SPECIAL ARTICLE
The International Society of Urological Pathology (ISUP)
Vancouver Classification of Renal Neoplasia
John R. Srigley, MD,* Brett Delahunt, MD,w John N. Eble, MD,z Lars Egevad, MD, PhD,y
Jonathan I. Epstein, MD,8 David Grignon, MD,z Ondrej Hes, MD, PhD,z Holger Moch, MD,#
Rodolfo Montironi, MD,** Satish K. Tickoo, MD,ww Ming Zhou, MD, PhD,zz
Pedram Argani, MD,yy and The ISUP Renal Tumor Panel
Abstract: The classification working group of the International
Society of Urological Pathology consensus conference on renal
neoplasia was in charge of making recommendations regarding
additions and changes to the current World Health Organization Classification of Renal Tumors (2004). Members of
the group performed an exhaustive literature review, assessed
the results of the preconference survey and participated in the
consensus conference discussion and polling activities. On the
basis of the above inputs, there was consensus that 5 entities
should be recognized as new distinct epithelial tumors within the
classification system: tubulocystic renal cell carcinoma (RCC),
acquired cystic disease–associated RCC, clear cell (tubulo)
papillary RCC, the MiT family translocation RCCs (in particular t(6;11) RCC), and hereditary leiomyomatosis RCC
syndrome–associated RCC. In addition, there are 3 rare carcinomas that were considered as emerging or provisional new
entities: thyroid-like follicular RCC; succinate dehydrogenase B
deficiency–associated RCC; and ALK translocation RCC.
Further reports of these entities are required to better understand the nature and behavior of these highly unusual tumors.
There were a number of new concepts and suggested modifications to the existing World Health Organization 2004 categories. Within the clear cell RCC group, it was agreed upon
From the *Department of Pathology and Molecular Medicine,
McMaster University, Hamilton, ON, Canada; wDepartment of
Pathology and Molecular Medicine, Wellington School of Medicine,
University of Otago, Wellington, New Zealand; zDepartment of
Pathology, Indiana University School of Medicine, Indianapolis, IN;
Departments of 8Pathology, Urology and Oncology; yyPathology
and Oncology, Johns Hopkins Medical Institutions, Baltimore, MD;
wwMemorial Sloan Kettering Cancer Centre, NY; zzDepartment of
Pathology, in New York University Medical Centre, New York, NY;
yDepartment of Oncology and Pathology, Karolinska University
Hospital Solna, Stockholm, Sweden; zDepartment of Pathology,
University Hospital Plzen, Plzen, Czech Republic; #Institute of
Surgical Pathology, University of Zurich, Switzerland; and **Section
of Pathological Anatomy, Polytechnic University of Medicine,
United Hospitals, Ancona, Italy.
Conflicts of Interest and Source of Funding: The authors have disclosed
that they have no significant relationships with, or financial interest
in, any commercial companies pertaining to this article.
Correspondence: John R. Srigley, MD, Department of Laboratory
Medicine, Trillium Health Partners, Credit Valley Hospital, 2200
Eglinton Avenue West, Mississauga, ON, Canada L5M 2N1 (e-mail:
[email protected]).
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Am J Surg Pathol
Volume 37, Number 10, October 2013
that multicystic clear cell RCC is best considered as a neoplasm
of low malignant potential. There was agreement that subtyping
of papillary RCC is of value and that the oncocytic variant of
papillary RCC should not be considered as a distinct entity. The
hybrid oncocytic chromophobe tumor, which is an indolent
tumor that occurs in 3 settings, namely Birt-Hogg-Dubé Syndrome, renal oncocytosis, and as a sporadic neoplasm, was
placed, for the time being, within the chromophobe RCC category. Recent advances related to collecting duct carcinoma,
renal medullary carcinoma, and mucinous spindle cell and
tubular RCC were elucidated. Outside of the epithelial category,
advances in our understanding of angiomyolipoma, including
the epithelioid and epithelial cystic variants, were considered. In
addition, the apparent relationship between cystic nephroma
and mixed epithelial and stromal tumor was discussed, with the
consensus that these tumors form a spectrum of neoplasia. Finally, it was thought that the synovial sarcoma should be removed from the mixed epithelial and mesenchymal category and
placed within the sarcoma group. The new classification is to be
referred to as the International Society of Urological Pathology
Vancouver Classification of Renal Neoplasia.
Key Words: renal neoplasia, classification, renal cell carcinoma,
diagnosis, morphology, International Society of Urological
Pathology
(Am J Surg Pathol 2013;37:1469–1489)
T
he classification of renal epithelial neoplasia has undergone significant change over the last 3 decades.
Advances in our understanding of basic morphology,
immunohistochemistry (IHC), cytogenetics, and molecular pathology have led to an expansion in the number of
distinct tumor entities that we currently recognize.1–3 Two
important international consensus conferences (Heidelberg 1996, Rochester 1997) provided the basis for much
of the last World Health Organization (WHO) renal tumor classification, which appeared in 2004.2–4 Over the
last decade several new tumor entities have emerged, and
there have been refinements in many existing WHO categories.5 The classification working group of the International Society of Urological Pathology (ISUP)
consensus conference on renal neoplasia was entrusted
with the responsibility of reviewing available literature
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and making recommendations regarding additions,
changes, and refinements to the current renal tumor
classification system. The background and logistical
considerations related to this consensus conference are
dealt with in an introductory report.6 The literature review, results of a preconference survey, and deliberations
at the consensus conference yielded recommendations
relating to proposed new epithelial neoplasms, emerging/
provisional new entities, and new concepts and clarifications regarding the existing WHO renal tumor entities. The proposed new epithelial neoplasms and
emerging/provisional new entities are shown in Table 1.
Emerging/provisional new entities, while appearing distinctive, are so rarely reported that the working group
reserved judgment regarding their place in the classification system pending publication of additional reports
and/or further refinements in diagnostic criteria.
The ISUP-recommended modifications of the WHO
2004 renal tumor classification are displayed in Table 2.
PROPOSED NEW EPITHELIAL NEOPLASMS
Tubulocystic Renal Cell Carcinoma
The concept of tubulocystic renal cell carcinoma
(TC-RCC) evolved from the literature on putative lowgrade collecting duct carcinoma (CDC).7,8 A similar-appearing tumor was depicted in an early textbook by Pierre
Masson,9 who used the term “Bellinian epithelioma.” In
recent years, 3 large series of TC-RCC have been published and provide the basis for recognizing this distinctive tumor.10–12 In total, <70 cases have been reported;
patients have a mean age of about 60 years (range, 18
to 94 y) with a strong male predominance (Z7:1).10–13
Patients are usually asymptomatic, and on imaging TCRCC is usually seen as a complex cyst, often type 3 or 4 in
the Bosniak classification system. These tumors are generally low stage and amenable to either partial or radical
nephrectomy.
Tubulocystic carcinomas typically have a cortical or
cortical-medullary epicenter and are defined by characteristic macroscopic and microscopic appearances. These
tumors are well circumscribed, usually encapsulated, and
have a white or gray “bubble wrap” cut surface. Histologically, they are composed of well-formed small-sized to
TABLE 1. Proposed New Renal Epithelial Tumors and
Emerging/Provisional Tumor Entities
New epithelial tumors
Tubulocystic renal cell carcinoma
Acquired cystic disease associated renal cell carcinoma
Clear cell (tubulo) papillary renal cell carcinoma
MiT family translocation renal cell carcinoma (including t(6;11) renal
cell carcinoma)
Hereditary leiomyomatosis renal cell carcinoma syndrome associated
renal cell carcinoma
Emerging/provisional entities
Thyroid-like follicular renal cell carcinoma
Succinic dehydrogenase B deficiency associated renal cell carcinoma
ALK-translocation renal cell carcinoma
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TABLE 2. ISUP Vancouver Modification of WHO (2004)
Histologic Classification of Kidney Tumors
Renal cell tumors
Papillary adenoma
Oncocytoma
Clear cell renal cell carcinoma
Multilocular cystic clear cell renal cell neoplasm of low malignant
potential*
Papillary renal cell carcinomaw
Chromophobe renal cell carcinoma
Hybrid oncocytic chromophobe tumor*
Carcinoma of the collecting ducts of Bellini
Renal medullary carcinoma
MiT family translocation renal cell carcinoma*
Xp11 translocation renal cell carcinoma
t(6;11) renal cell carcinoma*
Carcinoma associated with neuroblastoma
Mucinous tubular and spindle cell carcinoma
Tubulocystic renal cell carcinoma*
Acquired cystic disease associated renal cell carcinoma*
Clear cell (tubulo) papillary renal cell carcinoma*
Hereditary leiomyomatosis renal cell carcinoma syndrome-associated
renal cell carcinoma*
Renal cell carcinoma, unclassified
Metanephric tumors
Metanephric adenoma
Metanephric adenofibroma
Metanephric stromal tumor
Nephroblastic tumors
Nephrogenic rests
Nephroblastoma
Cystic partially differentiated nephroblastoma
Mesenchymal tumors
Occurring mainly in children
Clear cell sarcoma
Rhabdoid tumor
Congenital mesoblastic nephroma
Ossifying renal tumor of infants
Occurring mainly in adults
Leiomyosarcoma (including renal vein)
Angiosarcoma
Rhabdomyosarcoma
Malignant fibrous histiocytoma
Hemangiopericytoma
Osteosarcoma
Synovial sarcoma*
Angiomyolipoma
Epithelioid angiomyolipoma*
Leiomyoma
Hemangioma
Lymphangioma
Juxtaglomerular cell tumor
Renomedullary interstitial cell tumor
Schwannoma
Solitary fibrous tumor
Mixed mesenchymal and epithelial tumors
Cystic nephroma/mixed epithelial stromal tumor
Neuroendocrine tumors
Carcinoid (low-grade neuroendocrine tumor)
Neuroendocrine carcinoma (high-grade neuroendocrine tumor)
Primitive neuroectodermal tumor
Neuroblastoma
Pheochromocytoma
Hematopoietic and lymphoid tumors
Lymphoma
Leukemia
Plasmacytoma
Germ cell tumors
Teratoma
Choriocarcinoma
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TABLE 2. (continued)
Metastatic tumors
Other tumors
*Additions and changes in terminology or position in classification.
wThe majority of consensus attendees subtype papillary carcinoma (type 1,
type 2 or not otherwise specified).
medium-sized tubules and cystically dilated larger tubules
in varying proportions (Fig. 1). The luminal spaces are
lined by atypical cells with abundant eosinophilic cytoplasm and often have, at least focally, a hobnail configuration. The nuclei are enlarged and have prominent
nucleoli (nucleolar grade 3). Mitoses are inconspicuous.
The intervening stroma is generally hypocellular and fibrotic. Occasional chronic inflammatory cells may be
present.
By IHC, the tumor cells stain positively for cytokeratins CK8, CK18, and CK19 and less frequently for
CK7.10–12 A small percentage of cases stain positively for
high–molecular weight keratin (34bE12). Nearly all cases
show positivity for CD10 and racemase (AMACR). Less
than half of the cases will show positivity for PAX2 and
carbonic anhydrase IX (CA-IX).
Ultrastructural studies show glandular epithelial
cells with short microvilli having a brush border configuration and complex cytoplasmic interdigitation. These
features along with IHC results, show mixed features of
proximal convoluted tubules and distal tubules.12
There have been limited molecular studies of TCRCC because of its rarity. A gene expression study of 1
case showed molecular clustering with papillary renal cell
carcinoma (PRCC).11 In another study no molecular
overlap with clear cell or chromophobe renal cell carcinoma (RCC) was demonstrated.13 Using oligonucleotide
microanalysis, a unique signature has been identified for
Classification of Renal Neoplasia
TC-RCC, and gains in chromosomes 7 and 17 and loss of
the Y chromosome using fluorescence in situ hybridization (FISH) analysis were commonplace, suggesting a
relationship between TC-RCC and PRCC.12,13
The morphology of TC-RCC may overlap to some
extent with PRCC and CDC.11,13–15 Some type 2 PRCCs
have areas that are virtually indistinguishable from TCRCC suggesting a possible relationship. Furthermore,
separate TC-RCC and PRCC tumors may be found in the
same kidney.13 These observations suggest a relationship
between these 2 tumors.
Less commonly, CDC may show areas resembling
TC-RCC, a finding which is not surprising given the fact
that TC-RCC evolved out of the concept of low-grade
CDC.16 Conversely, rare cases of TC-RCC can have areas
that overlap with CDC.16 However, CDC typically shows
distinct histologic features including a medullary/hilar
epicenter, an infiltrative growth pattern, and a desmoplastic stromal reaction. Both CDC and TC-RCC show
high-grade nucleolar features. Gene expression profiling
studies show that TC-RCC and CDC are distinctive entities at a molecular level.17
The term TC-RCC should be restricted to those
tumors that display typical macroscopic and microscopic
appearance as described above. The term should not be
used in situations in which there is a tubulocystic pattern
admixed with the usual elements of PRCC or CDC. Some
would allow focal areas similar to PRCC in an otherwise
typical TC-RCC.16
The great majority of reported TC-RCCs (>90%)
have behaved in an indolent manner. In one report, the
role of extended active surveillance has been suggested.18
The resected tumors are generally low stage (pT1, pT2)
with <10% showing pT3 features. A local recurrence has
been documented,11 and 4 cases with metastatic disease
including pelvic lymph nodes, liver, and bone have been
noted.11–13,16 There is a report of sunitinib being used to
treat a patient with metastatic TC-RCC.19
Acquired Cystic Disease–associated RCC
FIGURE 1. TC-RCC. Note variably sized simple tubules, some
of which are cystically dilated. The tubules are lined by
cuboidal cells showing nuclear enlargement and prominent
nucleoli.
