSKs are
reactive for vimentin but little else.17,18,25 However, the
possibility of cytokeratin expression in epithelioid areas
of CCSK has not been addressed. This issue is high-
lighted by isolated reports of epithelial differentiation in
CCSK, both in primary16,31 and cultured tumors.13 In
addition, one study found a high frequency of p53 pro-
tein overexpression in these tumors as determined by
immunohistochemistry, suggesting frequent mutations in
this gene.6
Diagnostic criteria for the renal tumors of childhood
have evolved over the years. Recognition of new entities,
such as metanephric stromal tumor,2 embryonal sarcoma
of the kidney,7 primary renal peripheral neurorectoder-
mal tumor (PNET),29 and cystic hamartoma of the renal
pelvis,27 has allowed previously recognized tumors, such
as congenital mesoblastic nephroma, to become more
sharply defined. Staging criteria have also changed over
the course of the NWTS. Finally, immunohistochemical
studies have become more reliable and adaptable to ar-
chival material using the heat-induced epitope retrieval
method. With these considerations in mind, we have re-
viewed all cases of CCSK available at the NWTSG
Pathology Center, which holds the largest collection of
pediatric renal tumors in existence. The goals of this
study were to define more sharply the clinicopathologic
and immunohistochemical spectra of CCSK, and to
search for clinical and pathologic variables of prognostic
import.
MATERIALS AND METHODS
Clinicopathologic Correlative Study
The initial study population included 214 cases en-
tered as CCSK on NWTS trials 1 through 4, running
from August 1969 to August 1995. Patients on these
trials were treated by standardized protocols and most
had complete clinical follow up of at least 3 years. All
histologic slides and the institutional pathologic report,
with the operative note when available, were reviewed
by one of the authors (P.A.). All tumors for which an
alternative diagnosis was suggested were reviewed by
two authors (J.B.B., P.A.) using a dual-observer micro-
scope. Twenty-two cases were excluded; the revised di-
agnoses were blastemal Wilms tumor (6 cases), PNET (6
cases), stromal tumor not otherwise specified (3 cases),
congenital mesoblastic nephroma (2 cases), metanephric
stromal tumor (2 cases), sarcoma not otherwise specified
(2 cases), and rhabdoid tumor of the kidney (1 case). Five
additional cases were excluded because slides from the
nephrectomy specimen were unavailable for review. This
left 187 cases of CCSK representing 2.8% of 6650 ma-
lignant pediatric renal tumors entered on the NWTS over
5
this time. From this group, five cases were excluded as a
result of insufficient clinical follow up. This left 182
patients (the study cohort, or prognostic group) for clin-
icopathologic correlation analysis and evaluation of
prognostic factors.
One hundred eleven additional cases of CCSK from
the outside consultation (OCWT) files of the NWTSG
Pathology Center and 53 cases of CCSK entered on
NTWS 5 were also reviewed for purposes of the demo-
graphic and morphologic portions of the study. These
cases were not included in the evaluation of prognostic
factors because of the lack of uniform therapy or ad-
equate clinical follow up.
All cases of CCSK featured either the classic pattern
of histology, characterized by an arborizing vasculature
separating cords of plump cells with indistinct cell bor-
ders and open chromatin, or multiple characteristic vari-
ant patterns of CCSK (see Results). The predominant
histologic pattern and the presence of any variant pattern
in each case were recorded. Tumor necrosis, whether
identified microscopically or noted in the institutional
gross pathologic or microscopic description, was also
recorded. Specimen weight and maximal tumor diam-
eter, when measured, were obtained from the institu-
tional pathology report. On the basis of our examination
of the histologic slides as well as the institutional patho-
logic and operative reports, tumors were restaged using
updated NWTS 5 definitions as follows:
Stage 1: Tumor confined to the kidney and completely
resected. No penetration of the renal capsule or in-
volvement of renal sinus vessels.
Stage 2: Tumor extends beyond kidney but completely
resected. Tumor penetrates renal capsule, invades si-
nus vessels, was biopsied before removal, or spilled
locally during removal, but margins are negative.
Stage 3: Gross residual tumor, positive surgical margins,
massive tumor spill or lymph node metastases.
Stage 4: Hematogenous metastases.
Stage 5: Bilateral renal tumors.
When the stage on review differed from the stage re-
corded by the NWTSG Data and Statistical Center, the
relevant slides, gross pathologic findings, or operative
findings were reviewed by two authors (J.B.B., P.A.) to
resolve the discrepancy. Among the 187 verified CCSK
cases in NWTS 1–4, the stage of 42 (23%) was revised.
Twenty-three tumors were changed from stage 1 to stage
2, 10 from stage 2 to stage 3, 6 from stage 1 to stage 3,
2 from stage 3 to stage 2, and 1 from stage 3 to stage 4.
The number of staging changes primarily reflects the
evolution of staging criteria over the course of the study,
and accounts for any discrepancies related to tumor stage
between this report and previous NWTS studies of
CCSK.10
Am J Surg Pathol, Vol. 24, No. 1, 2000
6 P. ARGANI ET AL.

