Clear Cell Tubulopapillary Renal Cell Carcinoma: A Study of 36 Distinctive Low-grade Epithelial Tumors of the Kidney

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DOI: 10.1097/PAS.0b013e3181f2ee0b · Source: PubMed
Abstract
Recently several low-grade renal cell tumors, distinct from those recognized by the 2004 World Health Organization classification of renal tumors, have been described. These tumors had similar clinicopathologic features, being low-stage tumors with cystic, tubuloacinar, and/or papillary architecture. The tumor cells were low grade with variable amounts of clear cytoplasm that was positive for cytokeratin 7 (CK7), but negative for CD10. Genetic changes characteristic of clear cell or papillary renal cell carcinoma were not seen in these tumors. We investigated the morphologic, immunohistochemical, and genetic features of 36 additional tumors. Immunohistochemistry was carried out for CK7, carbonic anhydrase 9, α-methylacyl-CoA racemase, CD10, TFE-3, and desmin. Interphase fluorescence in situ hybridization was carried out with centromeric probes for chromosomes 3, 7, 17, and a subtelomeric probe for 3p25. Sequencing of von Hippel-Lindau gene and analysis of the methylation status of the promoter region was also carried out in 2 tumors. Thirty-six tumors from 33 patients (mean age: 60.4 , range: 26 to 88; 17 men and 16 women) were studied. Three patients had bilateral tumors and 1 patient had von Hippel-Lindau disease. Follow-up was available in 60% (20/33) of the patients for a mean of 27.4 (range 1 to 85) months. No patient had evidence of the disease after surgery except for the patient with von Hippel-Lindau disease, who was alive with stable disease in the contralateral kidney. All 36 tumors were small (mean size 2.4 cm; range 0.9 to 4.5 cm) and low stage (pT1). The majority was cystic and had prominent fibrous capsule and stroma. The tumors were composed of variable amount of cysts, papillae, tubules, acini, and solid nests. The most characteristic histologic features were branching tubules and acini and anastomosing clear cell ribbons with low-grade nuclei. All tumors were strongly positive for CK7 and variably positive for CA9, but largely negative for CD10, and negative for α-methylacyl-CoA racemase and TFE-3. All but 1 tumor had no gains of chromosomes 7 and 17 and deletion of 3p. Only 1 tumor had low copy number gains of chromosomes 7 and 17. VHL gene mutation and promoter methylation were negative in 2 tumors analyzed. We show that these tumors, which we term as "clear cell tubulopapillary renal cell carcinoma," constitute a unique subtype in the spectrum of renal epithelial neoplasia based on their characteristic morphologic and immunohistochemical features.

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Available from: Huiying He, Sep 22, 2015
Clear Cell Tubulopapillary Renal Cell Carcinoma:
A Study of 36 Distinctive Low-grade Epithelial
Tumors of the Kidney
Hakan Aydin, MD,* Longwen Chen, MD, PhD,* Liang Cheng, MD,
w
Susan Vaziri, PhD,
z
Huiying He, MD, PhD,* Ram Ganapathi, PhD,
z
Brett Delahunt, MD,
y
Cristina Magi-Galluzzi, MD, PhD,* and Ming Zhou, MD, PhD*
Abstract: Recently several low-grade renal cell tumors, distinct
from those recognized by the 2004 World Health Organization
classification of renal tumors, have been described. These
tumors had similar clinicopathologic features, being low-stage
tumors with cystic, tubuloacinar, and/or papillary architecture.
The tumor cells were low grade with variable amounts of clear
cytoplasm that was positive for cytokeratin 7 (CK7), but
negative for CD10. Genetic changes characteristic of clear cell or
papillary renal cell carcinoma were not seen in these tumors. We
investigated the morphologic, immunohistochemical, and genet-
ic features of 36 additional tumors. Immunohistochemistry was
carried out for CK7, carbonic anhydrase 9, a-methylacyl-CoA
racemase, CD10, TFE-3, and desmin. Interphase fluorescence in
situ hybridization was carried out with centromeric probes for
chromosomes 3, 7, 17, and a subtelomeric probe for 3p25. Seq-
uencing of von Hippel-Lindau gene and analysis of the methy-
lation status of the promoter region was also carried out in 2
tumors. Thirty-six tumors from 33 patients (mean age: 60.4 ,
range: 26 to 88; 17 men and 16 women) were studied. Three
patients had bilateral tumors and 1 patient had von Hippel-
Lindau disease. Follow-up was available in 60% (20/33) of the
patients for a mean of 27.4 (range 1 to 85) months. No patient
had evidence of the disease after surgery except for the patient
with von Hippel-Lindau disease, who was alive with stable
disease in the contralateral kidney. All 36 tumors were small
(mean size 2.4 cm; range 0.9 to 4.5 cm) and low stage (pT1). The
majority was cystic and had prominent fibrous capsule and
stroma. The tumors were composed of variable amount of cysts,
papillae, tubules, acini, and solid nests. The most characteristic
histologic features were branching tubules and acini and
anastomosing clear cell ribbons with low-grade nuclei. All
tumors were strongly positive for CK7 and variably positive for
CA9, but largely negative for CD10, and negative for a-
methylacyl-CoA racemase and TFE-3. All but 1 tumor had no
gains of chromosomes 7 and 17 and deletion of 3p. Only 1
tumor had low copy number gains of chromosomes 7 and 17.
VHL gene mutation and promoter methylation were negative
in 2 tumors analyzed. We show that these tumors, which we
term as “clear cell tubulopapillary renal cell carcinoma,”
constitute a unique subtype in the spectrum of renal epithelial
neoplasia based on their characteristic morphologic and
immunohistochemical features.
Key Words: kidney, renal neoplasm, clear cell tubulopapillary
renal cell carcinoma, low-grade neoplasm, cytogenetics, clear
cell renal cell carcinoma, papillary renal cell carcinoma
(Am J Surg Pathol 2010;34:1608–1621)
Recently several examples of low-grade renal cell
tumors, distinct from those recognized by the 2004
World Health Organization classification of renal tumors,
have been described. In 2000 and 2009 Michal et al
23,24
described, in 2 reports, 6 cases of benign or indolent
“renal angiomyoadenomatous tumor.” These were bi-
phasic tumors with a characteristic epithelial component
that exhibited immunopositivity for cytokeratin 7 (CK7),
but not for CD10, and an angioleiomyomatous stroma
that was HMB45 negative. No mutations in the von
Hippel-Lindau (VHL) gene, nor loss of heterozygocity
involving chromosome 3p, was found in these tumors.
Tickoo et al,
27
in their study of the epithelial neoplasms
in the end-stage renal diseases, described 15 “clear-cell
papillary renal cell carcinoma of the end-stage kidneys,”
which were predominantly cystic tumors and showed
prominent papillary architecture with purely clear-cell
cytology. Gobbo et al
10
later reported 7 clear cell papill-
ary renal cell carcinomas composed mainly of cells with
clear cytoplasm arranged in papillary patterns in the
kidneys unaffected by end-stage renal disease. All tumors
showed strong positive staining for CK7, but were
negative for CD10. None had gains of chromosome 7
or loss of Y chromosome, typical of papillary renal cell
carcinoma (PRCC), and none had deletion of 3p, a
finding seen in clear cell renal cell carcinoma (CCRCC).