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Acquired cystic disease–associated RCC (ACDRCC) is the most common subtype of RCC occurring in
end-stage kidneys, specifically those with acquired cystic
disease. The tumor is characterized by cells with eosinophilic cytoplasm, cribriform/sieve-like architecture, and
intratumoral oxalate crystals. At the 2012 ISUP consensus conference, 91% of respondents thought that
ACD-RCC should be recognized as a distinct renal cell
tumor entity.
ACD-RCC accounts for 36% of the largest tumors
present in end-stage kidneys, and 46% of these are in endstage kidneys with acquired cystic disease.20 Most tumors
are diagnosed incidentally on radiologic follow-up in
patients with chronic renal disease.20,21 In some recent
publications, a long duration of dialysis (>10 y) has had a
stronger association with ACD-RCC compared with
other subtypes of RCC arising in this setting,22–24 although such an association was not identified in another
large series.20
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FIGURE 2. ACD-RCC. Note tubules lined by multilayered
atypical epithelium showing prominent vacuolation yielding a
cribriform-like pattern. Note also the presence of oxalate
crystals.
The tumors often appear as nodules arising from
cyst walls, occasionally completely filling these cysts, or as
solid masses separate from the cysts. The noncystic tumors are well circumscribed and may be surrounded by a
thick fibrous capsule showing dystrophic calcification.
Cut surfaces are tan to yellow, and hemorrhage and necrotic/friable areas are commonplace. Multifocality and
bilaterality are seen in >50% and >20% of the cases,
respectively.20
ACD-RCC shows acinar, tubular, solid-alveolar,
microcystic and macrocystic, papillary, and solid
sheet-like architectural patterns in various combinations
and proportions.5,20–22,24,25 Most tumor cells have abundant granular eosinophilic cytoplasm, with round to oval
nuclei showing vesicular chromatin and prominent nucleoli. Foci with clear to vacuolated cytoplasm may also
be present. One characteristic feature is the presence of
intracellular and/or intercellular microscopic lumina
(holes), imparting a cribriform/sieve-like appearance5,20,22,24,25 (Fig. 2). Another characteristic feature is
the presence of intratumoral oxalate crystals in most, but
not all, tumors.5,20,22,24–26 Some tumors may also show
sarcomatoid or rhabdoid features.5,20,27
As many tumors show a variable proportion of
papillary architecture, misinterpretation as type 2 PRCC
is not uncommon, and it is not surprising that PRCC was
previously considered to be the most common RCC
subtype in end-stage kidneys. Similarly, the presence of
cytoplasmic clarity and acinar architecture in some areas
of the tumor may lead to the diagnosis of clear cell RCC.
However, in the background of acquired cystic disease,
careful attention to morphology of the entire tumor is
essential. The presence of multiple small sieve-like lumina/cribriform architecture and intratumoral oxalate
crystals are diagnostic of this entity.
These tumors by definition are associated with features of end-stage kidney with acquired renal cysts in the
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background kidney.20 The cysts are usually numerous and
mostly unilocular. However, multilocular cysts, and
multiple cysts clustered together, are not infrequent. The
cysts are predominantly lined by large cells with eosinophilic cytoplasm and large nuclei with prominent nucleoli
(morphologically similar to the cells of the tumors). Although most cysts are lined by a single layer of epithelium, multilayering and papillary proliferation of the
cyst lining cells identical to what is seen in ACD-RCC is
not infrequent.
In end-stage kidney disease and in a sporadic setting, there was no consensus at the ISUP meeting regarding the nomenclature of such cysts with proliferative
epithelium; 46% of the respondents favored the nomenclature of “atypical cysts,” and 54% favored calling them
“cysts with epithelial proliferation.”
ACD-RCCs stain diffusely positive for AMACR
and negative or, at the most, only very focally positive for
CK7. Positivity for CD10, RCC, CD57, and GST-a is
also described.20,21,24,27–29 However, a specific IHC profile
is not required to make this diagnosis.
Molecular genetic studies have revealed gains and
losses of multiple chromosomes. Although gains of
chromosomes 7 and/or 17 in some tumors have been reported, gains of chromosomes 1, 2, 3, 6, 7, 16, and Y were
also frequently observed.28–31 Gains of chromosome 3,
in particular, have been among the more consistent
findings.27–30
ACD-RCC has a relatively good prognosis, because
most cases are diagnosed early in patients on long-term
follow-up for chronic renal disease.20,21,23,26 However,
some rare typical cases, as well as tumors with sarcomatoid or rhabdoid features, can metastasize.20,27 In addition, among all histologic types arising in the setting of
end-stage kidney disease, ACD-RCC is reported to have
relatively more aggressive behavior than other RCC
subtypes.20,22
Clear Cell (Tubulo) Papillary RCC
Clear cell (tubulo) papillary renal cell carcinomas
(CCPRCCs) are composed of clear cells of low nuclear
grade, variable papillary, tubular/acinar, and cystic architecture, and a characteristic linear arrangement of
nuclei away from the basal aspect of cells.32,33 These neoplasms have a distinctive IHC profile of CK7/CA-IX/
high–molecular weight cytokeratin positivity and CD10
and AMACR negativity. Eight-five percent of participants believed that this neoplasm should be recognized as
a distinctive entity at this time, and 65% of respondents
by consensus believed that both morphology and IHC are
required to diagnose this neoplasm.
The original term clear cell papillary RCC and a
proposed synonym clear cell tubulopapillary RCC have
been used interchangeably.32,33 Approximately half of the
participants preferred the former term, whereas the remaining preferred the latter term. Tumors of similar
morphology and immunophenotype but with prominent
smooth muscle stroma have been reported under the
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name renal angiomyoadenomatous tumor.34 Clear cell
RCC with diffuse CK7 positivity is now considered to be
the same tumor as CCPRCC.35
CCPRCC was initially reported in patients with
end-stage renal disease20; however, the majority of cases
reported subsequently have been sporadic.25,32,33,36,37 On
the basis of a few reports, CCPRCC comprises about 1%
of all renal cell neoplasms.21,33 The age at presentation is
similar to that for RCCs in general (mean 60 y; range, 18
to 88 y), and there is no sex predilection.33,36,37
Grossly, CCPRCCs are well circumscribed and
usually well encapsulated. The cut surface is tan-white to
yellow with grossly apparent fibrotic areas and ranges
from completely solid to predominantly cystic. These
tumors are usually unicentric, unilateral, and small, the
largest one in the literature being 6 cm in diameter.
Multifocality and bilaterality, however, may be present in
some cases20,22,26; the latter setting raises the differential
diagnosis of von Hippel-Lindau–associated renal neoplasia. On microscopy, CCPRCCs have variable tubular/
acinar, papillary, and cystic architecture.20,21,26,32,33 In
some cases papillae are tightly packed giving rise to a
solid appearance. Sometimes these papillary structures
project into cystic spaces. In other cases, the tubules show
branching and in foldings, imparting an incipient papillary architecture. Still other tumors have markedly
crowded, very small, “collapsed” acini, containing scant
cytoplasm, giving the tumor a solid nested appearance.
Fibrous stroma separating tumor nodules within a single
tumor mass is frequently evident. Some tumors with
grossly apparent fibrotic cut surface show extensive myoid
metaplasia of the capsule, with extensions of smooth
muscle into the tumor mass and encasing nests of tumor
cells. Tumors with “collapsed” acini, variable tubular/acinar architecture, myoid metaplasia, and diffuse CK7 positivity have been considered to be separate tumor entities
(renal angiomyoadenomatous tumor/RCC with diffuse
CK7 immunoreactivity) by some authors.34,35 However,
these morphologic patterns can be seen in otherwise typical
CCPRCC, and most experts believe that they are part of
the morphologic spectrum of CCPRCC.21,33,38
By definition, the neoplastic cells have clear cytoplasm with low nuclear grade (nucleolar grade 1 or 2).
The existence of cases of CCPRCC of higher nuclear
grade is not well established at this time, although it is
certainly possible. One characteristic feature of this tumor
is the linear arrangement of the nuclei away from the
basal aspect, toward the middle or the apex of the
cells20,21,31,33,36,37 (Fig. 3). Foamy macrophages, tumor
necrosis, and vascular invasion are not seen. Most tumors
are small and confined to the renal parenchyma, although
rare cases extending into the renal sinus have been described.36,37
The IHC features of the tumor are quite characteristic.20,21,32,33,36 The tumors show diffuse and intense
staining with CK7, almost always in 100% of the tumor
cells. Tumor cells also express CA-IX diffusely in a
membranous distribution; the absence of staining along
the luminal borders of the tumor cells is quite characr
2013 Lippincott Williams & Wilkins
Classification of Renal Neoplasia
FIGURE 3. Clear cell (tubulo) PRCC. Note bland-appearing
tubules and occasional small papillae. Uniform small nuclei are
arranged in a linear manner away from the basal aspect of the
tubules.
teristic (cup-shaped distribution).21 Stains for AMACR,
CD10, and RCC are negative in most cases, whereas it is
common to see patchy to diffuse immunoreactivity for
high–molecular weight cytokeratin (34bE12) in the majority of these neoplasms. Given that the proposed definition of CCPRCC includes typical morphology and IHC
findings, cases with typical morphology, but without the
typical IHC profile, cannot be definitively placed in this
category, although it does seem likely that they do belong.
The main differential diagnosis of CCPRCC is with
clear cell RCC. Some clear cell RCCs may have foci resembling CCPRCC with subnuclear clearing causing linear arrangement of the nuclei.21,39 Some cases may even
show CK7 positivity, but such positivity is only focal.
Unlike CCPRCC, they are also CD10 positive and
34bE12 negative. The CA-IX staining pattern is also
different, with the luminal aspects of the cells also staining
positive (box-shaped distribution) in clear cell RCC.
At the molecular genetic level, CCPRCCs lack deletions of 3p25, VHL gene mutations, VHL promoter
hypermethylation, or trisomies of chromosomes 7 and
17.21,29,32,33 However, although the mechanism is not
clear, VHL transcripts are underexpressed, and SNParray and microarray comparative genomic hybridization
analyses have confirmed such findings in 2 different series.36,37 Low copy number gains of chromosomes 7 and 17
have been reported in a few cases.32,33 Rare cases considered as CCPRCC with other chromosomal aberrations
have also been reported.40
The number of cases in the literature with extended clinical follow-up information is small; however, published data indicate that these are neoplasms
with indolent clinical behavior. No cases with metastasis
have been reported.5,20,21,25,32,33,36,37 If further studies confirm their apparent indolent course, it is possible
that neoplasms meeting the criteria for CCPRCC will
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subsequently be reclassified as being of “low malignant
potential” rather than as a carcinoma.
MiT Family Translocation RCC
The MiT subfamily of transcription factors includes
TFE3, TFEB, TFEC, and MiTF. Gene fusions involving
2 of these factors have been implicated in RCC. The Xp11
translocation RCCs, first recognized in the 2004 WHO
Renal Tumor Classification, harbor fusions involving
TFE3. The t(6;11) RCCs have recently been shown to
harbor a gene fusion involving TFEB but have yet to be
formally recognized. On the basis of clinical, morphologic, IHC, and genetic similarities to the Xp11 translocation RCC, 69% of respondents by consensus believed
that the t(6:11) RCC should be included with the Xp11
translocation RCC under the category of MiT translocation RCC. Recent findings regarding these neoplasms
are summarized below.
Xp11 Translocation RCC
Xp11 translocation RCCs are a group of neoplasms
distinguished by chromosomal translocations with
breakpoints involving the TFE3 transcription factor gene,
which maps to the Xp11.2 locus. The result is a TFE3
transcription factor gene fusion with one of multiple reported genes including ASPL, PRCC, NonO (p54nrb),
PSF, and CLTC.41–45 Variant translocations with no
known fusion partner include t(X;3)(p11.2;q23) and
t(X;10)(11.2;q23) translocations.
Although RCCs account for <5% of renal tumors
in children, Xp11 translocation RCCs likely constitute
approximately 50% of these cases. It has been estimated
that 1% to 4% of adult RCC are Xp11 translocation
RCCs.46–48 Although Xp11 translocation RCC is relatively rare in the adult population, RCC is overall much
more common in adults than in children. Thus, adult
Xp11 translocation RCC may vastly outnumber pediatric
Xp11 translocation RCC because of the much higher incidence of RCC in the adult population. Up to 15% of
patients with Xp11 translocation RCC have had a history
of chemotherapy exposure.49
The most distinctive histologic pattern of the Xp11
translocation RCC is that of a neoplasm with both clear
cells and papillary architecture and abundant psammoma
bodies. Xp11 translocation RCCs can also present with
unusual morphology mimicking other types of RCCs,
including multilocular cystic RCC–like features, pleomorphic giant cells, tubular growth reminiscent of CDC,
and well-developed fascicles of spindled neoplastic cells
with bland nuclei and focal myxoid stroma.46
Xp11 translocation RCCs underexpress epithelial
markers such as cytokeratins and EMA. In contrast,
Xp11 translocation RCCs do consistently express CD10
and RCC marker, and most express PAX2 and PAX8.50
Some Xp11 translocation RCCs with typical morphology express melanocytic markers such as Melan-A and
HMB-45.