All patients in the prognostic group underwent unilat-
eral nephrectomy. Adjuvant therapy varied depending on
when they entered the NWTS. Children enrolled on
NWTS 1 and 2 (August 1969 through May 1979) were
treated according to tumor stage, regardless of histology.
Hence, the 36 CCSK patients entered on these two stud-
ies received regimen A (dactinomycin), B (vincristine),
C (dactinomycin and vincristine), or D (dactinomycin,
vincristine, and doxorubicin). All patients with CCSK on
NWTS 3 received unfavorable histology therapy regi-
mens DD (dactinomycin, vincristine, and doxorubicin)
or J (dactinomycin, vincristine, doxorubicin, and cyclo-
phosphamide). Given the lack of demonstrated effective-
ness of cyclophosphamide in NWTS 3, all patients on
NWTS 4 received a regimen containing dactinomycin,
vincristine, and doxorubicin, many receiving more inten-
sive vincristine and doxorubicin therapy than on previ-
ous studies. Only four patients received preoperative
chemotherapy before nephrectomy. Eighty-five percent
of patients in the prognostic group received radiation
therapy to the tumor bed.
Six-year survival and relapse-free survival were used
as the prognostic end points. Differences between sur-
vival curves were evaluated by the log rank test. Vari-
ables proving significant by univariate analysis were
evaluated in multivariate analysis using the Cox propor-
tional hazards model.
Immunohistochemical Stains
Paraffin tissue blocks were available from 45 cases for
immunohistochemical studies. Five-micron sections
were deparaffinized with xylene for 30 minutes and re-
hydrated using graded ethanol concentrations. Antigen
retrieval was performed using either protease digestion
or a heat-induced epitope retrieval method. Immunohis-
tochemical staining was performed using the avidin-
biotin-peroxidase technique with 3,3⬘-diamino-benzidine
as chromogen on the automated Bio-Tek-1000 system
(Ventana/Biotek Solutions, Inc, Tucson, AZ, USA). The
antibodies used, vendors and dilutions are listed in
Table 1.
RESULTS
Clinical Features
The age at presentation for NWTS cases ranged from
2 months to 14 years, with a mean age of 36 months.
Among 351 total patients in this study, the highest inci-
dence of CCSK was in years 2 and 3 of life in which 50%
of cases were diagnosed. A sharp decline occurred there-
after (Fig. 1). A male predominance was noted: there
were 231 males and 113 females (ratio: 2.04:1) in the
study. Only one CCSK among the 351 reviewed was
associated with perilobar nephrogenic rests. No case was
associated with intralobar nephrogenic rests. Only a
single CCSK was associated with renal dysplasia. No
familial or syndrome-associated CCSKs were identified.
However, the brother of one patient with CCSK subse-
quently developed a nephrogenic (metanephric) adeno-
fibroma,12 another rare renal neoplasm with a stromal
component.
The revised tumor stage distribution at presentation
for NWTS 1–4, using NWTS 5 criteria, was as follows:
25% of patients had localized stage 1 tumors, a majority

TABLE 1. Antibodies used in immunohistochemical staining

Antibody Pretreatment Dilution Vendor

Vimentin Steam 1:100 Zymed, San Francisco, CA

Cam5.2 Protease Prediluted Becton Dickinson, San Jose, CA
AE1/AE3 Protease 1:2000 Boeringer Mannheim, Indianapolis, IN
EMA Steam 1:1000 Dako, Carpinteria, CA
Polyclonal CEA Steam 1:20,000 Dako
Desmin (clone D33) Steam 1:20,000 Dako
Muscle Specific Actin Steam 1:50 Dako
p53 (DO-7 clone) Steam 1:250 Dako
Synaptophysin Steam 1:50 Boeringer Mannheim
NSE Steam 1:500 Dako
S100 protein Steam 1:6000 Dako
CD34 Steam 1:500 Immunotech, Westbrook, ME
Ulex Steam 1:2000 Becton Dickinson
Leukocyte Common Antigen (LCA) Steam 1:200 Dako
MIC2 (O13 clone) Steam 1:400 Signet, Dedham, MA
Factor 13a Protease 1:2000 Calbiochem, La Jolla, CA
MIB-1 Steam 1:100 Immunotech
GFAP Steam 1:6000 Dako
Factor 8 Protease 1:100 Dako
c-kit Steam 1:500 Santa Cruz Biotechnology, Santa Cruz, CA

Steam: 15 minutes in steam chamber in 10 mM citrate buffer.

Protease: Pretreatment with 5 µg/ml Protease type 27 (Sigma, St. Louis, MO) in PBS.

Am J Surg Pathol, Vol. 24, No. 1, 2000

 CLEAR CELL SARCOMA OF THE KIDNEY 7

FIG. 1. Age distribution of the 334 patients for whom age and sex were recorded.

of patients presented with stage 2 (37%) or 3 (34%) patients relapsed at extraordinarily long intervals of 9
disease, whereas only 4% of patients presented with dis- and 10 years, respectively. One of these patients had a
tant metastasis (stage 4). No true bilateral primary tu- stage 1 tumor that was treated by nephrectomy alone.
mors were identified. In one case, a 1-cm tumor was Five other extremely unusual clinical presentations of
found in the kidney contralateral to a kidney harboring a CCSK were encountered in the OCWT files. Two were
13-cm CCSK. Because the patient presented with widely adult CCSKs presenting as primary renal tumors in a
disseminated stage IV disease, we interpreted the con- 28-year-old man and a 54-year-old woman. In addition,
tralateral tumor as a metastasis. we encountered three extrarenal tumors which presented
The distribution of all sites of metastases at presenta- histologic features identical to those of CCSK. One was
tion and relapse identified among 351 total patients is a pelvic soft tissue tumor in a 13-year-old boy,33 the
illustrated in Table 2. Ipsilateral renal hilar lymph nodes second was an ovarian tumor in a 7-month-old girl, and
were by far the most common site of metastasis at the the third was a retroperitoneal tumor in an 11-year-old
time of presentation. Of the 159 NWTS cases in which boy. While we cannot prove that all of these tumors are
lymph nodes were sampled, 46 (29%) revealed meta- extrarenal CCSKs, they represent, at the very least, per-
static disease. Of note, three NWTS cases showed “skip” fect phenocopies that suggest the possible existence of
metastases to periaortic lymph nodes in the face of his- this neoplasm in extrarenal sites.
tologically confirmed negative hilar lymph nodes. As Seven nontumor deaths were identified among 182
expected from previous studies,20,21 bone metastases was patients in the prognostic group: 3 patients died of sec-
the most common mode of relapse, followed closely by ond malignant neoplasms, 3 of drug toxicity, and 1 of an
lung metastases. Abdominal/retroperitoneal relapses, in-
dicating local recurrence, were the next most frequent, TABLE 2. Sites of metastasis at presentation and sites
followed by brain and liver metastases. Noteworthy is of recurrence in the overall study group
the fact that a significant number of unusual soft tissue Sites of metastasis Sites of
(scalp, epidural, nasopharynx, neck, paraspinal, abdomi- at presentation recurrence
nal wall, axilla) and other (orbital) sites of metastasis Site (no. of cases) (no. of cases)
were also encountered. Bone 5 49
The time interval to relapse among NWTS cases Lung 4 37
ranged from less than 116 months to 4 years. A trend Abdomen/retroperitoneum 0 25
Brain 0 16
toward a longer interval to relapse was noted among Liver 4 10
patients treated with doxorubicin compared with those Soft tissue 2 11
who did not receive this drug (Fig. 2). Longer intervals to Mediastinum 0 4
Orbit 0 3
relapse were encountered in the OCWT files, in which Lymph nodes 71 2
the exact therapy given was not always known to us. Bone marrow 0 1
Among these cases, three patients relapsed after 3 years, Pleura 0 1
Contralateral kidney 1 0
four at 4 years, and one at 5 years. In addition, two