Mai et al
20
described 21 small tumors from 10 patients that
had a distinct tubular, cystic, and papillary architecture.
Copyright r2010 by Lippincott Williams & Wilkins
From the *Pathology and Laboratory Medicine Institute; zTaussig
Cancer Institute, Cleveland Clinic, Cleveland, OH; wDepartment of
Pathology, Indiana University Medical School, Indianapolis, IN;
and yDepartment of Pathology and Molecular Medicine, University
of Otago, Wellington, New Zealand.
Correspondence: Ming Zhou, MD, PhD, Pathology and Laboratory
Medicine Institute, Cleveland Clinic, 9500 Euclid Ave/L25, Cleve-
land, OH, 44195 (e-mail: zhoum@ccf.org).
ORIGINAL ARTICLE
1608 |www.ajsp.com Am J Surg Pathol Volume 34, Number 11, November 2010
Advertisement:
These showed diffuse CK7 reactivity, but were negative for
CD10 and for this reason the designation sporadic clear cell
renal cell carcinoma with diffuse cytokeratin 7 immunor-
eactivity was applied.
Although bearing different names, the renal tumors
reported in these 5 studies had similar clinicopathologic
features, being low-stage tumors with cystic, tubuloacinar,
and/or papillary architecture. The tumor cells were low
grade with variable amounts of clear cytoplasm that was
positive for CK7 but negative for CD10. Genetic changes
characteristic of CCRCC or PRCC were not seen in these
tumors.
In this study, we have investigated the morphologic,
immunohistochemical, and genetic features of 36 additional
renal tumors that are similar to those described
in the earlier studies, and which seem to constitute a novel
form of low-grade renal malignancy. We propose the term
“clear cell tubulopapillary renal cell carcinoma (CCTP-
RCC)” for these tumors to emphasize their dominant
morphologic features. This new terminology would unify
this novel renal tumor that was reported under several
different names in the literature and clarify confusions
resulting from the polynomial nature of this tumor.
MATERIALS AND METHODS
Pathology Review
Tumors accessioned between 1991 and 2009 were
identified from the senior authors’ surgical pathology files.
Demographic and clinical information was collected
according to the protocols approved by the authors’
institutional review boards. The gross appearance of the
tumors was retrieved from the pathology database. All the
cases were reviewed to confirm the microscopic features.
Immunohistochemistry
One representative block from each case was cut at
5-mm thickness and stained for; CK7 (1:40 dilution, Dako,
Carpinteria, CA), racemase (AMACR) (1:100 dilution,
Zeta, Sierra Madre, CA), CD10 (1:5 dilution, Novacastra,
Newcastle upon Tyne, UK), carbonic anhydrase 9 (CA9)
(1:5000 dilution, Novus Biologicals, Littleton, CO), TFE3
(1:5 dilution, Abcam, Cambridge, MA), and desmin (1:10
dilution, Dako, Carpinteria, CA). In brief, the antigen
retrieval was undertaken according to the specifications
of the manufacturers of the primary antibodies. The slides
were then incubated sequentially with primary antibody,
biotinylated secondary antibody, avidin-peroxidase com-
plex (Ventana, Tucson, AZ), and diaminobenzidine. The
staining protocol for TFE3 was modified from Argani et
al method.
2
Immunostaining was done using a Ventana
Benchmark automatic stainer (Ventana, Tucson, AZ).
Fluorescence in Situ Hybridization (FISH)
For each case, a representative section was selected
and a further section was cut from the paraffin-embedded
block at 4-mthickness. The section was baked at 65 ± 51C
overnight or for a minimum of 5 hours, deparaffinized in
xylene, washed in absolute alcohol, and air dried. Pepsin
was used to digest the tissue at 371C for 40 minutes. FISH
was done with a UroVysion bladder cancer recurrence kit
that contained the centromeric probes for chromosome
7 (CEP7, spectrum green) and chromosome 17 (CEP17,
spectrum aqua) (Abbott Molecular/Vysis Cat. No.
36-161070). Probes for chromosome 3 (CEP3, Spectrum
orange) and subtelomeric probe for 3p25 (3pTel25,
Spectrum green) were also used. The slide was cover-
slipped and sealed with rubber cement. Codenaturation
was carried out at a melt temperature of 731C for
5 minutes by placing the slide in Hybrite. Hybridization
was carried out in a 371C humidified C incubator
overnight (12 to 18 h). The coverslip was then removed
and the slides were washed in 1 SSC/0.3% NP-40
followed by wash in 2 SSC/0.1% NP-40 at room
temperature. Slides were then air dried completely in
darkness. Fifteen to 20 mL Vectashield with DAPI
counterstain was applied to the target area of the slide.
We also carried out the FISH assay using the same probes
(CEP7, 17, 3, and 3pTel25) on sections of CCRCC and
PRCC as positive controls.
FISH Analysis
The FISH data were analyzed using the methods
described earlier.
10,33
The corresponding H&E stained
slides were reviewed before FISH study and areas of
tumor, and normal renal tubules, were marked. For each
case, 100 nuclei from the normal and tumor areas were
examined for signals from probes under fluorescence
microscopy at 1000 magnification. Normal renal tubu-
les were used as a control. Definitions of chromo-
somal gain and loss of chromosomes 7, 17, and Y were
based on the Gaussian model and related to the nonneo-
plastic controls. Any tumor with a signal score beyond the
cutoff value of Mean ± 3 SD of control tissue
wasconsideredtohaveagainorlossofthespecic
chromosome. The statistical method to analyze 3p deletion
was based on earlier studies.
9,10
Analysis of VHL Gene Sequence
and Promoter Methylation Status
For VHL gene sequence analysis, PCR-based ampli-
fication of each of the 3 exons was done as earlier
described,
14
using these VHL primers sets; exon1 forward,
50-TGGAGGATCCTTCTGCGCAC-30; exon 1 reverse;
50-GGCTTCAGACCGTGCTATCG-30; exon 2 forward,
50-GGCTCTTTAACAACCTTTGC-30; exon 2 reverse, 50-
TTGGATACCGTGCCTGACATC-30; exon 3 forward, 50-
ACAGGTAGTTGTTGGCAAAGCC-30; exon 3 reverse,
50-GAAGGAACCAGTCCTGTATC-30. The amplicons
were sequenced using an ABI377 automated sequencer
(Applied Biosystems, Foster City, CA). Sequences derived
from the amplified samples were compared with the wild-
type VHL sequence (GeneBank Accession No. AF010238)
using LaserGene software (DNAStar, Perkin Elmer, Foster
City, CA) to identify and characterize mutations.
The methylation status of the VHL gene promoter
was determined using VHL methylation-specific PCR
primers after DNA bisulfite modification. Genomic DNA
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was modified using the CpGenomeTM DNA modification
kit according to the manufacturer’s protocol (Chemicon
International, Temecula, CA). The product then underwent
PCR-based amplification using methylation-specific pri-
mers. The methylation status was determined by gel
electrophoresis of the PCR products as described earlier.