The most sensitive and specific IHC marker for
the Xp11 translocation RCC is strong nuclear TFE3
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immunoreactivity, using an antibody to the C-terminal
portion of TFE3.51 One drawback is that the assay is
technically challenging, and suboptimal fixation or detection methods can result in detection of native TFE3
protein causing high background staining. Another is
that genetic mechanisms other than TFE3 gene fusions,
such as TFE3 amplification, can upregulate TFE3 expression.52 A TFE3 break-apart FISH assay performed
on paraffin-embedded tissue has been reported for molecular confirmation of alveolar soft part sarcoma and
Xp11 translocation RCC. Hybridization with probes
centromeric and telomeric to TFE3 normally show a fusion signal, but TFE3 rearrangement results in a split
signal.53,54 This assay is very useful for detecting TFE3
gene fusions in Xp11 translocation RCC and suffers less
from the technical issues involved with the TFE3 IHC
assay.
Expression of cathepsin-K has been shown to be
mediated by overexpression of MiTF in osteoclasts. As
TFE3 belongs to the MiTF family, Martignoni et al55,56
hypothesized that overexpression of TFE3 protein in
Xp11 translocation carcinoma might also mediate cathepsin-K expression. As suspected, cathepsin-K labels approximately 60% of Xp11 translocation RCCs, almost all
t(6;11) RCCs, but no other common RCC subtype.
As these neoplasms have only been recently recognized as a distinct entity by the WHO, outcome data on
Xp11 translocation RCC are still premature at this time.
Children with regional nodal metastases but without
hematogenous spread have a favorable short-term prognosis, even though these cases qualify as high-stage presentation. In a literature review, >90% of these patients
remained disease free at last follow-up having a median of
4.4 years and a mean of 6.3 years.57 Adults may have a
worse prognosis and do poorly when presenting with
systemic metastases. Unfortunately, Xp11 translocation
RCCs in adults often present with advanced disease and
distant metastases. Mean survival after diagnosis is in the
range of 1 to 2 years.46,58 Regardless of the age of the
patient, Xp11 translocation RCCs have the potential to
metastasize late, as many as 20 or 30 years after diagnosis.
Satisfactory long-term follow-up data are necessary before any favorable short-term outcome can be confirmed.
Specific therapies for Xp11 translocation RCC are not
clear at this time. Because of upregulation of C-Met, these
tumors are eligible for clinical trials using Met inhibitors.
Overexpression of phosphorylated S6 suggests the potential utility of mTOR pathway inhibitors in therapy.50
An unusual malignant melanotic epithelioid renal
neoplasm bearing a TFE3 gene fusion has been reported
and designated “melanotic Xp11 translocation renal
cancer.” Two initial cases occurred in children and presented with widespread metastatic disease.59 An additional case report described a specific PSF-TFE3 gene
fusion.60 These neoplasms are difficult to classify, overlapping with Xp11 translocation RCC, melanoma, and
perivascular epithelioid cell neoplasm (PEComa). Although they are immunoreactive to TFE3, all reported
cases were negative for renal tubular markers CD10,
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FIGURE 4. t(6;11) RCC. Note distinctive biphasic morphology
comprising larger and smaller epithelioid cells, the latter
of which are clustered around eosinophilic basement
membrane–like material.
PAX2, and PAX8, in contrast to the typical Xp11
translocation RCC. The neoplastic cells were not immunoreactive to MiTF, in contrast to melanoma. PEComas represent the most closely associated phenotype.
Interestingly, a subset of PEComas in extrarenal sites
have recently been shown to harbor TFE3 gene fusions
and demonstrate aberrant strong TFE3 expression by
IHC. Although the cases are few, distinctive features included young age, absence of association with tuberous
sclerosis, minimal immunoreactivity for muscle markers,
and prominent epithelioid clear cell morphology.61,62
Recently, a renal PEComa in a 57-year-old, which labeled
for muscle markers and harbored a TFE3 gene fusion,
was reported.63 Both melanotic Xp11 translocation carcinoma and PEComas harboring TFE3 gene fusions may
represent distinct entities, which overlap with Xp11
translocation RCC and broaden the spectrum of TFE3associated cancers.
t(6;11) Renal Cell Carcinomas
A lesser well-known member of the translocation
RCC family are tumors characterized by the
t(6;11)(p21;q12), which results in an Alpha-TFEB gene
fusion,64–70 and approximately 30 genetically confirmed
cases of t(6;11) RCC have been reported.55,65–67,69,71–73
This neoplasm typically demonstrates distinctive biphasic
morphology, comprising larger and smaller epithelioid
cells, with the latter often clustered around basement
membrane material; however, the full spectrum of the
morphologic appearances of the t(6;11) RCC is not
known (Fig. 4). Cases without the small cell component
and instead dominated by sclerosis, clear cells, or papillary architecture have been reported. The t(6;11) RCC
differs from most conventional RCCs in that they consistently express melanocytic IHC markers such as
HMB-45 and Melan-A but are either negative or only
focally positive for epithelial markers such as cytokeratins. Virtually all cases express the cysteine protease
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cathepsin-K,55 which is expressed in osteoclasts and a
subset of Xp11 translocation RCCs but in no other
common RCC subtype. The majority of cases express
PAX8, supporting renal tubular differentiation.73
As a result of promoter substitution, the AlphaTFEB gene fusion results in overexpression of native
TFEB in the t(6;11) RCC. Nuclear labeling for TFEB
protein by IHC is a sensitive and specific assay for these
neoplasms.65 However, IHC is highly fixation dependent
and has proven to be particularly difficult for this protein.
Recently, a break-apart FISH assay for TFEB gene fusions has been developed for archival material and has
allowed the expansion of the clinical and morphologic
spectrum of the t(6;11) RCC.66
Of the approximately 30 genetically confirmed cases
that have been reported, 3 have metastasized and caused
death of the patient. Although the initially reported cases
occurred in young patients less than 20 years of age, the
majority of cases reported to date has occurred in young
adults (mean age = 28.5 y; median age = 25 y). The clinicopathologic spectrum of these neoplasms remains to be
determined. Utilization of TFEB IHC and a break-apart
TFEB FISH assay in archival paraffin-embedded material
should further our understanding of this distinctive
neoplasm.
Hereditary Leiomyomatosis RCC
Syndrome–associated RCC
Hereditary leiomyomatosis RCC–associated RCC
(HLRCC) is not a “new” entity, and indeed it was described in the 2004 WHO classification of renal neoplasms in the section related to hereditary RCC.4,74–79
Nevertheless, at that time it was not listed as a distinct
subtype of RCC, and there was a suggestion that HLRCC
was a hereditary counterpart of type 2 PRCC. It is now
known that HLRCC, although usually having a papillary
pattern, is a tumor with an aggressive behavior and
as such should be recognized as a distinctive tumor
subtype.80,81
The HLRCC syndrome is autosomal dominant and
associated with germline mutations in the fumarate hydratase gene located at chromosome 1q42. The main
features of this syndrome are smooth muscle and renal
neoplasms. These patients frequently harbor multiple
cutaneous and uterine leiomyomas. The uterine leiomyomas are particularly difficult to manage, and approximately 50% of women require hysterectomy before
reaching the age of 30 years. Rare cases of leiomyosarcoma have been reported.
The renal carcinomas associated with this syndrome
affect approximately one third of patients and have been
reported to resemble sporadic type 2 PRCC or even CDC.
Unlike most hereditary RCC syndromes, these syndromic
neoplasms are solitary but are highly aggressive. A majority of patients have presented with advanced-stage
disease and have died of these cancers.80 Morphologically, the most distinctive feature of these neoplasms is
cytologic—namely, a distinct prominent eosinophilic nucleolus with a clear halo, similar to the cytology of a
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FIGURE 5. HLRCC. Note large tubular-alveolar structures
lined by eosinophilic cells with enlarged nuclei and prominent
nucleoli.
FIGURE 6. TLF-RCC. Note microfollicular architecture and
dense colloid-like material.
cytomegalovirus inclusion81 (Fig. 5). Interestingly, the
distinctive eosinophilic nucleolus is also found in the
leiomyomas that these patients typically harbor. The renal neoplasms frequently have papillary architecture, but
other architectures such as cribriform and solid may
also be present. RCCs and leiomyomas in the HLRCC
syndrome demonstrate biallelic inactivation of fumarate
hydratase, with germline mutations in one allele and loss
of the second allele, typical of a tumor-suppressor gene.
Although these neoplasms have been considered to be the
hereditary counterpart to type 2 PRCC, it is noted that
somatic mutations in fumarate hydratase are in fact rare
in sporadic type 2 PRCC. Moreover, type 2 PRCC, as
defined by some authors, may be a heterogenous “entity,”
which includes multiple distinct renal carcinomas. Although experience with HLRCC is largely limited to the
National Institutes of Health (NIH) Group, approximately 80% of the respondents by consensus believed
that it was important to recognize HLRCC as a distinctive entity at this time, as the diagnosis carries significant
implication for both patient management and follow-up
of family members. For example, patients with this syndrome (unlike patients with other hereditary RCC syndromes) are followed more closely for even small (<3 cm)
renal masses and are taken to surgery more quickly
because of the highly aggressive nature of these RCCs,
relative to other hereditary RCCs.
range is wide (29 to 83 y), and there is a slight female
predominance.82–87 Macroscopically, these tumors are
well circumscribed, solid, and generally homogenous tanbrown in color. At the microscopic level, the neoplasms
are typically encapsulated and have a macrofollicular
and/or microfollicular architecture with associated dense
colloid-like material (Fig. 6). Although cases with a focal
papillary architecture have been cited in the literature on
TLF-RCC, it is thought that this category should be reserved for tumors with a pure follicular architecture.88,89
The nuclei are generally round and regular and contain
enlarged nucleoli (nucleolar grade 2 or 3). A solitary case
without papillary architecture showed clearing and
grooves, which raised the differential diagnosis of a
metastasis from the follicular variant of papillary carcinoma.84 By IHC these neoplasms stain negatively for
thyroid transcription factor-1 and thyroglobulin, allowing
their distinction from metastatic follicular thyroid cancer
to kidney, which has been more commonly described than
TLF-RCC.82,83 Labeling for CK7, PAX2, and PAX8 has
been variable. Only limited genetic studies have been
performed on this neoplasm without any distinctive pattern emerging. Although the majority of cases have behaved in an indolent manner, 2 examples of TLF-RCC
metastatic to regional lymph nodes in 1 example showing
metastases to lung have been described.83,84
Problematic issues with TLF-RCC at this time include the limited number of reported cases; the issue of
whether a papillary component is allowable and the fact
that a follicular pattern may be seen focally in other established types of RCC including PRCC and CCPRCC.
Furthermore, follicular patterns may be seen in benign
renal epithelial neoplasms including oncocytoma and
metanephric adenoma. The majority of conference respondents did not think that TLF-RCC should be recognized as a distinctive entity at this time. It is therefore
placed in a provisional category.
EMERGING/PROVISIONAL NEW
TUMOR ENTITIES
Thyroid-like Follicular RCC
Thyroid-like follicular renal cell (TLF-RCC) is
provisionally defined as RCC resembling well-differentiated follicular carcinoma of the thyroid gland. In the
fewer than 15 cases reported in the literature, the age
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FIGURE 7. SDHB RCC. Note compact nests of eosinophilic
polygonal cells with vacuolated cytoplasm. Distinctive pale
eosinophilic cytoplasmic inclusions are present.
Succinate Dehydrogenase B
Mutation–associated RCC
Renal carcinomas have been reported with germline
succinate dehydrogenase B mutations that are associated
with the pheochromocytoma/paraganglioma syndrome
type 4 (PGL4).90–95 This syndrome is characterized by a
predilection to pheochromocytoma, paraganglioma, socalled type 2 gastrointestinal stromal tumors (similar to
those frequently seen in children and in association with
Carney syndrome), and an estimated approximately 14%
lifetime risk of renal neoplasia. Fewer than 10 cases of
RCC associated with germline succinate dehydrogenase B
mutations (SDHB RCC) have been reported. Most have
affected young adults, and most cases have been associated with an indolent course on limited follow-up. The
exceptions are 2 cases that underwent sarcomatoid
change, both of which metastasized and 1 of which resulted in death of the patient.
Morphologically, these neoplasms are most usually
unencapsulated and composed of compact nests of eosinophilic polygonal cells, with entrapped renal tubules at
the periphery. The cells may have vacuolated cytoplasm
or distinctive pale eosinophilic cytoplasmic inclusions,
which correspond to giant mitochondria by ultrastructural examination (Fig. 7). Loss of SDHB protein by
IHC is reported to be a sensitive and specific marker for
these neoplasms.
Although these findings suggest that SDHB RCC
may be a distinctive entity, problematic areas remain.
First, there is limited experience (<10 cases published),
and some renal neoplasms associated with pheochromocytoma/paraganglioma syndrome type 4 have been reported as clear cell RCC and oncocytoma, although these
have not been illustrated. Secondly, there is relatively
limited experience with SDHB IHC in the kidney (unlike
the situation with gastrointestinal stromal tumors). As
SDHB normally localizes to the mitochondria, one
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should see granular mitochondrial-pattern staining in
cells with eosinophilic cytoplasm and intact SDHB.