Am J Surg Pathol, Vol. 24, No. 1, 2000

8 P. ARGANI ET AL.
FIG. 2. Cumulative incidence of relapse (1 minus the relapse-free survival curve) among CCSK patients treated with or
without doxorubicin on NWTS 1–4. Whereas the overall relapse rate is lower for patients treated with doxorubicin, the risk
of relapse persists for a longer time.
infectious process. These patients were included in the
survival analyses as survivors until the date at which they
died, when they were withdrawn (censured) from the
analyses. The two patients who died of a combination of
relapsed tumor and drug toxicity were included among
the 47 tumor-related deaths. One hundred twenty-six pa-
tients (69%) survived and are free of disease, whereas
another two are alive with disease. One hundred ten pa-
tients (60%) experienced relapse-free survival.
FIG. 3. Intermediate power view of the classic pattern of
CCSK characterized by cord cells with fine chromatin and
indistinct borders within an arborizing capillary vascula-
ture.
Am J Surg Pathol, Vol. 24, No. 1, 2000
Gross Pathologic Features
CCSK usually presented as a large, unicentric mass
markedly distorting or nearly completely replacing the
kidney; the mean diameter of measured tumors was 11.3
cm (range, 2.3–24 cm). The mean of the more consis-
tently measured combined kidney–tumor specimen
weight was 661 g (range, 43.5–1950 g). When an epi-
center could be determined, the renal medulla was the
most common location. No case of multicentric origin
was identified.
On cut section, tumors were most commonly de-
scribed as tan–grey, soft, and mucoid. Cystic foci were
nearly universal and occasionally represented the domi-
nant feature such that a radiologic and gross pathologic
diagnosis of multilocular renal cyst (cystic nephroma)
was made. The microscopic appearance of such lesions
also mimicked cystic nephroma (see below). Within
these typically large and relatively homogeneous tumors,
discrete foci of necrosis (73% of cases) and hemorrhage
were common. A subset of tumors had a more firm,
whorled appearance. Tumors usually appeared grossly
well-circumscribed with a sharp kidney–tumor border.
Gross extension into the renal vein (tumor thrombus)
was evident in 5% of cases.
Light Microscopic Features
The classic pattern of CCSK was defined by nests or
cords of cells separated by regularly spaced, arborizing
fibrovascular septa (Fig. 3). The regularity of the septal
spacing resulted in cord widths of between four and 10
cells. While usually plump and ovoid, the cord cells not
uncommonly assumed a spindle shape. The septa ranged
from thin, regularly branching “chicken-wire” capillaries
highly reminiscent of the architecture of myxoid liposar-
coma to capillaries enmeshed by sheaths of fibro-
blast-like cells set in a collagenous matrix. These “cel-
lular septa” measured up to 50 ␮m in width and are
 CLEAR CELL SARCOMA OF THE KIDNEY 9