13
RESULTS
Thirty-six tumors from 33 patients were identified
from the authors’ surgical pathology files that had been
accessioned between 1991 and 2009. Cases from 2006 to
2009 represented consecutive cases identified in daily sign-
out and the tumors identified represented 0.8% (23/3000)
of all adult renal tumors diagnosed during this period.
Clinical Features and Outcomes
There were 17 men and 16 women and the mean
age was 60 years (range 26 to 88). Three patients had
bilateral tumors. One patient, a 26-year-old female, had a
history of von Hippel-Lindau disease (VHLD). None had
a history of tuberous sclerosis. The surgical treatment was
radical/total nephrectomy for 10 tumors and partial
nephrectomy for 26 tumors.
Follow-up was available for 60% (20/33) of the
patients, with a mean follow-up interval of 27.4 months
(range 1 to 85). Nineteen patients had no evidence of
disease during this follow-up period. The patient with
VHLD was alive with stable disease in the contralateral
kidney 15 months after partial nephrectomy.
Pathologic Findings
Gross findings: Of the 28 tumors whose gross
features were described, 23 (82%) were cystic, and 5
(18%) were solid. The mean tumor size was 2.4 cm (range
0.9 to 4.5 cm). Six (17%) tumors were multifocal, with the
number of grossly identifiable tumor nodules ranging
from 2 to 6.
Microscopic findings: Sixty-four percent of tumors
(23/36) were multicystic. A thick circumferential capsule
was present in 72% (26/36) (Fig. 1A), and a partial
capsule was present in the remaining 28% (10/36) of
FIGURE 1. Clear cell tubulopapillary renal cell carcinoma with a thick circumferential capsule (A). Some tumors had tumor cells
embedded in a prominent fibrotic stroma that may show myxoid areas (B). Immunostains for desmin highlighted circumferential
smooth muscle fibers in the tumor capsule (C) and within the stroma (D) in some tumors.
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tumors. There was a prominent fibrotic stroma with
embedded neoplastic cells in 61% of tumors (22/36) (Fig.
1B). Immunostaining for desmin showed 4 tumors (11%)
to have aggregates of circumferential smooth muscle
fibers (Fig. 1C). Focal smooth muscle fibers were seen in 25
(69%) tumors, whereas in 7 (19%) tumors no smooth
muscle fibers were seen in the tumor capsule. One tumor
had fascicles of smooth muscle diffusely scattered through-
out (Fig. 1D), whereas a further 6 (17%) had smooth
muscle fibers present focally within the stroma.
The tumors showed several morphologic patterns
and these were found to frequently coexist within the
same tumor. In 92% (33/36) of the tumors, cysts of
different sizes were present and often contained serosan-
guineous fluid or colloid-like secretion (Fig. 2A). Short
papillae arose from the cyst wall in some cases (Fig. 2B)
and both the cyst wall and papillae were lined by a single
layer of cuboidal cells, with scant eosinophilic cytoplasm
or a moderate amount of clear cytoplasm (Fig. 2B).
In 97% (35/36) of tumors, tubules and acini of
variable sizes and shape were present. These were lined
with a single layer of cells that had scant eosinophilic
cytoplasm or moderate amount of clear cytoplasm. Some
tubules and acini were small with ill-formed lumens and
were compressed to impart a solid appearance (Fig. 3A).
More frequently, tubules and acini were well-formed with
intraluminal proteinaceous secretion (Fig. 3B). Occasion-
ally, the tubules and acini had branching morphology and
focally formed small papillae (Fig. 3C) or formed long
interconnecting ribbons that were lined with clear cells
(Fig. 3D). The nuclei were often not basally oriented;
rather they were oriented away from the basement
membrane and toward the apical surface of the tubules,
acini, and papillae (Fig. 3E). Branching acini (Fig. 3C)
and clear cell ribbons (Fig. 3D) were present in 92%
(33/36) and 44% (16/36) of the tumors respectively,
whereas 94% (34/36) tumors had either feature and 42%
(15/36) had both features.
Papillae were present in 81% (29/36) of the tumors.
One tumor was entirely papillary and consisted of thick
papillae in 1 area (Fig. 4A) and arborizing, thin, and
delicate papillae in the other areas (Fig. 4B). The papillae
were lined with single layer of cells with small amount of
eosinophilic or clear cytoplasm (Fig. 4C). In the majority
of cases, papillae were a minor component of the tumor
that arose within cysts (Fig. 2B). No foamy histiocytes,
psammomatous calcification, or hemosiderin was present
in the papillary areas.
Clear cell nests that were more than 2 cells thick and
without well-formed lumens similar to the cells seen in
CCRCC (Fig. 5A), were present in 58% (21/36) tumors.
These usually formed a minor component, constituting an
average of 8% (range 0% to 50%) of the tumor tissue.
The distribution of the architectural patterns within
the tumors is shown in Table 1. Two tumors contained only
1 pattern, 1 with only papillae and the other with tubules. A
further 11% (4/36) had 2 patterns, 39% (14/36) had 3
patterns, and 62% (16/36) had all the 4 patterns.
Three patients had a concomitant renal cell
carcinoma of a different histologic type within the same
nephrectomy specimen. One patient had a CCRCC with
leiomyomatous stroma, whereas a second patient had a
CCRCC. The patient with VHLD had 3 tumors in her
right kidney, 1 of which was CCRCC (Figs. 6A–D).
Pathologic stage and grade: The pathologic
stage was pT1a in 94% (34/36) and pT1b in 6% (2/36)
tumors. Forty-two percent (15/36) of the tumors were
Fuhrman nuclear grade 1, whereas 58% (21/36) were
nuclear grade 2. No coagulative necrosis, sarcomatoid
dedifferentiation, nor microscopic vascular invasion was
present. Changes of end-stage kidney, including glomer-
ulosclerosis and tubular atrophy, were present in 9%
(3/33) of kidneys.
Immunophenotype: CK7 expression was positive in
all 36 tumors, with cysts, tubules/acini, and papillae; all
being strongly and diffusely positive (Figs. 4D, 5C and 6C).
FIGURE 2. Clear cell tubulopapillary renal cell carcinoma with cysts containing serosanguineous fluid or colloid-like secretion (A).
Short blunt papillae arose from the cyst wall in some cases (B). The cystic wall and papillae were lined with the single layer of
cuboidal cells with scant eosinophilic cytoplasm or moderate amount of clear cytoplasm.
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FIGURE 3. Tubules and acini in the clear cell tubulopapillary renal cell carcinoma . Some tubules and acini were small with
compressed lumens to impart a solid appearance (A). Some were well-formed and had pink intraluminal secretions (B). Branching
pattern with papillary formations (C). In some cases, the tubules and acini formed complex interconnecting ribbons that were
lined with clear cells (D). These tubules, acini, and ribbons were lined with single layer of cells that had scant eosinophilic
cytoplasm or moderate amount of clear cytoplasm. The nuclei were oriented away from the basement membrane and toward the
apical surface of tubules (E).