However, it has been stated that cells with clear cytoplasm (usually reflecting displacement of mitochondria
from the cytoplasm and replacement by glycogen or fat)
may give a false-negative result on SDHB IHC. It is not
clear whether there is a minimal size of tumor that needs
to be evaluated before loss of SDHB labeling can accurately predict syndromic cases. Some authors have suggested that only whole sections should be evaluated and
that tissue microarrays may falsely suggest loss of labeling
because of the limited tissue size. Finally, mutations in
other subunits of succinate dehydrogenase (such as succinate dehydrogenase A, B, C, or D) can abrogate SDHB
labeling. At this time, SDHB RCC is considered a provisional entity, which requires further experience before it
can be accepted as a distinctive recognized entity by the
ISUP. Only approximately half of the respondents with
knowledge of this entity felt that the lesion deserved
recognition as a distinctive entity at this time, whereas the
other half either did not or were uncertain.
ALK Translocation RCC
Two cases of RCC harboring a t(2;10)(p23;q22)
translocation resulting in a fusion of the gene for the
cytoskeletal protein vinculin (VCL) with the anaplastic
lymphoma kinase (ALK) gene have been reported.96,97 It
is noteworthy that both cases occurred in young patients
(ages 6 and 16 y) with sickle cell trait (raising the differential diagnosis of renal medullary carcinoma [RMC])
and demonstrated distinctive morphology characterized
by polygonal to spindle cells with abundant eosinophilic
cytoplasm and frequent intracytoplasmic lumina (Fig. 8).
Although the case numbers are small, the findings suggest
that VCL-ALK RCC have distinctive clinical and pathologic features. A recent study from Japan98 identified
FIGURE 8. ALK-translocation RCC. Note large irregular polygonal cells with pleomorphic nuclei, abundant eosinophilic
cytoplasmic, and focal vacuolation.
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2 further RCCs in adults (ages 36 and 53 y) associated
with ALK fusions involving partner genes (TPM3,
EML4) other than VCL. Interestingly, neither of these
cases was associated with sickle cell trait, and morphology
(papillary and unclassified) was different from that reported for the VCL-ALK fusion. The Mayo Clinic Group
recently reported 2 additional ALK-positive cases (fusion
partner not determined) in adults, both of which demonstrated clear cells and papillary architecture and behaved aggressively.99 The majority of respondents did not
think that ALK translocation–associated RCC should be
recognized as a distinctive entity at this time given the
paucity of cases reported.
NEW CONCEPTS AND REFINEMENTS TO
EXISTING WHO (2004) RENAL CELL TUMOR
CATEGORIES
Clear Cell Renal Cell Carcinoma
Multilocular Cystic Renal Cell Neoplasm of Low
Malignant Potential (Multilocular Cystic RCC)
Multilocular cystic RCC accounts for approximately 4% of all clear cell RCCs and affects mid-age
adults with a male to female ratio of 1.2 to 2.1:1. Up to
90% of cases are discovered incidentally on radiologic
evaluation for other causes100,101 and usually present as
a unilateral solitary lesion.102 Macroscopically, multilocular cystic RCC consists exclusively of variably sized
cysts separated by thin septa and filled with clear, serous,
or gelatinous fluid. The 2004 WHO defines multilocular
cystic RCC as a tumor composed entirely of numerous
cysts, the septa of which contain groups of clear cells indistinguishable from grade 1 clear cell carcinoma (Fig. 9).
The clear cells can be focal and mistaken for lymphocytes
or histiocytes, although their prominent associated vas-
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cularity is an important diagnostic clue. The cysts themselves are often denuded, but may be lined by a single
layer of flat to cuboidal epithelium, which may have clear
cytoplasm. Occasional small papillae may be seen.
Genetic studies have clearly linked multilocular
cystic RCC and clear cell RCC.103,104 Similar to clear cell
RCC, chromosome 3p deletions have been found in 74%
of multilocular cystic RCC, and VHL mutations have
been identified in 25% of cases. Like clear cell RCC, the
neoplastic cells in most cases are strongly reactive to
PAX2 and CA-IX.
In line with the minimal tumor burden present in
these neoplasms, their prognosis is excellent. Multiple
publications spanning >200 patients, with a follow-up
time of >5 years, have shown no recurrence or metastases in patients whose tumor was defined according to
the definition adopted by the WHO (see above). On the
basis of the excellent outcomes, 65% of the participants at
the RCC Consensus Conference in Vancouver by consensus support redesignation of these lesions as multilocular cystic renal cell neoplasms of low malignant
potential.105 Furthermore, the majority of participants
(78%) by consensus believed that cells displaying nucleolar grade 2 are acceptable in multilocular cystic RCC.
The main differential diagnosis is clear cell RCC
with extensive cystic change. Expansile solid nodules of
clear cells, which alter the natural septal configuration,
serve to differentiate extensively cystic RCC from multilocular cystic RCC, although it is clear that these 2 entities exist in a spectrum. RCC with extensive cystic
necrosis also enters the differential diagnosis.106–108 The
latter is typically composed of multiple cysts filled with
hemorrhagic and necrotic debris and separated by irregularly thick shaggy walls composed of variable mixtures
of fibrous tissue and neoplastic cells. This distinction is
highly relevant, as even extensively necrotic cystic RCCs
(99% necrotic) have been shown to be capable of aggressive clinical behavior. An unresolved issue is when
one sees areas of hyalinization that form a mass; these
areas may reflect regression of RCC, and their significance is unknown. Other issues relate to whether
multilocular cystic RCC should be staged and whether
complete submission of the tumor is required before the
diagnosis can be rendered. Finally, the differential diagnosis also includes translocation RCC, which can closely
mimic multilocular cystic RCC.109 Attention to patient
age and the presence of psammoma bodies are clues to
suggest this diagnosis.
Papillary Renal Cell Carcinoma
FIGURE 9. Multilocular cystic renal cell neoplasm of low malignant potential. High-power image of septa containing
clusters of clear cells indistinguishable from grade 1 clear cell
carcinoma.
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RCC with a papillary architecture was recognized in
early studies and was considered by Grawitz to be a true
renal malignancy, different from tumors with alveolar
architecture, which he considered to be of adrenal origin.110 The publication of a series of cases by MancillaJimenez and colleagues in 1976 established PRCC as a
specific tumor morphotype, and this was formalized
through its inclusion in the Mainz Classification and the
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Heidelberg and Rochester consensus conferences recommendations.1–3,111
PRCC is now recognized as the second most common type of RCC, comprising 6% to 18% of tumors
in reported series ,and detailed studies have shown
these tumors to have distinctive clinical and genetic
features.112,113
Approximately 20% of PRCCs are discovered as
incidental findings, and unlike clear cell RCC, spontaneous hemorrhage is a presenting feature in 8% of cases.114 Additional differentiating clinical features from
both clear cell and chromophobe RCC (CHRCC) are that
these tumors are more likely to be multifocal, whereas
calcification is seen in 30% of cases on imaging.111,115 In
contrast to the main morphotypes of RCC, PRCC is most
commonly associated with trisomy/tetrasomy of chromosome 7, trisomy of chromosomes 12, 16, 17, and/or 20,
and loss of the Y chromosome.113 Loss of heterozygosity
at both the VHL and FHIT loci, but no loss of chromosome 3p, has also been reported.116–118
Papillary RCC is characterized by the presence of a
papillary or tubulopapillary architecture, with neoplastic
cells overlying a delicate fibrovascular core or forming
compact tubules. Two subtypes of PRCC have been described.119,120 Type 1 tumors are characterized by a simple cuboidal or columnar covering of tumor cells on
papillary stalks, with nuclei aligned in a linear manner.
Other features frequently associated with type 1 tumors
are scanty and pale tumor cell cytoplasm, as well as the
presence of psammoma bodies and aggregates of foamy
macrophages. Type 2 tumors show pseudostratification of
tumor nuclei with cells often having voluminous cytoplasm and moderate to marked nuclear pleomorphism
usually with prominent nucleoli.4 The subtypes of PRCC
differ in IHC staining with type 1 tumors showing expression of CK7, vimentin, and MUC1, whereas CK20
and E-cadherin expression is more frequently seen in type
2 tumors.121–124
Several studies have shown type 1 and 2 tumors to
differ in genotype, with type 1 tumors showing chromosome 7p and 17p gains and type 2 tumors showing allelic
imbalance of one or more of chromosomes 1p, 3p, 5, 6, 8,
9p, 10, 11, 15, 18, and 22.125–128 In gene profile studies,
high-grade type 2 tumors have been differentiated from a
mixed group of PRCC consisting of type 1 tumors, lowgrade type 2 tumors, and tumors showing a mixed type 1
and low-grade type 2 morphology.129
It has been noted that in published series of PRCC,
there is considerable variation in the proportion of type 1
and 2 tumors, and this highlights the importance of assigning tumors into their correct subtype according to
established criteria.130 Subtyping of PRCC has been further compounded by the recent identification of PRCC
mimics, with clear cell tubulopapillary RCC, TC-RCC,
and mucinous tubular and spindle carcinoma now being
recognized as novel or emerging forms of RCC.5
In the preconference survey, participants were asked
to specify the classification they utilized to subtype papillary RCC. In all, 59% of respondents noted that they
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FIGURE 10. Oncocytic PRCC. Note tightly packed papillary
structures lined by large cells with abundant granular eosinophilic cytoplasm resembling oncocytes.
classified tumors according to types 1 and 2, whereas 10%
also incorporated oncocytic papillary RCC as an additional type (type 3) in their classification of these tumors.
Of the remainder, 16% utilized Fuhrman grading only,
whereas 10% utilized other criteria, including the option
of not subtyping these tumors according to morphologic
characteristics. Only 3% of respondents assigned subtype
on the basis of molecular classification (type 1 vs. type 2a
vs. type 2b).129
At the conference there was consensus (75%) that
tumors should be classified as type 1 or type 2 and that
oncocytic tumors should not be identified as a specific
subtype (Fig. 10). In addition to this, a further 14% of
participants considered that tumor should be classified as
either type 1 or type 2 without taking into account those
tumors identified as oncocytic papillary RCC. Retention
of oncocytic papillary RCC as a specific subtype was
recommended by only 3% of the participants, whereas 7%
preferred to grade tumors rather than formally subtyping
them. No respondent was in favor of the use of the subtyping classification based on molecular characteristics.
CHRCC and Hybrid Oncocytic/Chromophobe
Tumors
Hybrid oncocytic/chromophobe tumors (HOCTs)
are described as tumors having a mixture of cells with the
morphologic features of those seen in CHRCC and renal
oncocytoma (RO). HOCTs occur in 3 clinicopathologic
situations, being found sporadically, in association with
renal oncocytosis/oncocytomatosis, or in patients with
the Birt-Hogg-Dubé syndrome (BHD). From published
data it would seem that tumors from all 3 groups share
similar morphologic features but that they have a differing molecular genetic background.131–139
HOCTs, regardless of the associated clinicopathologic situation, occur in adult patients, with no sex
predilection,134,136,137 although HOCTs in oncocytosis/
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FIGURE 11. Sporadic HOCT. Note tightly packed nests of
eosinophilic cells with minimal nuclear pleomorphism. The
nuclei are regular without raisinoid features, and small perinuclear halos are seen.
FIGURE 12. HOCT associated with BHD syndrome. Note admixture of chromophobe and oncocytic-type cells. Many large
eosinophilic cells have prominent intracytoplasmic vacuoles.
oncocytomatosis are occasionally associated with longterm hemodialysis.133,137,139–141 There are no specific
clinical signs and symptoms for sporadic tumors and
those associated with oncocytosis/oncocytomatosis. Patients with BHD syndrome–associated HOCT usually
show signs of the syndrome consisting of adnexal skin
tumors (fibrofolliculomas, trichodiscomas, acrochordons), pulmonary cysts, spontaneous pneumothorax,
bronchiectasis, colonic tumors, medullary thyroid carcinoma, and multiple lipomas.131 Clinically, sporadic
HOCTs are mostly unilateral and solitary, whereas
HOCTs in individuals with BHD or oncocytosis/oncocytomatosis are often bilateral and multiple. The majority
of HOCTs are category pT1 or pT2 at presentation
(TNM seventh Edition).
Tumors are usually well circumscribed and nonencapsulated with homogenous tan to brown cut surface.
Although necrosis is not frequently seen, central fibrotic
strands/scars may be present.131–139,142
Sporadic HOCTs are composed of neoplastic cells
predominantly arranged in a solid-alveolar pattern, with
nuclei showing mild nuclear pleomorphism and abundant
granular eosinophilic to oncocytic cytoplasm (Fig. 11).
Frequently, neoplastic cells have a perinuclear halo
and are occasional binucleate. No raisinoid nuclei of the
type seen in classic CHRCC are present. Usually tumor
cells resemble cells of RO with perinuclear cytoplasmic clearing, and, occasional, small tubules may be
present.132,134,136,138
HOCTs in oncocytosis/oncocytomatosis are almost
identical to those tumors that occur sporadically, being
composed of sheets of cells separated by a delicate vasculature. The cells are round to polygonal with finely
granular cytoplasm, and the nuclei are slightly pleomorphic and irregular with visible nucleoli. Again no typical
raisinoid nuclei are seen, and mitotic figures are inconspicuous. There has been consensus that oncocytosis-
related HOCT are distinct tumors and that they do not
represent a stage of morphologic progression between RO
and CHRCC.133,137,139,141,142
HOCTs associated with BHD typically show 3
morphologic patterns: (1) an admixture of areas typical of
RO and CHRCC; (2) scattered chromophobe cells in the
background of a typical RO; and (3) large eosinophilic
cells with intracytoplasmic vacuoles (Fig. 12). In these
tumors, the nuclei are often more pleomorphic than other
forms of HOCT and occasionally have a “raisinoid”
morphology.131,135,143,144
The IHC profile of HOCT differs slightly according
to clinicopathologic groups The majority of the tumors
express parvalbumin, antimitochondrial antigen, and
CK7. CD117 is invariably positive.