a characteristic feature of CCSK (Fig. 4). Rarely, dilation 7. Storiform pattern (4%)
of the thin septal capillaries created a staghorn, heman- 8. Anaplastic pattern (2.6%)
giopericytomatous appearance.
As has been previously conceptualized,23 the variant
The cord cells featured nuclei that were overall uni-
patterns of CCSK can best be understood as alterations
form in shape, although fine irregularities in contour
of either cord or septal cell morphology. This concept
could be appreciated at high magnification. The chroma- does not imply these cell types are biologically distinct.
tin was characteristically of a fine, dusty texture without The myxoid pattern featured pools of amphophilic ex-
prominent nucleoli or coarse condensations. Empty- tracellular material separating the cord cells. This mate-
appearing “Orphan Annie” eye nuclei were frequent. rial ranged from the minute deposits to large grossly
These characteristic nuclear features were usually not evident expanses of mucin (Fig. 4) creating large pseu-
evident on either original frozen sections or permanent docysts that were difficult to distinguish from the true
sections prepared from previously frozen tissue, and cysts formed from entrapped tubules at the tumor periph-
hence are fixation-dependent. ery. The extracellular mucoid material possessed the his-
The cord cells were usually loosely spaced, separated tochemical staining characteristics of hyaluronic acid;
from their neighbors by optically clear material that has whether between closely spaced cells or in large pools, it
proven to be extracellular mucopolysaccharide matrix, was light blue on alcian blue stain, and staining was
and gives rise to the clear cell appearance.11 Nuclear sensitive to hyaluronidase treatment. The appearance of
overlap was less common than in Wilms tumor, PNET, the cord cells at the periphery of these mucoid pools was
or other more cellular pediatric renal neoplasms. The variable. Some remained similar to their neighboring cells
cytoplasm was generally sparse with indistinct cell bor- closer to the septa. Others acquired a more epithelioid ap-
ders. However, well-demarcated pink cytoplasm was oc- pearance, simulating gland formation around the smaller
casionally evident, particularly in areas of acinar-type pools. Others clung to the septa, creating an anastamosing
epithelioid pattern (see below) or following fixation in channel pattern that simulated a vascular neoplasm.
mercuric fixatives such as B5. The combination of focal The sclerosing pattern usually featured deposition of
cord cell crowding and acidophilic cytoplasm imparted a acellular, osteoid-like material between the septa and the
“dark cell” appearance. Rarely, rhabdoid cytoplasmic in-
clusions were identified, but these cells lacked the promi-
nent nucleolus characteristic of true rhabdoid tumors.
While tumors appeared circumscribed both grossly
and under low-power microscopic examination, on
closer inspection they entrapped individual tubules of the
medulla and occasionally cortical glomeruli. Entrapped
tubules often acquired a metaplastic “embryonal” ap-
pearance with occasional mitoses, simulating the neo-
plastic tubules of Wilms tumor. Alternatively, the en-
trapped tubules dilated extensively, giving rise to grossly
evident cysts with paucicellular septa. In six cases, an
exaggerated cystic appearance microscopically simu-
lated cystic nephroma in the majority of the slides (Fig.
5). Only focally did areas diagnostic of CCSK emerge.
While most tumors (91%) had the classic pattern as
either a predominant or a secondary morphology, a ma-
jority also demonstrated one or more variant patterns.
These patterns usually blended smoothly with the classic
pattern or another variant pattern, with two exceptions
below. The variant patterns recognized and the percent-
age of cases in which they were seen are as follows:

1. Myxoid pattern (50%)

2. Sclerosing pattern (35%)
3. Cellular pattern (26%)
4. Epithelioid pattern (trabecular or acinar type) (13%)
5. Palisading (verocay-body) pattern (11%) FIG. 4. Intermediate power view of CCSK showing cellu-
6. Spindle cell pattern (7%) lar fibroblastic septa and myxoid pools.

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10 P. ARGANI ET AL.
FIG. 5. (A) Dilation of entrapped renal tubules in the medulla simulates cystic nephroma. (B) Focal areas within the septa
show the classic features of CCSK on high magnification.
cord cells. In this configuration, the cord cells became
compressed on both sides by the hyaline material result-
ing in an Indian-file pattern (Fig. 6). When the cord cell
cytoplasm became attenuated and the nucleus was com-
pressed against the extracellular hyaline material, the ap-
pearance mimicked the hyaline intracytoplasmic inclu-
sions of RTK. Lesions acquired a paucicellular atrophic
appearance when the sclerosis was less hyaline and more
collagenous in nature. The sclerosing pattern appeared to
arise from the myxoid pattern in some tumors in which
the amphophilic extracellular material became progres-
sively hyalinized and pink. This sometimes resulted in
nodules of hyaline sclerosis separated by a background
of loose myxoid material. The hyaline sclerotic material
stained blue on Masson trichrome stains, indicating its
collagenous nature.
The cellular pattern formed discrete, well-demarcated
nodules within a less cellular background. In these areas,
the intercellular material spacing the nuclei apart was
diminished, and nuclear overlap was common. Mitotic
activity in these areas often appeared increased, and the
septa were limited to thin capillaries (Fig. 7). The ap-
pearance approached that of an undifferentiated small,
round, blue cell tumor, raising the differential diagnosis
of PNET and blastemal Wilms tumor.
Am J Surg Pathol, Vol. 24, No. 1, 2000
The epithelioid trabecular pattern featured plump cord
cells uniformly retracted away from surrounding septa
such that the cord cells aligned themselves into ribbons
one or two cells thick (Fig. 8). This appearance was
highly reminiscent of the trabecular growth pattern of
epithelial tumors such as hepatocellular carcinoma and
thyroid follicular carcinoma. When viewed in cross sec-
tion, the uniform alignment of these plump cord cells
about the thin vascular septa created the appearance of a
perivascular pseudorosette. When the central vessel was
not visible, the appearance mimicked that of the Homer
Wright rosettes of PNET or the true tubular differentia-
tion of Wilms tumor. Like the cellular pattern, the tra-
becular pattern also tended to form discrete nodules
within a tumor containing other CCSK patterns.
An acinar epithelioid appearance (Fig. 8) occurred
when the cord cells aligned their nuclei against the septa
and their prominent eosinophilic cytoplasm toward the
center of the cord cell clusters. In contrast to the true
tubules of a Wilms tumor, such structures did not feature
well-defined luminal borders.
The palisaded “verocay-body” pattern resulted from
the alignment of spindled cord cells in parallel linear
arrays with nuclei perpendicular to the septa (Fig. 9). The
septa were usually surrounded by collagenous material
 CLEAR CELL SARCOMA OF THE KIDNEY 11

therapy. The anaplasia was focal and no preoperative

biopsy had been performed. In the other treated case,
anaplasia appeared in a brain metastasis of a non-
anaplastic primary tumor following intensive cranial ra-
diation therapy.
No one histologic pattern was overrepresented in
lymph node metastases at presentation. Occasionally, a
pattern not seen in the primary tumor was evident in its
metastasis. However, the entrapped renal tubules and the
epithelioid patterns seen in primary tumors were not en-
countered in a metastasis.
Posttreatment relapses generally displayed the same
range of patterns seen in primary tumors, with the no-
table absence of the epitheliod pattern. However, a trend
toward more sclerotic, less cellular lesions was seen,
possibly reflecting treatment effect. These non-
pleomorphic, sclerotic relapses often entrapped native
epithelial structures (bile ducts, alveoli) in their meta-
static sites, mimicking benign bile duct or pulmonary
hamartomas. Two unique patterns were identified among
the metastases. The first was a hypocellular spindle cell
pattern that simulated fibromatosis (Fig. 13). On diligent
search, small residual foci of epithelioid cord cells could
be identified, allowing a diagnosis of metastatic CCSK to
be made with confidence. The second was a paucicellular