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Clear cell nests were also positive for CK7 in all of the 21
tumors in which clear cell nests were identified. However,
the staining intensity in clear cell nests was weaker than
that of the other epithelial components in 43% (9/21)
tumors (Table 2 and Fig. 5C) and in 2 tumors only 60%
and 95% of cells in clear cell nests were positive for CK7.
CA9 was positive in 94% (34/36) of tumors (Fig. 5C),
with a mean of 51% (range 1% to 100%) positive tumor
FIGURE 4. Clear cell tubulopapillary renal cell carcinoma composed exclusively of papillary architecture. Papillary structures with
thick fibrotic stalk were seen in 1 area (A). Thin and arborizing papillae were seen in other areas of the same tumor (B). The
papillae were lined with single layer of cells with small amount of eosinophilic or clear cytoplasm (C). Immunohistochemical stains
show that tumor cells are strongly and diffusely positive for CK7 (D) and negative for CD10 (E).
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cells. CA9 was positive in clear cell nests of only 38%
(8/21) of the tumors (Fig. 5D). Most tumors were
negative for CD10 (Figs. 4E, 5E), being positive in only
17% (6/36) of tumors examined. Where positive, CD10
expression was limited to 1% to 10% of the tumor cells.
CD10 was positive in clear cell nests in only 1 of the 21
FIGURE 5. Clear cell nests in clear cell tubulopapillary renal cell carcinoma. Tumor cells with clear cytoplasm formed nests that
were more than 2-cell thick and did not have well-formed lumens (A). The adjacent branching glands and tubules were lined with
single layer of clear cells. A stain for CD31, a marker for vascular endothelial cells, highlighted the delicate capillary network that
separate clear cells into nests (B). A stain for CK7 stained tubules, glands, and clear cell nests. However, the staining intensity in
clear cell nests was weaker than that in the tubules and glands (C). Although the tubules and glands were positive for CA9, the
clear cell nests were negative (D). CD10 was negative in the tumor cells (E).
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tumors and in these cells there was 100% positivity.
AMACR and TFE3 were negative in all the tumors.
Molecular characteristics: Eleven cases selected for
molecular studies were representative cases that did not
significantly differ from those that were not examined
in their clinical, pathologic, and immunohistochemical
characteristics (Tables 1–3). FISH was used to enumerate
the copy numbers of chromosomes 7, 17, and 3p in 10
tumors. Of these tumors only 1 had low copy number
gain of chromosomes 7 and 17 (Table 1, tumor No. 12).
This tumor showed chromosome 7 gain in 12%, and
chromosome 17 gain in 6% of tumor cells and the
mean ± 3 SD for chromosome 7 and 17 gain in non-
neoplastic tissue was 7.5% and 3.2%, respectively. This
tumor was morphologically similar to other tumors
included in this study. As shown in Tables 1 and 2, this
tumor composed 75% cysts, 5% tubuloacini, and 20%
papillae, and was positive for cytokeratin 7 and CA9 but
negative for CD10. For PRCC controls, the chromo-
somes 7 and 17 gain was 82% and 69%, respectively, in
20 tumors. Chromosome 3p deletion was not detected in
any tumor.
The VHL gene was sequenced and the methylation
status of the VHL promoter region was analyzed by the
methylation-specific PCR in 2 tumors. No mutation or
promoter methylation was detected (Table 3).
DISCUSSION
We reported 36 renal epithelial tumors with
distinctive pathologic features that we term “clear cell
tubulopapillary renal cell carcinoma (CCTP-RCC).” We
believe CCTP-RCC to represent a unique subtype of the
renal parenchymal neoplasia that is distinct from other
renal tumors. Microscopically, the presence of branching
tubules/acini and/or complex clear cell ribbons in the
cysts with fibrotic stroma is the key to the identification
of these tumors, whereas the constant finding of positive
CK7 and negative CD10 immunoexpression is also an
important diagnostic feature.
Tumors with similar morphologic and immunohis-
tochemical features have been reported. Michal et al
23,24
described 6 cases of renal angiomyoadenomatous tumor
that seem to be identical to CCTP-RCC reported in this
study. In their studies, the authors describe “abortive
vascular structures” in the tumors, although no detailed
description or illustration was provided. Contrary to that,
we did not observe any significant vascular component
in our tumors. In addition, in the report by Michel,
24
the
emphasis was placed on the leiomyomatous stroma
present within the tumors.
24
They used several antibodies,
including caldesmon, calponin, vimentin, and smooth
muscle actin, to highlight the “leiomyomatous” compo-
nent. Although caldesmon is more specific for smooth
muscle, smooth muscle actin also stains myofibroblasts
within the stroma. Desmin, in contrast, a marker more
sensitive than caldesmon, only showed patchy and weak
staining in their cases. We used the immunostain for
desmin and found that diffuse smooth muscle fascicles
were within the tumor in only minority of our cases.
Therefore, leiomyomatous stroma is not a conspicuous
component of majority of CCTP-RCC.
Recently Tickoo et al
27
described 15 “clear-cell
papillary renal cell carcinoma of the end-stage kidneys,”
which were predominantly cystic tumors and showed
prominent papillary architecture with purely clear-cell
cytology. Seven cases of clear cell papillary renal cell
carcinomas were later reported by Gobbo et al,
10
majority
of which occurred in kidneys unaffected by end-stage
renal diseases. These were low-grade and low-stage renal
tumors, composed mainly of cells with clear cytoplasm
arranged in papillary patterns. All tumors showed strong
positive staining for CK7, but were negative for CD10.
None had gains of chromosome 7 or 17, loss of
Y chromosome, or deletion of 3p. Although the papillary
structures lined with a single layer of clear cells were
identical to the papillary patterns seen in our tumors, it is
uncertain as to whether the papillary component was the
only component of their tumors. Our tumors showed a
spectrum of morphology and papillary structures, cysts,
TABLE 1. Morphologic Characteristics of 36 Clear Cell
Tubulopapillary Renal Cell Carcinomas
Morphologic Pattern (% of Tumor Mass)
Tumor # Cyst Tubulo-acini Papillae Clear Cell Nest
11575 5 5
21550 15 20
31080 5 5
48015 5 0
53065 5 0
63070 0 5
71059 1 30
81079 1 10
9 0 0 100 0
10 5 90 5 0
11 40 50 5 5
12 75 5 20 0
13 60 35 5 0
14 5 65 5 25
15 30 45 20 10
16 20 80 0 0
17 0 100 0 0
18 80 5 15 0
19 60 40 0 0
20 10 85 5 0
21 40 40 10 10
22 70 20 5 5
23 10 70 0 20
24 50 25 5 20
25 5 85 0 10
26 90 5 5 0
27 20 50 5 25
28 50 40 5 5
29 10 85 5 5
30 75 10 15 0
31 90 0 10 0
32 15 70 10 5
33 0 95 0 5
34 0 60 30 10
35 10 85 5 0
36 5 35 10 50
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glands/acini, and clear cell nests were frequently present
within the same tumor. In only 1 tumor did we find an
entirely papillary architecture.