Ultrastructurally, neoplastic cells from sporadic
HOCTs consistently show numerous mitochondria of
varying sizes. In addition, sparse microvesicles with
amorphic lamellar content and abundant microvesicles in
the cytoplasm are present.136 In HOCT in patients with
oncocytosis/oncocytomatosis, the cytoplasm of tumor
cells shows RO-like areas with numerous mitochondria
containing lamellar cristae, whereas the cytoplasm in the
CHRCC-like areas show a significantly diminished
number of mitochondria with lamellar cristae, increased
amounts of glycogen, and no cytoplasmic microvesicles.142 To date there has not been any study dealing
with the ultrastructure of HOCTs in BHD in the English
language.
At the molecular level, sporadic HOCTs are characterized by multiple monosomies and polysomies of
chromosomes 1, 2, 6, 9, 10, 13, 17, 20, 21, and 22, with
lack of mutations in the VHL, c-kit, PDGFRA, and
FLCN genes. Monosomy of chromosome 20 is the most
frequent finding, and this is of importance as this is highly
unusual for both RO and CHRCC.136 HOCTs associated
with oncocytosis/oncocytomatosis are characterized by
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variable genetic profiles. The majority of tumors show no
losses of chromosomes 1, 2, 6, 10, and 17; however, losses
of chromosomes 1, 14, 21, and Y have been documented.133,140,141 HOCTs in BHD show a similarly variable profile. Rarely, multiple abnormalities are seen in
chromosomes 2, 3, 4, 5, 6, 13, and 18, although, to date,
loss of chromosome 1 or translocation of 11q13 has not
been reported. Loss of heterozygosity of 3p is rarely seen
in this type of tumor.131,135,143 The most prominent molecular feature of HOCT in BHD is an elevated expression of mitochondria and oxidative phosphorylation
(OXPHOS)–associated genes and germline mutations
in the FLCN gene, the latter being easily detected in
formalin-fixed, paraffin-embedded material.
HOCT, regardless of clinical association, seems to
behave indolently and no evidence of aggressive behavior
has been documented. At worst, these tumors may exhibit
a low malignant potential, although this will require
longer follow-up of cases for confirmation.
The majority of ISUP conference participants
(73%) reported that they recognize HOCT as a subcategory of CHRCC, with some preferring the designation oncocytic neoplasia of uncertain malignant
potential. At the present time it was considered that it was
not possible to determine whether each of the 3 subtypes
of HOCTs should be recognized as separate entities.
From a morphologic perspective, there are similarities
between HOCT, RO, and CHRCC. However, all 3 subtypes of HOCT have molecular genetic profiles that differ
from both RO and CHRCC.131,133,135,140,141,143
Classification of Renal Neoplasia
component that met the criteria for CDC, then the diagnosis should be poorly differentiated CDC as opposed
to “unclassified carcinoma.” The majority opinion was
that CDCs are, by definition, high grade and as a consequence should not be assigned a grade.
Immunohistochemically, there is clear overlap between CDC and urothelial carcinoma. PAX8 labeling is
seen in virtually all CDCs, with the majority showing
moderate to strong immunoreactivity, and in 17% to
20% of upper tract urothelial carcinomas.147 Similarly,
p63 positivity, which is seen in almost all urothelial carcinomas, is also seen in a minority (14%) of CDCs.147
Although the distinction of CDC from urothelial carcinoma can be difficult and is somewhat controversial, it
does have significant clinical implications, as patients with
urothelial carcinomas of the kidney usually undergo
evaluation of their bladder for additional tumors,
whereas patients with CDC do not.
Complete loss of INI1 expression was observed in 3
of 20 (15%) cases of CDC, and another 15% of cases
showed focal and weak staining. Despite this no significant differences were found in the clinicopathologic
and outcome features relating to INI1 status.148 As a
consequence INI1 immunoexpression was considered to
be of limited value in the differential diagnosis of CDC
versus RMC (see below).
The 3-year relative survival rates for localized, regional, and distant disease have been reported to be 93%,
45%, and 6%, respectively (P < 0.001), although most
patients present with T3 and T4 disease.149 Some patients
with CDC do respond to combination chemotherapy.150
Collecting Duct Carcinoma
At the consensus conference it was agreed upon that
for a diagnosis of CDC to be made a tumor should show
the following features: (1) at least some of the lesion involves the medullary region; (2) there is a predominant
formation of tubules; (3) a desmoplastic stromal reaction
should be present; (4) cytologic features are high grade;
(5) growth pattern is infiltrative; and (6) there is an
absence of other typical RCC subtypes or urothelial
carcinoma.145,146
Several controversial issues were addressed at the
consensus conference. The first was related to those tumors in which >95% has the morphology of CDC, but
focal urothelial carcinoma is also present. By consensus
68% of the respondents considered that these cases
should be diagnosed as urothelial carcinoma with prominent glandular differentiation. An argument supporting
this is that the stroma of the bladder and kidney are very
different and may account for the different morphologic
appearance of a urothelial carcinoma when it involves the
kidney. A contrary argument is that the variable morphology in these tumors represents divergent differentiation from the site where the collecting ducts joined
the urothelium, so that a minor component of urothelial
carcinoma is acceptable within what is otherwise a typical
CDC. Second, in the setting of an undifferentiated carcinoma, the consensus (85%) was that if there was any
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Renal Medullary Carcinoma
RMC was recognized by Davis et al in 1995 and
occurs almost exclusively in children and young adults
with sickle cell trait.151 It is highly invasive and almost
uniformly lethal. These tumors often have rhabdoid
cytology, and inflamed desmoplastic stroma.
RMC, both with and without rhabdoid histology,
shows loss of INI1 labeling by IHC, similar to pediatric
rhabdoid tumors. In contrast, most RCCs or urothelial
carcinomas, including those with histologic rhabdoid
features, express INI1.152 However, CDC, which can be
difficult to distinguish morphologically from medullary
carcinoma,153 can, in a minority of cases, show a loss of
INI1.148
RMCs in patients with or without sickle cell disease
show involvement of genes important in hypoxia-induced
signaling pathways and, in particular, show increased
hypoxia-inducible factor-1a expression. Expanded wholegenome expression analysis also shows increases of
TopoII in all cases. There is also overall deregulation of
DNA remodeling and repair and an ontological association between RMC and urothelial carcinoma.154,155
However, there is not a single consistent chromosomal or
molecular abnormality in medullary carcinoma.156 There
is accumulating evidence that chemotherapy can prolong
life and offer palliation to patients with RMC.157
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FIGURE 13. Mucinous tubular and spindle cell RCC. Note
admixture of small tubules and elongated spindle cells. A small
amount of mucin is present focally. Some mucinous tubular
and spindle cell carcinomas may be mucin poor and resemble
type 1 PRCC.
Mucinous Tubular and Spindle Cell RCC
Reports of a distinctive low-grade renal neoplasm
composed of tubules lined by bland cuboidal cells together with spindle cells and intercellular mucin first
emerged in the 1990s, and this tumor was included in the
2004 WHO Classification under the rubric of mucinous,
tubular, and spindle cell RCC (MTS RCC).4,158–163 This
rare tumor affects adults over a wide age range and shows
a female predominance (3 to 4:1). Some patients with
MTS RCC have nephrolithiasis, but most are asymptomatic.161 The tumors are generally of low-staging category (pT1, pT2) at diagnosis and are amenable to partial
or complete nephrectomy.
MTS RCCs are usually found in the cortex, and
they have a solid cut surface. Their coloration can vary
from white or gray to yellow, tan, or even pink. Histologically, there are bland tubules, many of which are
elongated and merge into cord-like structures. Transitions
between elongated tubules and spindle cells are seen, and
in some tumors the spindle cell pattern is dominant, at
times resembling a mesenchymal neoplasm such as leiomyoma. A lightly basophilic mucin is present at least
focally in most tumors (Fig. 13). Sometimes large lakes of
mucin are seen, and this may be highlighted by the Alcian
blue stain. Occasional other features include collections of
chronic inflammatory cells and foam cells, foci of clear
cells, and small foci of necrosis.
By IHC the tumor cells stain positively for low–
molecular weight keratins (CK8, CK18) and CK7.158–162
Stains for high–molecular weight keratins show variable
expression, and Ulex europeaus and other markers of
lower nephron differentiation are often negative but may
occasionally be positive.
Subsequent to the description of MTS RCC in the
WHO 2004 Classification, additional series of tumors
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have been published, including ones showing “mucinpoor” patterns.163,164 Cases with no mucin display a
prominence of small tightly packed tubules, some of
which are elongated and spindled, resembling type 1
PRCC.163,165 Some authors have suggested that MTS
RCC itself may represent a variant of papillary RCC.165
In fact, some cases of MTS RCC may be indistinguishable from type 1 papillary RCC on routine microscopy
and IHC, and the distinction between the 2 may require
molecular genetic studies. In a FISH-based study of 10
MTS RCCs, none showed the typical gains of chromosomes 7 and 17 and losses of chromosome Y, which are
found in PRCC.166 Other investigators have disputed this
point and suggest that some typical MTS RCCs show
gains in chromosomes 7 and 17, suggesting a close relationship with PRCC.165 Other molecular genetic analyses
have suggested that MTS RCC is a distinctive neoplasm.160–167
Most cases of MTS RCC behave in a rather indolent manner, although examples of local recurrence in
the renal bed and metastases to regional lymph nodes
have rarely been described.160 In one remarkable case, a
large (18 cm) tumor metastasized not only to abdominal
lymph nodes but also to the liver where it displayed the
typical morphologic pattern of MTS RCC.168 In addition,
recent examples of MTS RCC with sarcomatoid transformation have been recorded, and in some cases metastatic disease and tumor-associated death have been
described.169–173 In one case of metastatic MTS RCC, a
response to sunitinib has been documented.173
RECOMMENDATIONS REGARDING OTHER
RENAL TUMOR CATEGORIES
Angiomyolipoma Including Epithelioid Variant
PEComa lesions, including those composed predominantly of fat and those almost exclusively composed
of spindle-shaped smooth muscle cells, classic triphasic
angiomyolipomas (AMLs), microscopic AMLs, intraglomerular lesions, oncocytoma-like AMLs, epithelioid
AMLs; and the recently-described AMLs with epithelial
lined cysts, all strongly express cathepsin-K.174 Although
some AMLs express TFE3 immunohistochemically,175
especially when using automated IHC stainers with short
antibody incubation times, only a distinctive subset of
PEComas harbor TFE3 gene rearrangements.61 The latter
are typically not associated with tuberous sclerosis, are
purely epithelioid, label minimally for muscle markers,
and tend to affect young patients.
There was consensus (86%) that AMLs with epithelioid morphology should be divided into “epithelioid
AML with atypia” and “epithelioid AML without
atypia,” although the distinction is somewhat subjective
(Fig. 14). Two large retrospective studies have assessed
the issue of epithelioid AML. In 1 study with 33 cases of
pure epithelioid AML, the clinicopathologic parameters
associated with disease progression (recurrence, metastasis, or death due to disease) in univariate analysis
included associated tuberous sclerosis complex or
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Classification of Renal Neoplasia
FIGURE 14. Epithelioid AML. Note presence of large eosinophilic
epithelioid cells showing nuclear pleomorphism and mitoses.
FIGURE 15. CN. Note paucicellular fibrous septae covered by
attenuated and cuboidal cells.
concurrent AML (any metastasis, P = 0.046), necrosis
(metastasis at diagnosis, P = 0.012), tumor size >7 cm
(progression, P = 0.021), extrarenal extension and/or renal vein involvement (progression, P = 0.023), and a
carcinoma-like growth pattern (progression, P = 0.040)
(the 5 adverse prognostic parameters for pure epithelioid
PEComas).176 Tumors with <2 adverse prognostic parameters (13 cases) were considered to be low risk, with
15% having disease progression. Tumors with 2 to 3
adverse prognostic parameters (14 cases) were considered
to be “intermediate risk,” with 64% having disease progression. Tumors with Z4 adverse prognostic parameters
(6 cases) were considered to be high risk, with all patients
having disease progression. In 80% of tumors with Z3
adverse prognostic parameters, patients had disease progression. An exact logistic regression analytic model
showed that a only carcinoma-like growth pattern and
extrarenal extension and/or renal vein involvement were
significant predictors of outcome (P = 0.009 and 0.033,
respectively). The other large series specifically analyzed
epithelioid AMLs with at least moderate atypia.177 Follow-up information was available for 34 cases. A predictive model of 4 atypical features included: (1) Z70%
atypical epithelioid cells; (2) Z2 mitotic figures per
10 hpf; (3) atypical mitotic figures; and (4) necrosis. The
presence of 3 or all of the features was highly predictive of
malignant behavior. This model accurately categorized
78% of clinically malignant and 100% of the clinically
benign epithelioid AMLs with atypia.
It should be noted that both studies are retrospective and suffer from the biases inherent in consultation material. Prospective studies of epithelioid
AML outcome are in progress but have yet to be published, although it is suggested that the worrisome histologic features reported above do not necessarily predict
aggressive behavior.178 At the Vancouver Consensus
Meeting, there was near consensus (64%) that the prognosis of epithelioid AMLs should be based on published
criteria being divided into low, intermediate, and high risk
of malignant behavior, as opposed to benign or malignant; only 25% favored diagnosing tumors as benign or
malignant, and the remaining 11% were uncertain.