FIG. 6. Hyaline sclerosing CCSK pattern in which oste-

oid-like material compresses residual cord cells.

in these formations, creating a pink contrast to the

aligned blue nuclei. The appearance raised the differen-
tial diagnosis of schwannoma, particularly in soft tissue
metastasis.
Spindle cell patterns resulted in a variety of appear-
ances that suggested the diagnosis of other sarcomas.
Spindled transformation of both cord and septal cells
produced a storiform pattern of growth that mimicked
fibrohistiocytic neoplasms (Fig. 10). More commonly,
the cord cell/septal cell demarcation was completely lost,
resulting in a monomorphic high-grade sarcomatous ap-
pearance. In a spindled nucleus the fine chromatin char-
acteristic of CCSK was more difficult to appreciate. In
several cases, most of the sections showed a high-grade
spindle cell sarcoma appearance, with the diagnosis of
CCSK becoming evident only in small characteristic foci
or in recurrences (Fig. 11).
Anaplasia, defined by nuclear hyperchromasia,
nuclear gigantism, and atypical mitoses, was identified in
nine tumors (Fig. 12). Six of these tumors were un-
treated; in one the anaplasia was diffuse, whereas the
other five showed only discrete foci in anaplasia. Ana-
plasia was identified in three of 53 histologically exam-
ined posttreatment specimens. In two of these, the ana- FIG. 7. Cellular CCSK pattern showing small nodules of
plasia was identified in a nephrectomy specimen ob- overlapping cord cells, simulating blastemal condensa-
tained after preoperative dactinomycin/vincristine tions of Wilms tumor.

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12 P. ARGANI ET AL.
FIG. 8. Epithelioid patterns of CCSK. (A) Acinar epithelioid pattern simulates the tubules of Wilms tumor. (B) Trabecular
epithelioid pattern simulates carcinoma. Neither pattern is immunoreactive for cytokeratin (not shown).
myxoid pattern that featured pools of myxoid material
bearing only rare free-floating tumor cells.9 Confusion
with myxoma was heightened by a focal absence of the
characteristic CCSK vasculature.
Immunohistochemical Findings
A paraffin-embedded tissue block was available for
immunohistochemical staining from a total of 45 cases of
CCSK. Vimentin was immunoreactive in all cases, with
staining often accentuated in a perinuclear dot-like pat-
tern. This consistent staining served as a control for an-
tigen preservation in each of the blocks studied, making
negative results with other immunostains believable even
in the absence of internal controls on the slide.
In 13 of 31 cases studied, the cord cells showed weak
cytoplasmic staining for muscle specific actin. However,
the reactivity was always less intense than that of the
pericytic cells surrounding internal capillaries. All 30
cases tested were negative for desmin, including all of
the ones that showed weak actin staining.
Tumor cells were not immunoreactive for either cyto-
keratin AE1/AE3 or CAM5.2 in any of the 41 cases
studied. Stains for EMA were similarly negative in 31
cases. Nonetheless, these stains highlighted entrapped
native renal tubules that easily could be missed on rou-
Am J Surg Pathol, Vol. 24, No. 1, 2000
tine hematoxylin and eosin-stained sections, emphasiz-
ing the diagnostically helpful infiltrative nature of these
tumors. Of note, the cytokeratin-negative cases included
13 in which distinct epithelioid foci were present: 4
showed trabecular epithelioid patterns, 4 contained mi-
crocystic foci, and 5 showed acinar formation simulating
true glands. One of these acinar cases was previously
reported as a case of CCSK showing epithelial differen-
tiation.31 The authors illustrated a silver stain which had
converted from a single-cell (sarcomatous) pattern to a
nested (epithelial) pattern in the acinar foci, although all
their immunohistochemical stains had been unsuccessful.
By destaining a stained slide and performing antigen
retrieval before cytokeratin staining, we found the acinar
focus to be cytokeratin-negative with positive staining of
adjacent renal pelvic urothelial mucosa serving as an
internal control.
Immunohistochemical stains for the MIC2 antigen
failed to reveal the characteristic membranous pattern in
any of 24 cases studied, including four with cellular foci
that raised the differential diagnosis of PNET. Some
cases did show blush cytoplasmic staining, a pattern gen-
erally considered to be a negative result with this anti-
body. Other negative stains included S100 protein (23
cases), Factor 13a (18 cases), synaptophysin (20 cases),
GFAP (20 cases), LCA (20 cases), NSE (23 cases), c-kit
 CLEAR CELL SARCOMA OF THE KIDNEY 13

Prognostic Variables

Multivariate analysis revealed four independent sig-

nificant prognostic factors for survival: treatment with
doxorubicin, revised stage, patient age, and the presence
of tumor necrosis (Table 3). The significance of tumor
necrosis was lost when relapse-free survival was the end
point. Variables lacking statistical significance for either
survival or relapse-free survival included patient gender,
tumor diameter, specimen weight, lymph node status,
and any single histologic pattern other than necrosis.
The addition of doxorubicin to therapeutic regimens
significantly improved outcome for children with CCSK
(Fig. 2; Tables 4, 5, and 6). This beneficial effect ac-
counts for the progressive improvement in both relapse-
free survival and overall survival that was noted from
NTWS 1 through 4. Once the progressively increased
use of doxorubicin over these trials was taken into ac-
count, the survival differences across the trials lost their
significance.
The remarkable 98% overall survival rate among re-
vised stage 1 patients was significantly better than those
of the more advanced stages (Table 4; Fig. 14). The
survival rates for stages 2 and 3 were diminished, but
rose from approximately 30% to 75% with the addition

FIG. 9. Palisading pattern of CCSK simulates the verocay

bodies of schwannoma.