Mai et al
20
studied 21 small tumor nodules that
contained clear tumor cells that were diffusely positive
for CK7. Architecturally, the CK7-positive tumor cells
consisted of cysts and solid cell nests with tubuloacinar or
papillary formations. Although the immunohistochemical
findings from this series were limited, we believe that
these tumors were clear cell tubulopapillary renal cell
carcinomas.
This study contributed to our understanding of this
unique renal tumor in 3 aspects. First, it expanded the
morphologic spectrum of renal clear cell tubulopapillary
renal cell carcinomas and documented the characteristic
morphologic features of this tumor. Although this tumor
can have a plethora of morphologic patterns, including
cysts, tubules, acini, papillae, and clear cell nests; branching
tubules and anastomosing clear cell ribbons, however, are
most characteristic. Second, it provides the molecular and
genetic data on 11 additional tumors and establishes that
these tumors do not have the genetic changes that are
characteristic of CCRCC and PRCC. Third, we proposed
a unifying term, clear cell tubulopapillary renal cell carci-
noma, based on their dominant morphologic features,
for these tumors that shared similar morphologic and
immunohistochemical features but bore different names
owing to minor morphologic variations. The clinical,
pathologic, immunohistochemical, and molecular char-
acteristics of the 82 clear cell tubulopapillary renal cell
carcinomas were reported in the literature and these
reports are summarized in Table 4 and provide a
foundation for future studies of this unique renal tumor.
The overwhelming majority (80 of 82) of the clear
cell tubulopapillary renal cell carcinomas described to
date, including 36 cases in this study, and 46 earlier
reported cases for which data were available, have been
categorized as pathologic stage category pT1, and the
remaining 2 tumors were pT2.
10,20,23,24,27
All have ex-
hibited low-grade nuclear features (Fuhrman grade 1 or 2).
FIGURE 6. Concomitant clear cell tubulopapillary renal cell carcinoma and conventional clear cell renal cell carcinoma in a patient
with von Hippel-Lindau disease (VHLD). This patient had 3 tumor nodules in her right kidney. Two were clear cell tubulopapillary
renal cell carcinoma (A) and the 3rd tumor was a clear cell renal cell carcinoma (B). CK7 was positive in the clear cell
tubulopapillary renal cell carcinoma (C) and negative in the clear cell renal cell carcinoma (D).
Aydin et al Am J Surg Pathol Volume 34, Number 11, November 2010
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Evidence of biological aggressiveness, such as perirenal or
renal sinus invasion, vascular invasion, tumor necrosis,
and sarcomatoid dedifferentiation, has not been observed
in these tumors. Follow-up of 40 patients, including 19 in
this study, showed no evidence of disease after a mean
follow-up period of 28 months. The 1 patient with tumor
recurrence in our series had VHLD and was diagnosed
with stable disease in the contralateral kidney, 15 months
after initial partial nephrectomy. These observations
suggest that clear cell tubulopapillary renal cell carcino-
mas may be biologically indolent tumors; however,
further follow-up studies are needed to better define their
clinical behavior.
Patients may harbor multifocal renal tumors that
include CCTP-RCC and other types of RCC. One patient
in this study had a CCTP-RCC and a concomitant CC-
RCC with leiomyomatous stroma. Two other patients had
CCTP-RCC with coexisting CCRCC. In those patients, the
TABLE 2. Immunohistochemical Profiles of Clear Cell Tubulopapillary Renal Cell Carcinomas
Immunohistochemical Profile (% Positive Cells)
CK7 CA9 CD10
Tumor Overall Cyst
Tubulo-
acini Papillae
Clear
Cell
Nest Overall Cyst
Tubu-
loacini Papillae
Clear
Cell
Nest Overall Cyst
Tubu-
loacini Papillae
Clear
Cell
Nest
1 100 100 100 100 100* 10 80 0 0 0 0 0 0 0 0
2 100 100 100 100 100 10 100 10 80 10 5 0 0 5 5
3 100 100 100 100 100* 80 50 80 80 50 0 0 0 0 0
4 100 100 100 100 N.A. 20 80 20 20 0 0 0 0 0 0
5 100 100 100 100 N.A. 60 60 60 60 0 0 0 0 0 0
6 100 100 100 N.A. 100 1 0 1 0 0 10 0 10 0 0
7 100 100 100 100 100* 30 10 60 0 0 0 0 0 0 0
8 100 100 100 100 100* 70 30 60 30 5 0 0 0 0 0
9 100 N.A. N.A. 100 N.A. 10 N.A. N.A. 10 N.A. 0 N.A. N.A. 0 N.A.
10 100 100 100 100 N.A. 60 60 60 60 N.A. 0 0 0 0 N.A.
11 100 100 100 100 100 80 80 80 100 0 0 0 0 0 0
12 100 100 100 100 N.A. 100 100 100 100 N.A. 0 0 0 0 N.A.
13 100 100 100 100 N.A. 100 100 100 100 N.A. 0 0 0 0 N.A.
14 100 100 100 100 100 5 0 2 0 0 0 0 0 1 0
15 100 100 100 100 100* 80 100 90 100 5 0 0 0 0 0
16 100 100 100 N.A. N.A. 20 20 20 N.A. N.A. 0 0 0 N.A. N.A.
17 100 N.A. 100 N.A. N.A. 100 N.A. 100 N.A. N.A. 0 0 N.A. N.A.
18 100 100 100 100 N.A. 100 100 100 100 N.A. 0 0 0 0
19 100 100 100 N.A. N.A. 100 100 100 N.A. N.A. 0 0 0 N.A. N.A.
20 100 100 100 100 N.A. 80 80 80 100 N.A. 0 0 0 N.A. N.A.
21 99 100 100 100 95* 30 100 30 0 10 0 0 0 0 0
22 100 100 100 100 100 70 0 100 0 0 0 0 0 0
23 100 100 100 100 100 20 0 20 0 0 0 0 0 0 0
24 100 100 100 100 100 5 0 10 0 0 0 0 0 0 0
25 90 100 100 N.A. 60* 60 100 80 N.A. 0 0 0 0 0 0
26 100 100 100 100 N.A. 10 80 0 0 N.A. 0 0 0 0
27 100 100 100 100 100 90 100 100 100 50 0 0 0 0 0
28 100 100 100 100 100 5 10 0 0 0 5 5 0 0 0
29 100 100 100 100 100 10 100 10 0 0 10 0 5 0 100
30 100 100 100 100 N.A. 90 100 90 50 N.A. 0 0 0 0 0
31 100 100 N.A. 100 N.A. 100 100 N.A. 100 N.A. 0 0 0
32 100 100 100 100 100 95 100 95 100 100 0 0 0 0 0
33 100 N.A. N.A. N.A. 100* 0 N.A. 0 N.A. 0 0 0 N.A. 0
34 100 N.A. 100 100 100 0 N.A. 0 0 0 1 0 0 1 0
35 100 100 100 100 N.A. 10 10 10 10 N.A. 0 0 0 0
36 100 100 100 100 100* 30 30 30 30 10 5 0 5 0 0
N.A.-the morphologic component not present in the tumor.
*The staining intensity in clear cell nests was weaker than in other components.