Interestingly, epithelioid AMLs tend to be immunoreactive for estrogen receptor (ER) more than the
classic triphasic AML.179
An unusual variant of AML is oncocytic AML with
the same IHC profile as usual AML.180 A single case has
been reported of liposarcoma arising in AML.181 It is now
recognized that lesions that have in the past been designated as “capsular leiomyomas” are immunohistochemically identical to AML and are considered as variants of
AML.182 Rare cases of intraglomerular AML have also
been described.183
AML with epithelial cysts184 have 3 components: (1)
epithelial cysts lined by cuboidal to hobnail cells, which
label for PAX8 and PAX2 and likely represent entrapped
renal tubules; (2) a compact subepithelial “cambium-like”
layer of cellular, Müllerian-like AML stroma with
prominent admixed chronic inflammation; and (3) muscle-predominant AML with associated dysmorphic blood
vessels exterior to the cellular subepithelial stroma. Immunohistochemically, the stromal components label with
HMB-45 and Melan-A most intensely in the cellular
subepithelial stroma, whereas smooth muscle actin and
desmin demonstrate the opposite pattern, with greatest
intensity in the peripheral muscle–predominant AML
areas. Immunoreactivity for ER and progesterone receptors (PR) and CD10 shows the strongest and most
diffuse staining in the subepithelial AML cells.
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2013 Lippincott Williams & Wilkins
Cystic Nephroma/Mixed Epithelial and
Stromal Tumor
Cystic nephroma (CN) (also known as multilocular
renal cyst) and mixed epithelial and stromal tumor
(MEST) are each benign mixed mesenchymal and epithelial neoplasms of the kidney. In most cases, these entities can be readily distinguished from one another. CN
lacks solid areas and is composed of simple cysts lined by
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FIGURE 16. MEST. Note complex admixture of tubules, cysts,
and stroma. Tubules are lined by bland cuboidal cells.
a single layer of flat, low cuboidal, or hobnail epithelial
cells (Fig. 15). Fibrous septa may be paucicellular or
cellular with a density resembling that of ovarian stroma.
In contrast, MEST is variably cystic and solid and demonstrates a complex architecture of cysts, tubules, and
stroma of variable cellularity185–190 (Fig. 16). The epithelial elements comprise glands, cysts, and papillae of
variable sizes and architectures. They are lined by flatted,
cuboidal, or columnar cells or by urothelium, particularly
when the lesion projects into the renal pelvis. In rare
cases, the lining cells are ciliated.191 The stroma is variably cellular and ranges from markedly hyalinized fibrous tissue to smooth muscle, fat, or nondescript cellular
spindle cell stroma. In both lesions, the epithelial elements
label for renal lineage markers such as PAX2 and
PAX8,192 whereas the stroma labels for hormone receptors ER and PR.
Although many believe that the epithelium in
MEST represents altered entrapped renal tubules, a recent study presented molecular evidence that the epithelium and stroma are clonally related in at least some
cases.193 Rare cases of malignant MEST have been reported.194,195
In recent years, multiple observers have noted clinical, pathologic, and genetic similarities between CN and
MEST.196–201 First, both are associated with a strong
female sex predilection, with a female to male ratio of
approximately 5:1. Second, the lesions have a similar age
distribution, occurring predominantly in premenopausal
women. Third, cases overlapping morphologic features of
CN and MEST are well recognized and have been reported. Fourth, the stromal cells of both lesions label
similarly for ER and PR. Fifth, in a small study comparing 3 CNs and 3 MESTs, these 2 lesions had a similar
gene expression profile relative to renal carcinomas.199
The majority of respondents (72%) in the consensus
conference believed that CN and MEST are variations of
the same lesion. However, a minority of respondents
(16%) believe that CN and MEST are not the same entity. These respondents point out that the predilection to
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involve adult women is not at all specific in renal neoplasia, as AML, metanephric adenoma, and mucinous
tubular and spindle cell carcinoma also preferentially involve this demographic. Further, many other renal neoplasms beside MEST can have areas that mimic CN,
including multilocular cystic RCC, cystic partially differentiated nephroblastoma, and renal synovial sarcoma.
They also note that ER/PR labeling of the renal stroma is
not specific, as it is seen in AML and as a reaction to
obstruction. Fourthly, it is not clear whether MEST was
ever reported before 1950, suggesting that there may have
been a relatively recent environmental trigger for this
neoplasm (such as oral contraceptive use or other hormonal therapy), whereas CNs have been documented well
before this time. Finally, most classic CNs and MESTs
are, as mentioned above, readily distinguished from one
another.
Primary Renal Synovial Sarcoma
Primary renal synovial sarcoma had previously been
included under the category of mixed mesenchymal and
epithelial tumors.4,202 However, it is evident that the epithelial components of these tumors represent entrapped
native renal tubules. Therefore, primary renal synovial
sarcoma has been moved to the mesenchymal tumor
category.
REFERENCES
1. Thoenes W, Störkel S, Rumpelt HJ. Histopathology and classification of renal cell tumors (adenomas, oncocytomas and
carcinomas). The basic cytological and histopathological elements
and their use for diagnostics. Pathol Res Pract. 1986;181:125–143.
2. Kovacs G, Akhtar M, Beckwith BJ, et al. The Heidelberg
classification of renal cell tumours. J Pathol. 1997;183:131–133.
3. Störkel S, Eble JN, Adlakha K, et al. Classification of renal cell
carcinoma:Workgroup No. 1. Union Internationale Contre le
Cancer (UICC) and the American Joint Committee on Cancer
(AJCC). Cancer. 1997;80:987–989.
4. Eble JN, Sauter G, Epstein JI, et al. World Health Organization
Classification of Tumours. Pathology and Genetics of Tumours of the
Urinary System and Male Genital Organs. Lyon, France: IARC; 2004.
5. Srigley JR, Delahunt B. Uncommon and recently described renal
carcinomas. Mod Pathol. 2009;22(suppl 2):S2–S23.
6. Delahunt B, Egevad L, Montironi R, et al. International Society of
Urological Pathology (ISUP) consensus conference on renal
neoplasia: rationale and organization. Am J Surg Pathol.
2013;37:1463–1468.
7. Murphy WM, Beckwith JB, Farrow GM. Atlas of Tumor
Pathology Fascicle 11, Tumors of the Kidney, Bladder and Related
Urinary Structures. 3rd ed. Washington, DC: Armed Forces
Institute of Pathology; 1994.
8. MacLennan GT, Farrow GM, Bostwick DG. Low-grade collecting
duct carcinoma of the kidney: report of 13 cases of low-grade
mucinous tubolocystic renal carcinoma of possible collecting duct
origin. Urology. 1997;50:679–684.
9. Masson P. Tumeurs Humaines Histologie, Diagnostics et Techniques. 2nd ed. Paris: Librairie Maloine; 1956;1214.
10. Azoulay S, Viellefond A, Paraf F, et al. Tubulocystic carcinoma of
the kidney: a new entity among renal tumors. Virchows Arch.
2007;451:905–909.
11. Yang XJ, Zhou M, Hes O, et al. Tubulocystic carcinoma of the
kidney; clinicopathologic and molecular characterization. Am J
Surg Pathol. 2008;32:177–187.
12. Amin MB, MacLennan GT, Gupta R, et al. Tubulocystic
carcinoma of the kidney; clinicopathologic analysis of 31 cases of
r
2013 Lippincott Williams & Wilkins
Am J Surg Pathol
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
r
Volume 37, Number 10, October 2013
a distinctive rare subtype of renal cell carcinoma. Am J Surg
Pathol. 2009;33:384–392.
Zhou M, Yang XJ, Lopez JI, et al. Renal Tubulocystic carcinoma
is closely related to papillary renal cell carcinoma: implications for
pathologic classification. Am J Surg Pathol. 2009;33:1840–1849.
Hora M, Ürge T, Eret V, et al. Tubulocystic renal carcinoma: a
clinical perspective. World J Urol. 2011;29:349–354.
Deshmukh M, Shet T, Bakshi G, et al. Tubulocystic carcinoma of
kidney associated with papillary renal cell carcinoma. Indian J
Pathol Microbiol. 2011;54:127–130.
Al Hussain TO, Cheng L, Zhang S, et al. De-differentiated
tubulocystic carcinoma of the kidney: a series of 3 cases with FISH
analysis. Hum Pathol. 2013;44:1406–1411.
Osunkoya AO, Young AN, Wang W, et al. Comparison of gene
expression profiles in tubulocystic carcinoma and collecting duct
carcinoma of the kidney. Am J Surg Pathol. 2009;33:1103–1106.
Moses KA, DeCaro JJ, Osunkoya AO, et al. Tubulocystic
carcinoma of the kidney: a case report of natural history and
long-term follow-up. ScientificWorldJournal. 2010;10:586–589.
Mego M, Sycova-Mila Z, Rejlekova K, et al. Sunitinib in the
treatment of tubulocystic carcinoma of the kidney. A case report.
Ann Oncol. 2008;19:1655–1656.
Tickoo SK, dePeralta-Venturina MN, Harik LR, et al. Spectrum of
epithelial neoplasms in end-stage renal disease: an experience from
66 tumor-bearing kidneys with emphasis on histologic patterns
distinct from those in sporadic adult renal neoplasia. Am J Surg
Pathol. 2006;30:141–153.
Tickoo SK, Reuter VE. Differential diagnosis of renal tumors with
papillary architecture. Adv Anat Pathol. 2011;18:120–132.
Enoki Y, Katoh G, Okabe H, et al. Clinicopathological features
and CD57 expression in renal cell carcinoma in acquired cystic
disease of the kidneys: with special emphasis on a relation to the
duration of haemodialysis, the degree of calcium oxalate deposition, histological type, and possible tumorigenesis. Histopathology.
2010;56:384–394.
Nouh MA, Kuroda N, Yamashita M, et al. Renal cell carcinoma in
patients with end-stage renal disease: relationship between histological type and duration of dialysis. BJU Int. 2010;105:620–627.
Sassa N, Hattori R, Tsuzuki T, et al. Renal cell carcinomas in
haemodialysis patients: does haemodialysis duration influence
pathological cell types and prognosis? Nephrol Dial Transplant.
2011;26:1677–1682.
Bhatnagar R, Alexiev BA. Renal-cell carcinomas in end-stage
kidneys: a clinicopathological study with emphasis on clear-cell
papillary renal-cell carcinoma and acquired cystic kidney diseaseassociated carcinoma. Int J Surg Pathol. 2012;20:19–28.
Sule N, Yakupoglu U, Shen SS, et al. Calcium oxalate deposition
in renal cell carcinoma associated with acquired cystic kidney
disease: a comprehensive study. Am J Surg Pathol. 2005;29:
443–451.
Kuroda N, Tamura M, Hamaguchi N, et al. Acquired cystic
disease-associated renal cell carcinoma with sarcomatoid change
and rhabdoid features. Ann Diagn Pathol. 2011;15:462–466.
Pan CC, Chen YJ, Chang LC, et al. Immunohistochemical and
molecular genetic profiling of acquired cystic disease-associated
renal cell carcinoma. Histopathology. 2009;55:145–153.
Kuroda N, Yamashita M, Kakehi Y, et al. Acquired cystic diseaseassociated renal cell carcinoma: an immunohistochemical and
fluorescence in situ hybridization study. Med Mol Morphol.
2011;44:228–232.
Kuntz E, Yusenko MV, Nagy A, et al. Oligoarray comparative
genomic hybridization of renal cell tumors that developed in
patients with acquired cystic renal disease. Hum Pathol.
2010;41:1345–1349.
Kuroda N, Shiotsu T, Hes O, et al. Acquired cystic diseaseassociated renal cell carcinoma with gain of chromosomes 3, 7, and
16, gain of chromosome X, and loss of chromosome Y. Med Mol
Morphol. 2010;43:231–234.
Gobbo S, Eble JN, Grignon DJ, et al. Clear cell papillary renal cell
carcinoma: a distinct histopathologic and molecular genetic entity.
Am J Surg Pathol. 2008;32:1239–1245.
2013 Lippincott Williams & Wilkins
Classification of Renal Neoplasia
33. Aydin H, Chen L, Cheng L, et al. Clear cell tubulopapillary renal
cell carcinoma: a study of 36 distinctive low-grade epithelial tumors
of the kidney. Am J Surg Pathol. 2010;34:1608–1621.
34. Michal M, Hes O, Nemcova J, et al. Renal angiomyoadenomatous
tumor: morphologic, immunohistochemical, and molecular genetic
study of a distinct entity. Virchows Arch. 2009;454:89–99.
35. Mai KT, Kohler DM, Belanger EC, et al. Sporadic clear cell renal
cell carcinoma with diffuse cytokeratin 7 immunoreactivity.
Pathology. 2008;40:481–486.
36. Adam J, Couturier J, Molinié V, et al. Clear-cell papillary renal cell
carcinoma: 24 cases of a distinct low-grade renal tumour and a
comparative genomic hybridization array study of seven cases.
Histopathology. 2011;58:1064–1071.
37. Rohan SM, Xiao Y, Liang Y, et al. Clear-cell papillary renal cell
carcinoma: molecular and immunohistochemical analysis with
emphasis on the von Hippel-Lindau gene and hypoxia-inducible
factor pathway-related proteins. Mod Pathol. 2011;24:1207–1220.
38. Behdad A, Monzon FA, Hes O, et al. Relationship between
sporadic clear cell-papillary renal cell carcinoma (CP-RCC) and
renal angiomyoadenomatous tumor (RAT) of the kidney: analysis
by virtual-karyotyping, fluorescent in situ analysis and
immunohistochemistry (IHC). Mod Pathol. 2011;24(S1):179A.