(9 cases), and polyclonal CEA (23 cases). CD34, Factor

8, and Ulex immunostains highlighted thin capillaries
within the tumor, but neither antibody-stained tumor
cells in 20 cases studied.
To assess proliferative activity, immunohistochemical
stains for the MIB-1 antigen were performed on 22 cases.
One hundred tumor nuclei were counted from four sepa-
rate areas on each slide to obtain the percentage of nuclei
stained (staining index) for each case. A mean staining
index of 21% was obtained (range among cases: 8%–
32% of cells staining). No obvious correlation with his-
tologic pattern was noted in the sections available for
staining.
A similar scoring system was used to evaluate immu-
nohistochemical stains of p53. Among 29 non-anaplastic
CCSKs, 25 showed minimal (less than 5% of nuclei)
staining. The four other non-anaplastic CCSKs had in-
termediate staining indices of 11%, 18%, 25%, and 40%.
Of note, the lesion showing 40% staining was a post-
treatment metastasis. In contrast, two of three anaplastic
CCSKs available for staining showed intense, diffuse
(>75% of nuclei) staining for p53. Non-anaplastic foci
present on the slides in both of these cases showed the
minimal p53 staining pattern usually seen in non-
anaplastic CCSK, so that a sharp transition to the ana- FIG. 10. Storiform pattern of CCSK, reminiscent of that of
plastic foci could be appreciated (Fig. 12). fibrohistiocytic neoplasms.

Am J Surg Pathol, Vol. 24, No. 1, 2000

14 P. ARGANI ET AL.
FIG. 11. (A) Purely spindle CCSK raises the differential of a variety of sarcomas, such as monophasic synovial sarcoma
and cellular congenital mesoblastic nephroma. (B) The lesion’s identity is apparent in its recurrence, which shows the
characteristic cellular septa and myxoid pools.
of doxorubicin to therapeutic regimens. The few stage 4
patients had a poorer prognosis.
Patients within 1 year of the mean age of diagnosis
(ages 2–4 yrs) survived more frequently than those
younger (less than 2 years of age) or older (greater than
4 years) than the mean (Table 5). The survival for pa-
tients in the latter two categories was improved when
doxorubicin was added to therapy.
Necrosis proved to be an adverse prognostic factor for
survival. The minority of tumors lacking gross or histo-
logic evidence of necrosis were associated with a high
(97%) survival rate (Table 6).
Among 68 patients with tumor relapse, both doxoru-
bicin therapy and tumor necrosis significantly affected
tumor-specific survival, whereas age and stage at diag-
nosis did not. Doxorubicin therapy was associated with a
66% reduction in tumor-related mortality (p ⳱ 0.02),
whereas necrosis was associated with a 5.8-fold in-
creased risk of death resulting from tumor (p ⳱ 0.004).
DISCUSSION
This study is the largest series of CCSK ever reported.
We have confirmed several of the previous concepts of
this tumor originating from smaller studies and reached
Am J Surg Pathol, Vol. 24, No. 1, 2000
several new conclusions. We confirmed the beneficial
effect of doxorubicin therapy by multivariate analysis for
both survival and relapse-free survival. Prior studies had
demonstrated the trend toward better outcomes with
doxorubicin, but the results were not statistically signifi-
cant.10 The larger number of patients in the prognostic
group in this study and the requirement for central patho-
logic review likely permitted statistical significance to be
attained. With this review, 22 CCSKs were excluded
from analysis, leaving a more homogeneous population
of tumors. This study also confirmed the striking pro-
pensity of this tumor to metastasize to bone, which we
documented as its most common site of recurrence. In
contrast, Wilms tumor classically spreads to lymph
nodes, lung, and liver but rarely metastasizes to bone.
We have also documented a large number of unusual
sites of metastasis, particularly in the soft tissue, brain,
and orbit, that could potentially fool the unwary oncolo-
gist. These findings emphasize the need for complete
physical examinations and bone imaging8 in clinical fol-
low up of these patients. Prolonged vigilance is also re-
quired, because we found that approximately 20% of
documented CCSK metastases occurred 3 years or more
after diagnosis and some as long as 10 years later. In
contrast, recurrences of Wilms tumor almost always pre-
 CLEAR CELL SARCOMA OF THE KIDNEY 15

FIG. 13. Recurrent CCSK presenting as a leg mass. Hy-

pocellular spindled pattern, prominent vasculature, and
entrapment of muscle all are reminiscent of fibromatosis.
This lesion is the recurrence of the tumor having the clas-
sic pattern shown in Figure 3.