TABLE 3. Molecular Characteristics of 11 Clear Cell
Tubulopapillary Renal Cell Carcinomas
Chromosomal Alteration VHL Gene
Tumor # Cyst 3p +7 +17 Mutation Promoter Methylation
480 FF
90FFFF F
10 5 FFF
11 40 FFF
12 75 F++
15 30 FFF
16 20 FFF
18 80 FFF
19 60 FFF
21 40 FFF
22 70 FFF
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TABLE 4. Clinical, Immunohistochemical, and Molecular Characteristics of Clear Cell Tubulopapillary Renal Cell Carcinomas Reported in the Literature
Follow-up Immunohistochemistry Chromosomal Alteration VHL Gene
Case No* Sex Age Stage ESRD Duration (mo) OutcomewCK7 CD10 CA9 AMACR TFE3 7 Gain 17 Gain 3p Loss Mutation Promoter Methylation References
1 M 58 1a 9 NED + z+ N.A. N.A. N.A. N.A. N.A. 24
2 M 49 1b 12 NED + z+ N.A. N.A. N.A. N.A. N.A.
3 M 93 2 8 NED + z+ N.A. N.A. N.A. N.A. N.A.
4 F 73 1a 29 DOOC + z+ N.A. N.A. N.A. N.A. N.A.
5 M 50 1a N.A. N.A. + z+ N.A. N.A. N.A. N.A. N.A. N.A. N.A.
6 M 93 2 6 NED N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A. 23
7 M 50 1a + N.A. N.A. yN.A. N.A. JN.A. N.A. N.A. N.A. N.A. N.A. 27
8 F 35 1a + N.A. N.A. yN.A. N.A. JN.A. N.A. N.A. N.A. N.A. N.A.
9 M 50 1a + N.A. N.A. yN.A. N.A. JN.A. N.A. N.A. N.A. N.A. N.A.
10 F 56 1a + N.A. N.A. yN.A. N.A. JN.A. N.A. N.A. N.A. N.A. N.A.
11 F 57 1a + N.A. N.A. yN.A. N.A. JN.A. N.A. N.A. N.A. N.A. N.A.
12 M 78 1a + N.A. N.A. yN.A. N.A. JN.A. N.A. N.A. N.A. N.A. N.A.
13 M 60 1a + N.A. N.A. yN.A. N.A. JN.A. N.A. N.A. N.A. N.A. N.A.
14 F 50 1b + N.A. N.A. yN.A. N.A. JN.A. N.A. N.A. N.A. N.A. N.A.
15 F 75 1 + N.A. N.A. yN.A. N.A. JN.A. N.A. N.A. N.A. N.A. N.A.
16 M 48 1 + N.A. N.A. yN.A. N.A. JN.A. N.A. N.A. N.A. N.A. N.A.
17 F 64 1a 24 NED + + N.A. N.A. 10
18 M 63 1a 26 NED + + + N.A. N.A.
19 M 64 1b 1 NED + + N.A. N.A.
20 M 55 1b 48 NED + +(1-25%) + N.A. N.A.
21a F 53 1a + 22 NED + + N.A. N.A.
21b 1a + + – – N.A. N.A.
21c 1a + + – – N.A. N.A.
24 M 60 1a zNo Met + +(<5%) N.A. N.A. N.A. N.A. N.A. N.A. N.A. 21
25 F 72 1a zNo Met + N.A. N.A. N.A. N.A. N.A. N.A. N.A.
26a M 56 1a zNo Met + N.A. +(5-30%) N.A. N.A. N.A. N.A. N.A. N.A.
26b 1a + N.A. N.A. N.A. N.A. N.A. N.A. N.A.
27a M 73 1a zNo Met + N.A. N.A. N.A. N.A. N.A. N.A. N.A.
27b 1a + N.A. N.A. N.A. N.A. N.A. N.A. N.A.
28a F 65 1a zNo Met + N.A. N.A. N.A. N.A. N.A. N.A. N.A.
28b 1a + N.A. N.A. N.A. N.A. N.A. N.A. N.A.
29a M 29 1a zNo Met + +(< 5%) N.A. N.A. N.A. N.A. N.A. N.A. N.A.
29b 1a + N.A. N.A. N.A. N.A. N.A. N.A. N.A.
29c 1a + N.A. N.A. N.A. N.A. N.A. N.A. N.A.
29d 1a + N.A. N.A. N.A. N.A. N.A. N.A. N.A.
30a M 56 1a zNo Met + +(< 5%) N.A. N.A. N.A. N.A. N.A. N.A. N.A.
30b 1a + N.A. N.A. N.A. N.A. N.A. N.A. N.A.
31a M 53 1a zNo Met + +(5-30%) N.A. N.A. N.A. N.A. N.A. N.A. N.A.
31b 1a + N.A. +(< 5%) N.A. N.A. N.A. N.A. N.A. N.A.
31c 1a + N.A. N.A. N.A. N.A. N.A. N.A. N.A.
31d 1a + N.A. N.A. N.A. N.A. N.A. N.A. N.A.
32 M 65 1a zNo Met + +(<5%) N.A. N.A. N.A. N.A. N.A. N.A. N.A.
33a M 57 1a zNo Met + N.A. N.A. N.A. N.A. N.A. N.A. N.A.
33b 1a + N.A. N.A. N.A. N.A. N.A. N.A. N.A.
34 M 62 1a + + N.A. N.A. N.A. N.A. N.A. Current
study
35 F 67 1a 12 NED + + (5%) + N.A. N.A. N.A. N.A. N.A.
36 F 38 1a 48 NED + + N.A. N.A. N.A. N.A. N.A.
37 M 54 1a 85 NED + + N.A. N.A. N.A.
38 M 57 1a 77 NED + + N.A. N.A. N.A. N.A. N.A.
39 F 44 1a 81 NED + + (10%) + (1%) N.A. N.A. N.A. N.A. N.A.
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1618 |www.ajsp.com r2010 Lippincott Williams & Wilkins
40 M 56 1a N.A. N.A. + + N.A. N.A. N.A. N.A. N.A.
41 M 51 1a N.A. N.A. + + N.A. N.A. N.A. N.A. N.A.
42 M 61 1a N.A. N.A. + + -
43 F 67 1b N.A. N.A. + + - N.A. N.A.
44 F 72 1a 41 NED + + - N.A. N.A.
45a F 61 1a N.A. N.A. + + + + N.A. N.A.
45b 1a + + N.A. N.A. N.A. N.A. N.A.
46 F 57 1a 30 NED + +(5%) N.A. N.A. N.A. N.A. N.A.
47 F 60 1a + 33 NED + + N.A. N.A.
48a M 78 1b 1 NED + + N.A. N.A.
48b 1a + + N.A. N.A. N.A. N.A. N.A.