39. Kuroda N, Hosokawa T, Michal M, et al. Clear cell renal cell
carcinoma with focal renal angiomyoadenomatous tumorlike area. Ann Diagn Pathol. 2011;15:202–206.
40. Wolfe A, Dobin SM, Grossmann P, et al. Clonal trisomies 7,10 and
12, normal 3p and absence of VHL gene mutation in a clear cell
tubulopapillary carcinoma of the kidney. Virchows Arch. 2011;459:
457–463.
41. Argani P, Antonescu CR, Couturier J, et al. PRCC-TFE3 renal
carcinomas: Morphologic, immunohistochemical, ultrastructural,
and molecular analysis of an entity associated with the
t(X;1)(p11.2;q21). Am J Surg Pathol. 2002;26:1553–1566.
42. Argani P, Antonescu CR, Illei PB, et al. Primary renal neoplasms
with the ASPL-TFE3 gene fusion of alveolar soft part sarcoma: a
distinctive tumor entity previously included among renal cell carcinomas of children and adolescents. Am J Pathol. 2001;159:179–192.
43. Ladanyi M, Lui MY, Antonescu CR, et al. The der(17)t(X;17)
(p11;q25) of human alveolar soft part sarcoma fuses the TFE3
transcription factor gene to ASPL, a novel gene at 17q25. Oncogene.
2001;20:48–57.
44. Clark J, Lu YJ, Sidhar SK, et al. Fusion of splicing factor genes
PSF and NonO (p54nrb) to the TFE3 gene in papillary renal cell
carcinoma. Oncogene. 1997;15:2233–2239.
45. Argani P, Lui MY, Couturier J, et al. A novel CLTC-TFE3 gene
fusion in pediatric renal adenocarcinoma with t(X;17)(p11.2;q23).
Oncogene. 2003;22:5374–5378.
46. Argani P, Olgac S, Tickoo SK, et al. Xp11 translocation renal cell
carcinoma in adults: expanded clinical, pathologic, and genetic
spectrum. Am J Surg Pathol. 2007;31:1149–1160.
47. Komai Y, Fujiwara M, Fujii Y, et al. Adult Xp11 translocation
renal cell carcinoma diagnosed by cytogenetics and immunohistochemistry. Clin Cancer Res. 2009;15:1170–1176.
48. Zhong M, De Angelo P, Osborne L, et al. Dual-color, break-apart
FISH assay on paraffin-embedded tissues as an adjunct to
diagnosis of Xp11 translocation renal cell carcinoma and alveolar
soft part sarcoma. Am J Surg Pathol. 2010;34:757–766.
49. Argani P, Laé M, Ballard ET, et al. Translocation carcinomas of
the kidney after chemotherapy in childhood. J Clin Oncol.
2006;24:1529–1534.
50. Argani P, Hicks J, DeMarzo A, et al. Xp11 translocation renal cell
carcinoma (RCC): extended immunohistochemical (IHC) profile
emphasizing novel RCC markers. Am J Surg Pathol. 2010;34:
1295–1303.
51. Argani P, Lal P, Hutchinson B, et al. Aberrant nuclear
immunoreactivity for TFE3 in neoplasms with TFE3 gene fusions:
A sensitive and specific immunohistochemical assay. Am J Surg
Pathol. 2003;27:750–761.
52. Macher-Geoppinger S, Roth W, Wagener N, et al. Molecular
heterogeneity of TFE3 activation in renal cell carcinomas. Mod
Pathol. 2012;25:308–315.
www.ajsp.com |
1485
Srigley et al
53. Green WM, Yonescu R, Morsberger L, et al. Utilization of a
TFE3 break apart FISH assay in a renal tumor consultation
service. Am J Surg Pathol. 2013;37:1150–1163.
54. Mosquera JM, Dal Cin P, Mertz KD, et al. Validation of a TFE3
break-apart FISH assay for Xp11.2 translocation renal cell
carcinoma. Diagn Mol Pathol. 2011;20:129–137.
55. Martignoni G, Pea M, Gobbo S, et al. Cathepsin-K immunoreactivity distinguishes MiTF/TFE family renal translocation
carcinomas from other renal carcinomas. Mod Pathol. 2009;22:
1016–1022.
56. Martignoni G, Gobbo S, Camparo P, et al. Differential expression
of cathepsin-K in neoplasms harbouring TFE3 gene fusions. Mod
Pathol. 2011;24:1313–1319.
57. Geller JI, Argani P, Adeniran A, et al. Translocation renal cell
carcinoma: lack of negative impact due to lymph node spread.
Cancer. 2008;112:1607–1616.
58. Meyer PN, Clark JI, Flanigan RC, et al. Xp11.2 translocation renal
cell carcinoma with very aggressive course in five adults. Am J Clin
Pathol. 2007;128:70–79.
59. Argani P, Aulmann S, Karanjawala Z, et al. Melanotic Xp11
translocation renal cancers: a distinctive neoplasm with overlapping features of PEComa, carcinoma, and melanoma. Am J
Surg Pathol. 2009;33:609–619.
60. Chang IW, Huang HY, Sung MT. Melanotic Xp11 translocation
renal cancer: a case with PSF-TFE3 gene fusion and up-regulation of
melanogenetic transcripts. Am J Surg Pathol. 2009;33:1894–1901.
61. Argani P, Illei P, Netto G, et al. A distinctive subset of PEComas
harbor TFE3 gene fusions. Am J Surg Pathol. 2010;34:1395–1406.
62. Tanaka M, Kato K, Gomi K, et al. Perivascular epithelioid cell
tumor with SFPQ/PSF-TFE3 gene fusion in a patient with
advanced neuroblastoma. Am J Surg Pathol. 2009;33:1416–1420.
63. Ohe C, Kuroda N, Hes O, et al. A renal epithelioid angiomyolipoma/perivascular cell tumor with TFE3 gene break visualized
by FISH. Med Mol Morphol. 2012;45:234–237.
64. Argani P, Hawkins A, Griffin CA, et al. A distinctive pediatric
renal neoplasm characterized by epithelioid morphology, basement
membrane production, focal HMB45 immunoreactivity, and
t(6;11)(p21.1;q12) chromosome translocation. Am J Pathol.
2001;158:2089–2096.
65. Argani P, Laé M, Hutchinson B, et al. Renal carcinomas with the
t(6;11)(p21;q12). Clinicopathologic features and demonstration of
the specific Alpha-TFEB gene fusion by immunohistochemistry,
RT-PCR, and DNA-PCR. Am J Surg Pathol. 2005;29:230–240.
66. Argani P, Yonescu R, Morsberger L, et al. Molecular confirmation
of the t(6;11)(p21;q12) renal cell carcinomas in archival paraffinembedded material using a break-apart TFEB FISH assay expands
its clinicopathologic spectrum. Am J Surg Pathol. 2012;36:
1516–1526.
67. Camparo P, Vasiliu V, Molinie V, et al. Renal translocation
carcinomas: clinicopathologic, immunohistochemical, and gene
expression profiling analysis of 31 cases with a review of the
literature. Am J Surg Pathol. 2008;32:656–670.
68. Davis IJ, Hsi BL, Arroyo JD, et al. Cloning of an Alpha-TFEB
fusion in renal tumors harboring the t(6;11)(p21;q13) chromosome
translocation. Proc Natl Acad Sci USA. 2003;100:6051–6056.
69. Inamura K, Fujiwara M, Togashi Y, et al. Diverse fusion patterns
and heterogeneous clinicopathologic features of renal cell carcinoma with t(6;11) translocation. Am J Surg Pathol. 2012;36:35–42.
70. Kuiper RP, Schepens M, Thijssen J, et al. Upregulation of the
transcription factor TFEB in t(6;11)(p21;q13)-positive renal cell
carcinomas due to promoter substitution. Hum Mol Genet.
2003;12:1661–1669.
71. Pecciarini L, Cangi MG, Lo Cunsolo C, et al. Characterization of
t(6;11)(p21;q12) in a renal-cell carcinoma of an adult patient. Genes
Chromosomes Cancer. 2007;46:419–426.
72. Zhan HQ, Wang CF, Zhu XZ, et al. Renal cell carcinoma with
t(6;11) translocation: a patient case with a novel Alpha-TFEB
fusion point. J Clin Oncol. 2010;28:e709–e713.
73. Smith N, Illei P, Gonzalez N, et al. t(6;11) renal cell carcinoma
(RCC): report of six new genetically-confirmed cases and expanded
Immunohistochemical (IHC) profile. Mod Pathol. 2013;26(S2):250A.
1486 | www.ajsp.com
Am J Surg Pathol
Volume 37, Number 10, October 2013
74. Kiuru M, Launonen V, Hietal M, et al. Familial cutaneous
leiomyomas associated with renal cell cancer of characteristic
histopathology. Am J Pathol. 2001;159:825–829.
75. Kiuru M, Lehtonen R, Arola J, et al. Few FH mutations in
sporadic counterparts of tumor types observed in hereditary
leiomyomatosis and renal cell cancer families. Cancer Res.
2002;62:4554–4557.
76. Launonen V, Vierimaa O, Kiuru M, et al. Inherited susceptibility
to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci
USA. 2002;98:3387–3392.
77. Tomlinson IP, Alam NA, Rowan AJ, et al. Germline mutations in FH
predispose to dominantly inherited uterine fibroids, skim leiomyomata
and papillary renal cell cancer. Nat Genet. 2002;30:406–410.
78. Alam NA, Rowan AJ, Wortham NC, et al. Genetic and functional
analyses of FH mutations in multiple cutaneous and uterine
leiomyomatosis, hereditary leiomyomatosis and renal cancer, and
fumarate hydratase deficiency. Hum Mol Genet. 2003;12:
1241–1252.
79. Toro JR, Nickerson ML, Wei MH, et al. Mutations in the
fumarate hydratase gene cause hereditary leiomyomatosis and
renal cell cancer in families in North American. Am J Hum Genet.
2003;73:95–106.
80. Grubb RL, Franks ME, Toro J, et al. Hereditary leiomyomatosis
and renal cell cancer: a syndrome associated with an aggressive
form of inherited renal cancer. J Urol. 2007;177:2074–2079.
81. Merino MJ, Torres-Cabala C, Pinto P, et al. The morphologic
spectrum of kidney tumors in hereditary leiomyomatosis and renal
cell carcinoma (HLRCC) syndrome. Am J Surg Pathol. 2007;31:
1578–1585.
82. Jung SJ, Chung JI, Park SH, et al. Thyroid follicular carcinomalike tumor of kidney. Am J Surg Pathol. 2006;30:411–415.
83. Amin MB, Gupta R, Ondrej HO, et al. Primary thyroid-like
follicular carcinoma of the kidney: report of 6 cases of a
histologically distinctive adult renal epithelial neoplasm. Am J
Surg Pathol. 2009;33:393–400.
84. Dhillon J, Tannir NM, Matin SF, et al. Thyroid-like follicular
carcinoma of the kidney with metastases to the lungs and
retroperitoneal lymph nodes. Hum Pathol. 2011;42:146–150.
85. Khoja HA, Almutawa A, Binmahfooz A, et al. Papillary thyroid
carcinoma-like tumor of the kidney: a case report. Int J Surg
Pathol. 2012;20:411–415.
86. Alessandrini L, Fassan M, Gardiman MP, et al. Thyroid-like
follicular carcinoma of the kidney: report of two cases with detailed
immunohistochemical profile and literature review. Virchows Arch.
2012;461:345–350.
87. Dhillon J, Mohanty SK, Krishnamurthy S. Cytologic diagnosis of thyroid-like follicular carcinoma of the kidney: a case
report. Diagn Cytopathol. 2012. DOI: 10.1002/dc.22930. [Epub
ahead of print].
88. Angell SK, Fruthi R, Freiha FS. Primary thyroid-like carcinoma of
the kidney. Urology. 1996;48:632–635.
89. William S, Irmgard V, Michael G, et al. Thyroid follicular
carcinoma-like renal tumor: a case report with morphologic,
immunophenotypic, cytogenetic and scintigraphic studies. Virchows Arch. 2008;452:91–95.
90. Gill AJ, Pachter NS, Chou A, et al. Renal tumors associated with
germline SDHB mutation show distinctive morphology. Am J Surg
Pathol. 2011;35:1578–1585.
91. Henderson A, Douglas F, Perros P, et al. SDHB-associated
renal oncocytoma suggests a broadening of the renal phenotype in hereditary paragangliomatosis. Fam Cancer. 2009;8:
257–260.
92. Housley SL, Lindsay RS, Young B, et al. Renal carcinoma with
giant mitochondria associated with germ-line mutation and
somatic loss of the succinate dehydrogenase B gene. Histopathology. 2010;56:401–410.
93. Van Nederven FH, Gaal J, Favier J, et al. An immunohistochemical procedure to detect patients with paraganglioma and
phaeochromocytoma with germline SDHB, SDHC, or SDHD
gene mutations: a retrospective and prospective analysis. Lancet
Oncol. 2009;10:764–771.
r
2013 Lippincott Williams & Wilkins
Am J Surg Pathol
Volume 37, Number 10, October 2013
94. Barletta JA, Hornick JL. Succinate dehydrogenase-deficient
tumors: diagnostic advances and clinical implications. Adv Anat
Pathol. 2012;19:193–203.
95. Gill AJ. Succinate dehydrogenase (SDH) and mitochondrial driven
neoplasia. Pathology. 2012;44:285–292.