TABLE 3. CCSK—multivariate analysis

Model for Tumor Death

Relative
risk 95% Confidence
Variable (RR) interval for RR p value

Doxorubicin 0.22 (0.12, 0.40) <0.001

Ages 2–4 versus age <2 0.26 (0.12, 0.60) <0.001
Age >4 versus age <2 1.65 (0.84, 3.24)
Stage 2 versus stage 1 14.97 (1.98, 113.44) <0.001
Stage 3 versus stage 1 12.07 (1.58, 91.96) <0.001
Stage 4 versus stage 1 71.22 (6.93, 732.15) <0.001
Necrosis 4.29 (1.31, 14.05) 0.016

Model for Relapse

Relative
risk 95% Confidence
Variable (RR) interval for RR p value

Doxorubicin 0.22 (0.13, 0.38) <0.001

FIG. 12. Anaplastic CCSK. (A) Anaplastic focus in this Ages 2–4 versus age <2 0.39 (0.20, 0.70) 0.001
untreated tumor appears as a discrete nodule at low Age >4 versus age <2 1.04 (0.57, 1.90)
power. (B) High-power view shows atypical mitoses and Stage 2 versus stage 1 4.85 (1.82, 12.91) <0.001
monstrous nuclei diagnostic of anaplasia. (C) Immunohis- Stage 3 versus stage 1 4.49 (1.69, 11.93) <0.001
Stage 4 versus stage 1 25.19 (6.72, 94.48) <0.001
tochemical stain for p53 shows selective intense staining Necrosis 1.73 (0.86, 3.50) 0.130
of the anaplastic focus.

Am J Surg Pathol, Vol. 24, No. 1, 2000

16 P. ARGANI ET AL.

TABLE 4. Tumor-specific survival by stage TABLE 6. Tumor-specific survival by necrosis

at presentation
With doxorubicin Without doxorubicin
With doxorubicin Without doxorubicin
Actuarial Actuarial
Actuarial Actuarial No. of No. of 6-year No. of No. of 6-year
No. of No. of 6-year No. of No. of 6-year Necrosis patients deaths survival patients deaths survival
Stage patients deaths survival patients deaths survival
No 41 1 97.6% 8 2 75.0%
1 41 1 97.6% 4 0 100% Yes 111 30 74.8% 21 15 23.8%
2 56 16 75.0% 13 9 30.8%
3 53 12 77.4% 10 7 30.0%
4 4 2 50.0% 1 1 0%
invasion of renal sinus vasculature, not gross protrusion
beyond the hilar plane, is a basis of upstaging from stage
sent within 2 years. Doxorubicin therapy tended to pro- 1 to stage 2. This criterion makes more biologic sense,
long the interval to relapse among NWTS cases, but because the sinus vessels represent the primary route of
therapy alone cannot account for the propensity to late lymphatic and venous outflow and hence tumor exit from
recurrence that CCSK exhibits. Indeed, the two patients the kidney. Twenty-three of the NWTS cases previously
with the longest intervals to relapse (9 and 10 years) did classified as stage 1 became stage 2 tumors on our re-
not receive doxorubicin. view, usually on the basis of renal sinus vascular inva-
An unexpected finding was the high (29%) frequency sion. These tumors, having access to the systemic circu-
of lymph node metastases identified at presentation. This lation, would be expected to have a diminished progno-
figure is extraordinarily high for sarcomas that classi- sis. Once this aggressive subset was excluded, a more
cally spread through hematogenous routes. This finding pristine population of stage 1 tumors was obtained which
is concordant with the high frequency of vascular inva- proved to have an excellent prognosis. The long-held
sion noted in this study, and together they suggest that concept that stage 1 CCSKs disseminate early seems at
CCSK has a propensity to permeate the renal and peri- variance with their slow growth rate, as reflected by the
renal lymphovascular system. This concept may explain relatively low MIB-1 staining indices we obtained, the
the high number of local (abdominal) recurrences that we documented long intervals to recurrence, and the low
have documented. Complete nodal dissections may be percentage of patients who initially presented with stage
required to remove all tumor in such cases, as is sug- 4 disease. Furthermore, the four revised stage 1 patients
gested by the cases in which we found positive periaortic in this study who did not receive the benefit of doxoru-
lymph nodes despite histologically confirmed benign hi- bicin therapy all survived, suggesting that these tumors
lar nodes. Whether such more extensive surgery would were not disseminated and may have been cured by sur-
decrease the chances of local recurrence or impact on gical excision. Instead, it is likely that stage 2 tumors
survival remains to be proven. disseminate microscopically in this fashion, as is re-
Another unexpected but likely related finding was the flected in their diminished prognosis compared with
high survival rate (98%) for patients with revised stage 1
disease, results that are at variance with previous studies
which have shown a high mortality among all stages.23,32
Such reports have fostered the view that CCSK dissemi-
nates early so that apparent low-stage patients have mi-
crometastases at presentation. Such studies also have
shaped NWTSG therapeutic protocols under which
CCSKs are treated similarly regardless of stage.
The difference in the staging system we used com-
pared with previous studies likely accounts for the dif-
ferences in our results. Under updated NWTS 5 criteria,

TABLE 5. Tumor-specific survival by age at diagnosis

With doxorubicin Without doxorubicin

Actuarial Actuarial
No. of No. of 6-year No. of No. of 6-year
Age patients deaths survival patients deaths survival

<2 years 55 16 72.7% 11 9 18.0%

2–4 years 69 7 90.0% 8 1 87.5%
>4 years 30 8 77.0% 10 7 30.0%
FIG. 14. Stage-specific survival curves for CCSK patients
treated with doxorubicin.