49 M 59 1a 21 NED + + N.A. N.A.
50 F 68 1a 14 NED + + N.A. N.A.
51 M 79 1a 23 NED + + N.A. N.A. N.A. N.A. N.A.
52 M 60 1a N.A. N.A. + + N.A. N.A.
53 M 59 1a 22 NED + + N.A. N.A.
54 M 41 1a 5 NED + + N.A. N.A. N.A. N.A. N.A.
55 F 72 1b N.A. N.A. + – 5 – N.A. N.A. N.A. N.A. N.A.
56 F 47 1a 10 NED + + N.A. N.A. N.A. N.A. N.A.
57 F 26 1a 15 AWD + + N.A. N.A. N.A. N.A. N.A.
58 M 53 1a N.A. N.A. + + N.A. N.A. N.A. N.A. N.A.
59 M 71 1a N.A. N.A. + +(5%) +(5%) N.A. N.A. N.A. N.A. N.A.
60 M 78 1b 4.5 NED + +(10%) + N.A. N.A. N.A. N.A. N.A.
61 M 52 1a + N.A. N.A. + + N.A. N.A. N.A. N.A. N.A.
62 M 68 1a 3 NED + + N.A. N.A. N.A. N.A. N.A.
63a F 49 1a 1 NED + + N.A. N.A. N.A. N.A. N.A.
63b 1a + – – – N.A. N.A. N.A. N.A. N.A.
64 F 61 1a N.A. N.A. + +(1%) N.A. N.A. N.A. N.A. N.A.
65 F 79 1a 83 NED + + N.A. N.A. N.A. N.A. N.A.
66 F 88 1a N.A. N.A. + +(5%) + N.A. N.A. N.A. N.A. N.A.
zReported as focally positive in 1, and negative in 4 of 5 cases.
yFour of 4 cases were positive for CK7.
JFour of 4 cases were negative for AMACR.
zFollow-up duration 12-120 months.
wFollow-up outcomes.
*Same number with different suffixes (a-d) denotes same patient with multiple or bilateral tumors.
indicates negative; +, positive; AWD, alive with disease; DOOC, dead of other cause; ESRD, end-stage renal disease; F, female; M, male; N.A., not available or not carried out; NED, no evidence of disease;
No Met, no metastasis; VHL, von Hippel Lindau.
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r2010 Lippincott Williams & Wilkins www.ajsp.com |1619
clinical outcome is likely to be driven by the behavior of the
other renal tumors rather than that of the CCTP-RCC.
Several other renal tumors, including conventional
CCRCC, CCRCC with leiomyomatous stroma, multi-
locular cystic renal cell carcinoma (MLCRCC), PRCC,
and the mixed epithelial and stroma tumor (MEST), have
morphologic features that resemble CCTP-RCC to some
extent. CCRCC and PRCC are most likely to be mistaken
for CCTP-RCC. Unlike PRCC, these tumors have a clear
cytoplasm and tumor necrosis, aggregates of foamy
macrophages, psammomatous calcification, and hemo-
siderin deposition are not observed. The presence of the
clear cells lining the cysts, tubules, and papillae may also
raise a suspicion for CCRCC. However, these tumors
lack the delicate sinusoidal vascular network typical of
CCRCC and the branched tubules and complex clear cell
ribbons of the clear cell tubulopapillary renal cell
carcinoma are not found in CCRCC.
The immunophenotype of this tumor is distinct
from CCRCC and PRCC. The CCRCC is positive
for CA9 and CD10
4,29,31
but negative for CK7 and
AMACR,
16,28
whereas PRCC is positive for CK7, CD10,
and AMACR,
8,28,31
but is usually negative for CA9.
22
All
of our cases of CCTP-RCC showed strong and diffuse
staining for CK7, variable staining for CA9, and negative
staining for AMACR. In addition, the CD10 immuno-
expression was negative in over 80% of the cases and was
only focally positive in the remaining cases. Furthermore,
staining for TFE3 protein, a distinctive and diagnostic
feature of Xp11.2 translocation RCC,
1,3
was not identi-
fied in any of our tumors.
The genetic findings in our tumors also differ from
those of CCRCC and PRCC. CCRCC shows a highly
specific deletion of chromosome 3p,
6
and mutations in
VHL gene and methylation of the gene promoter have been
detected in the vast majority of sporadic CCRCC.
7,15
Most
of the CCRCC that we used as controls showed deletion of
the subtelomeric locus 3p25, whereas in our control cases
of PRCC, deletion of 3p was not observed. Gains of
chromosomes 7 and 17, in contrast, are commonly
identified in PRCC
5
and our PRCC controls all showed
these gains. In contrast to this, 3p deletion was not
observed in any of our CCTP-RCCs. Two tumors whose
entire VHL gene was sequenced and the promoter region
was analyzed with methylation-specific PCR had no such
alterations. Furthermore, gains of chromosomes 7 and 17
were not present in 9 of our 10 tumors tested, whereas the
remaining tumor showed low copy number gains of
chromosomes 7 and 17.
CCTP-RCC should also be distinguished from rare
cases of the renal cell carcinomas with papillary architec-
ture and variable proportion of cells with clear cyto-
plasm.
11,21
These cases represent conventional CCRCC
with secondary papillary formation, PRCC with clear cell
changes, composite CCRCC and PRCC, or unclassified
RCC with both clear cell and papillary components.
Although superficially resembling CCTP-RCC, they are
easily distinguishable from the former as they often exhibit
pathologic features of aggressive RCC, including Fuhrman
grade 3 and 4 nuclei, coagulative necrosis, vascular
invasion, lymph node metastasis, and sarcomatoid differ-
entiation,
21
none of which is seen in CCTP-RCC. In
addition, none of these tumors were CK7 positive and
AMACR negative,
11,21
whereas all CCTP-RCC were CK7
positive and AMACR negative. Furthermore, except for 1
case,
11
these tumors had the cytogenetic changes character-
istic of either CCRCC, PRCC, or both.
11,21
The CCRCC with leiomyomatous stroma was
recently described as the tumors composed of nests of
clear cells similar to those seen in the CCRCC.
17,25
The
neoplastic epithelial cells of these tumors are diffusely
positive for CK7 and are also positive for CD10. In
addition, genetic studies of these have shown changes
typical of CCRCC,
25
and as such, the morphologic,
immunohistochemical, and genetic features of CCRCC
with leiomyomatous stroma seems to differ significantly
from those of CCTP-RCC.
Multilocular cystic renal cell carcinoma (MLCRCC)
is a variant of CCRCC characterized by multilocular cystic
pattern in which the cysts are lined by clear ells with low
nuclear grade.
12,26
The majority of our CCTP-RCC was
cystic and some had multilocular cystic component and
were lined with clear cells. It is reasonable to consider and
rule out MLCRCC. However, CCTP-RCC also has other
components such as nests of tubules, acini, and papillae
that are not seen in MLCRCC, and does not harbor
chromosome 3p alterations as MLCRCC does.
12
As CCTP-RCC also has a prominent fibrous stroma
in addition to the epithelial components, distinction from
mixed epithelial and stroma tumor (MEST) is also
warranted. MEST most commonly affects young and
middle-aged patients with a striking female predomi-
nance.
18,32
Clinically, our patients were older with no
gender predilection. Ovarian-type stroma is seen in the
majority of MESTs,
32
but is not seen in any CCTP-RCC.
Recognition of the CCTP-RCC as a distinctive form
of renal neoplasia may have important implications for
the management of small renal tumors. Small tumors in
poor surgical candidates and benign or low-grade renal
tumors diagnosed on renal biopsy are increasingly being
managed conservatively by active surveillance.
19
The
CCTP-RCC often contains clear cells that resemble
CCRCC and may be mistaken for the latter in small
needle biopsies. As a consequence, CCTP-RCC should be
included in the differential diagnosis of small renal tumors
with clear cells and prudent use of immunostains for
CK7, CD10, AMACR, and CA9 should lead to a correct
diagnosis.
An intriguing question arises as to whether CCTP-
RCC represents a precursor lesion to CCRCC, as it often
contains clear cells in the form of complex clear cell ribbons
and solid clear cell nests. One of the patients in our study had
VHLD and had CCTP-RCC in addition to CCRCC. This
may be construed to suggest that CCTP-RCC is the
precursor lesion to CCRCC. However, our study has shown
that CCTP-RCC and CCRCC do not share immunohisto-
chemical and molecular features. These findings do not lend
support for a precursor role of CCTP-RCC and the
Aydin et al Am J Surg Pathol Volume 34, Number 11, November 2010
1620 |www.ajsp.com r2010 Lippincott Williams & Wilkins
occurrence of this tumor in the patient with VHLD may
reflect the fact that clear cell tubulopapillary renal cell
carcinoma often occurs in renal cysts that are dominant
manifestation of VHLD.
30
In summary, we report a series of low grade and stage
clear cell tubulopapillary renal cell carcinomas. They
constitute a unique subtype in the spectrum of renal
epithelial neoplasia based on their morphologic and
immunohistochemical features that are distinct from other
renal epithelial tumors recognized in the latest WHO
classification. Their recognition is critical for diagnosis,
prognosis, and clinical management.
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Am J Surg Pathol Volume 34, Number 11, November 2010 Clear Cell Tubulopapillary Renal Cell Carcinoma
r2010 Lippincott Williams & Wilkins www.ajsp.com |1621
    • "Proteinaceous secretion is frequently observed within lumina of the tubules or acini, and cystic spaces contain seroanguinous fluid or colloid-like section [4] . Nuclei of most CCP- RCCs have a horizontally linear arrangement apart from the basement membrane (Figure 1B) [4, 5, 7, 8, 12, 14, 19, 21, 22]. According to the Fuhrman's criteria, nuclear atypia corresponds to Fuhrman Grade 1 or 2 [4-9, 12, 14, 17, 19, 21] . "
    [Show abstract] [Hide abstract] ABSTRACT: The disease concept of clear cell (tubulo) papillary renal cell carcinoma (CCP-RCC) as a distinct subtype of renal cell carcinoma has been recently established. First described in the setting of end stage renal disease, this tumor type is more frequently recognized and encountered in a sporadic setting. In this article, we provide an overview of the recent understanding of this tumor. Macroscopically, tumors are well circumscribed with well-developed tumor capsule. Histologically, the tumor cells are cuboidal to low columnar cell with clear cytoplasm and papillary and tubulo-papillary configuration. Immunohistochemically, tumor cells generally show diffuse expression for cytokeratin 7, CA9 (cup-shaped pattern), HIF-1, GLUT-1 and high molecular weight cytokeratin, but negative for AMACR, RCC Ma and TFE3. CD10 is negative or focally positive in most tumors. Genetically, this tumor has no characteristics of clear cell RCC or papillary RCC. Prognostically, patients with CCP-RCC behave in an indolent fashion in all previously reported cases. In conclusion, although this tumor has been integrated into recent International Society of Urologic Pathology Classification of renal neoplasia, both aspects of disease concept and clinical behavior are yet to be fully elucidated. Further publications of large cohorts of patients will truly help understand the biologic potential and the molecular underpinnings of this tumor type.
    Full-text · Article · Dec 2014
    • "Renal angiomyoadenomatous tumor (RAT) and clear cell papillary renal cell carcinoma (CCPRCC) are 2 relatively recently described low-grade neoplastic entities with overlapping histologic features and with indolent clinical behavior so far [1] [2] [3] [4] [5] [6]. Recently, RAT and CCPRCC have been thought of as 2 ends of a spectrum of 1 nosologic entity. "
    [Show abstract] [Hide abstract] ABSTRACT: We present a cohort of 8 renal carcinomas that displayed a variable (5%-95% extent) light microscopic appearance of renal angiomyoadenomatous tumor/clear cell papillary renal cell carcinoma (RAT/CCPRCC) without fulfilling the criteria for these tumors. All but 1 case predominantly (75%-95% extent) showed histopathologic features of conventional clear cell renal cell carcinoma. In 5 of 7 cases with mostly conventional clear renal cell carcinoma (CRCC) morphology, a diagnosis of CRCC was supported by the molecular genetic findings (presence of von Hippel-Lindau tumor suppressor [VHL] mutation and/or VHL promoter methylation and/or loss of heterozygosity [LOH] for 3p). Of the other 2 cases with predominantly characteristic CRCC morphology, 1 tumor did not reveal any VHL mutation, VHL promoter methylation, or LOH for 3p, and both chromosomes 7 and 17 were disomic, whereas the other tumor displayed polysomy for chromosomes 7 and 17 and no VHL mutation, VHL promoter methylation, or LOH for 3p. One tumor was composed primarily (95%) of distinctly RAT/CCPRCC-like morphology, and this tumor harbored a VHL mutation and displayed polysomy for chromosomes 7 and 17. Of the 5 cases with both histomorphologic features and molecular genetic findings of CRCC, we detected significant immunoreactivity for α-methylacyl-CoA racemase in 2 cases and strong diffuse immunopositivity for cytokeratin 7 in 3 cases. Despite the combination of positivity for α-methylacyl-CoA racemase and cytokeratin 7 in 2 cases, there was nothing to suggest of the possibility of a conventional papillary renal cell carcinoma with a predominance of clear cells.
    Full-text · Article · Feb 2013
    • "No recurrent DNA copy number aberrations have been identified. In particular, the copy number changes characteristic of clear-cell RCC and papillary RCC have not been seen[23]–[25]. A significant attribute of this tumor is its indolent clinical course, with no tumor recurrences or metastases reported to date[22]–[24]. "
    [Show abstract] [Hide abstract] ABSTRACT: Renal cell carcinoma (RCC) is an important contributor to cancer-specific mortality worldwide. Targeted agents that inhibit key subtype-specific signaling pathways have improved survival times and have recently become part of the standard of care for this disease. Accurately diagnosing and classifying RCC on the basis of tumor histology is thus critical. RCC has traditionally been divided into clear-cell and non-clear-cell categories, with papillary RCC forming the most common subtype of non-clear-cell RCC. Renal neoplasms with overlapping histologies, such as tumors with mixed clear-cell and papillary features and hybrid renal oncocytic tumors, are increasingly seen in contemporary practice and present a diagnostic challenge with important therapeutic implications. In this review, we discuss the histologic, immunohistochemical, cytogenetic, and clinicopathologic aspects of these differential diagnoses and illustrate how the classification of RCC has evolved to integrate both the tumor's microscopic appearance and its molecular fingerprint.
    Full-text · Article · Dec 2012
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