Am J Surg Pathol, Vol. 24, No. 1, 2000

 CLEAR CELL SARCOMA OF THE KIDNEY
stage 1, and account for the previously cited results with
“low-stage” tumors.
The only histologic variable that independently corre-
lated with survival was the presence of necrosis. Because
necrosis is typically a feature of aggressive high-grade
sarcomas, a correlation of the absence of necrosis with
favorable outcome is not unexpected. This concept is
supported by the magnified effect of tumor necrosis on
the outcome of relapsed tumors in which surgery is un-
likely to be curative but instead response to chemo-
therapy is required. As the effects of stage and age are
both mediated through relapse, these variables may re-
flect the probability of complete excision. Regardless of
the potential explanations, it is somewhat comforting that
we can identify subsets of CCSK (that is, stage 1, ages
2–4 yrs, no tumor necrosis) with a superior prognosis;
such patients may not need the intensive therapy given
for patients with advanced disease. The need to minimize
unnecessary therapy is underscored by the fact that treat-
ment-related deaths (2) outnumbered tumor-related
deaths (1) among our revised stage 1 patients.
Whereas the variant histopathologic patterns identified
in CCSK do not appear to carry prognostic import, they
do highlight differential diagnostic dilemmas. Of particu-
lar difficulty is the distinction of cellular CCSK from
blastemal Wilms tumor and PNET, both of which have a
prominent vascular pattern. Useful differential diagnostic
criteria are presented in Table 7. Both blastemal Wilms
tumor and PNET are more aggressively invasive than
CCSK, entrapping whole islands of native renal paren-
chyma as opposed to the single tubules entrapped by
CCSK. Both feature coarser chromatin than CCSK. Of
particular use is our finding of consistent MIC2 negativ-
ity in CCSK. Hence, in a small biopsy or other challeng-
ing case, true membranous MIC2 staining strongly ar-
gues against CCSK. An equally challenging diagnostic
problem is the distinction of epithelioid CCSK patterns,
particularly acinar types, from the true tubular differen-
tiation of a Wilms tumor. We show that stains for cyto-
keratin can reliably make this distinction; no CCSK in
our study expressed cytokeratin regardless of how epi-
thelioid it appeared. Finally, predominantly spindled
CCSKs can be difficult to distinguish from the plump
TABLE 7. Renal cellular blue cell lesions: differential diagnosis
CCSK
Tumor border Entrapping
Chromatin Fine
Nuclear Spacing Well-separated
Remainder of tumor Variable (other CCSK
patterns seen)
Immunohistochemical profile Vimentin + only
Mean age (yrs) 3 6
Genetics ? Complex. 11p13, 11p15 LOH
17
cell variant of cellular congenital mesoblastic nephroma,
metanephric stromal tumor, and other sarcomas. This is
particularly problematic because the characteristic fine
chromatin of CCSK is more difficult to appreciate in a
narrow spindled nucleus. Besides its chromatin, the best
clue to CCSK is the presence of foci of its classic pattern,
which may be absent in small biopsy samples of large
tumors. Given that all CCSKs in our study stained nega-
tively for desmin and S100 protein, positivity for either
of these markers can be used as strong evidence against
CCSK. In contrast, a significant percentage of congenital
mesoblastic nephromas stain with desmin.24
This study also clearly defines the existence of an
anaplastic subset of CCSKs. This subtype is slightly less
common (3%) among CCSKs than anaplasia among
Wilms tumors (5%). Our results refute our previous as-
sumption that anaplasia in CCSK was usually related to
treatment effect. First, anaplasia was not overwhelm-
ingly more frequent in post-therapy specimens examined
(3 of 53 [6%]). Second, in only one case did we docu-
ment that a non-anaplastic tumor became anaplastic after
therapy. Hence, anaplasia in CCSK, as with Wilms tu-
mor, appears to arise de novo. Of particular interest was
the dramatic p53 overexpression in the anaplastic foci of
two tumors in which the non-anaplastic regions did not
overexpress p53. The low frequency of p53 positivity in
non-anaplastic CCSK likely represents native p53 ex-
pressed by proliferating cells; it is unlikely to represent
mutated p53, which usually accumulates enough to be
detected in a higher percentage of cells. These results are
consistent with a model set by other pediatric tumors,
such as Wilms tumor and rhabdomyosarcoma, in which
only anaplastic tumors show p53 protein overexpression
that results from gene mutation.1,26 The absence of ge-
netic losses at 17p in a recently completed comparative
genomic hybridization study of CCSK further argues
against p53 alterations being a primary genetic event in
CCSK.28
This study more sharply defines the clinical behavior
and pathologic features of CCSK but the histogenesis of
this tumor remains an enigma. While its nearly exclusive
occurrence in the kidney suggests an origin from the
developing renal mesenchyme, no viable candidate cell
Blastemal Wilms PNET
Aggressively invasive Aggressively invasive
Coarse Intermediate
Overlapping, molding Even spacing
Often focal tubule formation Uniform
Vimentin+; often focally Vimentin+; MIC2+; often focally
cytokeratin + cytokeratin+
10
t(11;22) (q24;q22)
Am J Surg Pathol, Vol. 24, No. 1, 2000
18 P. ARGANI ET AL.
of origin is apparent. The presence of verified extrarenal
tumors in this and other studies14,33 that are indistin-
guishable from CCSK perhaps favors origin from a non-
organ-specific mesenchymal cell. The eventual delinea-
tion of this cell of origin will no doubt further our un-
derstanding of this tumor. 䊐 15. Kidd JM. Exclusion of certain renal neoplasms from the category
Acknowledgments: The National Wilms Tumor Study
Group is supported primarily by United States Public Health
Service Grant CA-42386. Additional funding for this study was
provided by a generous award from the Children’s Cancer
Foundation of Maryland. The authors thank the many institu-
tional pathologists who have over the years provided the case
material on which this study is based. They also thank those
pathologists who sent blocks specifically for use in this study:
Dr. David Kelly (Birmingham, AL) and Dr. Philip Faught
(Indianapolis, IN); the staff of the NWTSG Data and Statistical
Center, particularly Dr. Weiva Sieh, Tracy Bergemann, and
Janice Takashima, for their tireless work; Mary North, Jose-
phine Geh, and George Pettis for performing the immunohis-
tochemical stains; Lisa Madden for typing the manuscript and
creating Figure 1; and Pete Lund for photographic assistance.
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