96. Debelenko LV, Raimondi SC, Daw N, et al. Renal cell carcinoma
with novel VCL-ALK fusion: new representative of ALKassociated tumor spectrum. Mod Pathol. 2011;24:430–442.
97. Marino-Eñrı́quez A, Ou WB, Weldon CB, et al. ALK rearrangement in sickle cell trait-associated renal medullary carcinoma.
Genes Chromosomes Cancer. 2011;50:146–153.
98. Sugawara E, Togashi Y, Kuroda N, et al. Identification of
anaplastic lymphoma kinase fusions in renal cancer. Cancer.
2012;118:4427–4436.
99. Sukov WR, Hodge JC, Lohse CM, et al. ALK alterations in adult
renal cell carcinoma: frequency, cliniciopathologic features and
outcome in a large series of consecutively treated patients. Mod
Pathol. 2012;25:1516–1525.
100. Moch H. Cystic renal tumors: new entities and novel concepts. Adv
Anat Pathol. 2010;17:209–214.
101. You D, Shim M, Jeong IG, et al. Multilocular cystic renal cell
carcinoma: clinicopathological features and preoperative prediction using multiphase computed tomography. BJU Int. 2011;108:
1444–1449.
102. von Teichman A, Compérat E, Behnke S, et al. VHL mutations
and dysregulation of pVHL- and PTEN-controlled pathways in
multilocular cystic renal cell carcinoma. Mod Pathol. 2011;24:
571–578.
103. Halat S, Eble JN, Grignon DJ, et al. Multilocular cystic renal cell
carcinoma is a subtype of clear cell renal cell carcinoma. Mod
Pathol. 2010;23:931–936.
104. Williason SR, Halat S, Eble JN, et al. Multilocular cystic renal cell
carcinoma. Similarities and differences in immunoprolife compared
with clear cell renal cell carcinoma. Am J Surg Pathol. 2012;36:
1425–1433.
105. Suzigan S, López-Beltrán A, Montironi R, et al. Multilocular cystic
renal cell carcinoma: a report of 45 cases of a kidney tumor of low
malignant potential. Am J Clin Pathol. 2006;125:217–222.
106. Algaba F, Akaza H, López-Beltrán A, et al. Current pathology
keys of renal cell carcinoma. Eur Urol. 2011;60:634–643.
107. Stamatiou KN, Sofras F. Multilocular cystic nephroma and
multicystic clear cell carcinoma: two faces of the Roman
god Janus? Int J Surg Pathol. 2009;17:170–171.
108. Chen YB, Tickoo SK. Spectrum of preneoplastic and neoplastic
cystic lesions of the kidney. Arch Pathol Lab Med. 2012;136:
400–409.
109. Suzigan S, Drut R, Faria P, et al. Xp11 translocation carcinoma of
the kidney presenting with multilocular cystic renal cell carcinomalike features. Int J Surg Pathol. 2007;15:199–203.
110. Delahunt B, Thornton A. Renal cell carcinoma: a historical
perspective. J Urol Pathol. 1996;4:31–49.
111. Mancilla-Jimenez R, Stanley RJ, Blath RA. Papillary renal cell
carcinoma: a clinical radiologic and pathologic study of 34 cases.
Cancer. 1976;38:2469–2480.
112. Mydlo JH, Bard RH. Analysis of papillary renal adenocarcinoma.
Urology. 1987;30:529–534.
113. Kovacs G. Papillary renal cell carcinoma. A morphological and
cytogenetic study of 11 cases. Am J Pathol. 1989;134:27–34.
114. Hora M, Hes O, Klecka J, et al. Rupture of papillary renal cell
carcinoma. Scand J Urol Nephrol. 2004;38:481–484.
115. Cheville JC, Lohse CM, Zincke BS, et al. Comparison of outcome
and prognostic feature among histological subtypes of renal cell
carcinoma. Am J Surg Pathol. 2003;27:612–624.
116. Velickovic M, Delahunt B, Störkel S, et al. VHL and FHIT locus
loss of heterozygosity is common in all renal cancers morphotypes
but differs in pattern and prognostic significance. Cancer Res.
2001;61:4815–4819.
117. Morrissey C, Martinez A, Zatyka M, et al. Epigenetic inactivation
of RASSFIA 3p21.3 tumor suppressor gene in both clear
cell and papillary renal cell carcinoma. Cancer Res. 2001;61:
7277–7281.
r
2013 Lippincott Williams & Wilkins
Classification of Renal Neoplasia
118. Hughson MD, Dickman K, Bigler SA, et al. Clear-cell and
papillary carcinoma of the kidney: an analysis of chromosome 3, 7,
and 17 abnormalities by microsatellite amplification, cytogenetics,
and fluorescence in situ hybridization. Cancer Genet Cytogenet.
1998;106:93–104.
119. Delahunt B, Eble JN. Papillary renal cell carcinoma: a histological
and immunohistochemical study of 105 cases. Mod Pathol.
1997;10:537–544.
120. Delahunt B, Eble JN, McCredie M, et al. Morphologic typing of
papillary renal cell carcinoma: comparison of growth kinetics and
patient survival in 66 cases. Hum Pathol. 2001;32:590–595.
121. Leroy X, Zini L, Leteurtre E, et al. Morphologic subtyping of
papillary renal cell carcinoma: correlation with prognosis and
different expression of MUC1 between the two subtypes. Mod
Pathol. 2002;15:1126–1131.
122. Kim MK, Kim S. Immunohistochemical profile of common
epithelial neoplasms arising in the kidney. Appl Immunohistochem
Mol Morphol. 2002;10:332–338.
123. Lagner C, Wegscheider BJ, Ratschek M, et al. Keratin immunohistochemistry in renal cell carcinoma subtypes and renal
oncocytomas: a systematic analysis of 233 tumors. Virchows Arch.
2004;444:127–134.
124. Zhou M, Roma A, Magi-Galluzzi C. The usefulness of immunohistochemical markers in the differential diagnosis of renal
neoplasms. Clin Lab Med. 2005;25:247–257.
125. Jiang F, Richter J, Schraml P, et al. Chromosomal imbalances in
papillary renal cell carcinoma: genetic differences between histological subtypes. Am J Pathol. 1998;153:1467–1473.
126. Sanders ME, Mick R, Tomaszewski JE, et al. Unique patterns of
allelic imbalance distinguish type 1 from type 2 sporadic papillary
renal cell carcinoma. Am J Surg Pathol. 2002;161:997–1005.
127. Furge FA, Chen J, Koeman J, et al. Detection of DNA copy
number changes and oncogenic signaling abnormalities from gene
expression data reveals MYC activation in high grade papillary
renal cell carcinoma. Cancer Res. 2007;67:3171–3176.
128. Antonelli A, Tardanico R, Balzarim P, et al. Cytogenetic features,
clinical significance and prognostic impact of type 1 and type 2
papillary renal cell carcinoma. Cancer Genet Cytogenet. 2010;199:
128–133.
129. Yang XJ, Tan M-H, Kim HL, et al. A molecular classification of
papillary renal cell carcinoma. Cancer Res. 2005;65:5628–5637.
130. Delahunt B, Cheville JC, Martignoni G, et al. The International
Society of Urological Pathology (ISUP) grading system for renal
cell carcinoma and other prognostic parameters. Am J Surg Pathol.
2013;37:e33–e47.
131. Adley BP, Smith ND, Nayar R, et al. Birt-Hogg-Dube syndrome:
clinicopathologic findings and genetic alterations. Arch Pathol Lab
Med. 2006;130:1865–1870.
132. Delongchamps NB, Galmiche L, Eiss D, et al. Hybrid tumour
‘oncocytoma-chromophobe renal cell carcinoma’ of the kidney: a
report of seven sporadic cases. BJU Int. 2009;103:1381–1384.
133. Gobbo S, Eble JN, Delahunt B, et al. Sporadic hybrid oncocytic/
chromophobe tumor of the kidney: a clinicopathologic, histomorphologic, immunohistochemical, ultrastructural, and molecular
cytogenetic study of 14 cases. Renal cell neoplasms of oncocytosis
have distinct morphologic, immunohistochemical, and cytogenetic
profile. Am J Surg Pathol. 2010;34:620–626.
134. Mai KT, Dhamanaskar P, Belanger E, et al. Hybrid chromophobe
renal cell neoplasm. Pathol Res Pract. 2005;201:385–389.
135. Pavlovich CP, Walther MM, Eyler RA, et al. Renal tumors in the
Birt-Hogg-Dube syndrome. Am J Surg Pathol. 2002;26:1542–1552.
136. Petersson F, Gatalica Z, Grossmann P, et al. Sporadic hybrid
oncocytic/chromophobe tumor of the kidney: a clinicopathologic,
histomorphologic, immunohistochemical, ultrastructural, and
molecular cytogenetic study of 14 cases. Virchows Arch. 2010;456:
355–365.
137. Tickoo SK, Reuter VE, Amin MB, et al. Renal oncocytosis: a
morphologic study of fourteen cases. Am J Surg Pathol. 1999;23:
1094–1101.
138. Waldert M, Klatte T, Haitel A, et al. Hybrid renal cell carcinomas
containing histopathologic features of chromophobe renal cell
www.ajsp.com |
1487
Srigley et al
139.
140.
141.
142.
143.
144.
145.
146.
147.
148.
149.
150.
151.
152.
153.
154.
155.
156.
157.
158.
159.
160.
carcinomas and oncocytomas have excellent oncologic outcomes.
Eur Urol. 2010;57:661–665.
Warfel KA, Eble JN. Renal oncocytomatosis. J Urol. 1982;127:
1179–1180.
Al-Saleem T, Cairns P, Dulaimi EA, et al. The genetics of renal
oncocytosis: a possible model for neoplastic progression. Cancer
Genet Cytogenet. 2003;152:23–28.
Cossu-Rocca P, Eble JN, Zhang S, et al. Interphase cytogenetic
analysis with centromeric probes for chromosomes 1, 2, 6, 10, and
17 in 11 tumors from a patient with bilateral renal oncocytosis.
Mod Pathol. 2008;21:498–504.
Chen TS, McNally M, Hulbert W, et al. Renal oncocytosis
presenting in childhood: a case report. Int J Surg Pathol.
2003;11:325–329.
Klomp JA, Petillo D, Niemi NM, et al. Birt-Hogg-Dube renal
tumors are genetically distinct from other renal neoplasias and are
associated with up-regulation of mitochondrial gene expression.
BMC Med Genomics. 2010;3:59.
Murakami T, Sano F, Huang Y, et al. Identification and
characterization of Birt-Hogg-Dube associated renal carcinoma.
J Pathol. 2007;211:524–531.
Amin MD, Varma MD, Tickoo SK, et al. Collecting duct
carcinoma of the kidney. Adv Anat Pathol. 1997;4:85–94.
Srigley JR, Eble JN. Collecting duct carcinoma of the kidney.
Semin Diagn Pathol. 1998;15:54–67.
Albadine R, Schultz L, Illei P, et al. PAX8 (+)/p63 ( )
immunostaining pattern in renal collecting duct carcinoma
(CDC): a useful immunoprofile in the differential diagnosis of
CDC versus urothelial carcinoma of upper urinary tract. Am J
Surg Pathol. 2010;34:969–969.
Elwood H, Chaux A, Schultz L, et al. Immunohistochemical
analysis of SMARCB1/INI-1 expression in collecting duct carcinoma. Urology. 2011;78:474.e1–474.e5.
Pepek JM, Johnstone PA, Jani AB. Influence of demographic
factors on outcome of collecting duct carcinoma: a Surveillance,
Epidemiology, and End Results (SEER) database analysis. Clin
Genitourin Cancer. 2009;7:E24–E27.
Peyromaure M, Thiounn N, Scotte F, et al. Collecting duct
carcinoma of the kidney: a clinicopathological study of 9 cases.
J Urol. 2003;170:1138–1140.
Davis CJ Jr, Mostofi FK, Sesterhenn IA. Renal medullary carcinoma.
The seventh sickle cell nephropathy. Am J Surg Pathol. 1995;19:1–11.
Cheng JX, Tretiakova M, Gong C, et al. Renal medullary
carcinoma: rhabdoid features and the absence of INI1 expression
as markers of aggressive behavior. Mod Pathol. 2008;21:647–652.
Gupta R, Billis A, Shah R, et al. Carcinoma of the collecting ducts
of Bellini and renal medullary carcinoma. Am J Surg Pathol.
2012;36:1265–1278.
Albadine R, Wang W, Brownlee NA, et al. Topoisomerase II alpha
status in renal medullary carcinoma: immuno-expression and gene
copy alterations of a potential target of therapy. J Urol.
2009;182:735–740.
Schaeffer EM, Guzzo TJ, Furge KA, et al. Renal medullary
carcinoma: molecular, pathological and clinical evidence for treatment
with topoisomerase-inhibiting therapy. BJU Int. 2010;106:62–65.
Gatalica Z, Lilleberg SL, Monzon FA, et al. Renal medullary
carcinomas: histopathologic phenotype associated with diverse
genotypes. Hum Pathol. 2011;42:1979–1988.
Walsh A, Kelly DR, Vaid YN, et al. Complete response to
carboplatin, gemcitabine, and paclitaxel in a patient with advanced
metastatic renal medullary carcinoma. Pediatr Blood Cancer.
2010;55:1217–1220.
Srigley JR, Eble JN, Grignon DJ, et al. Unusual renal cell
carcinoma (RCC) with prominent spindle cell change possibly
related to the loop of Henle. Mod Pathol. 1999;12:107.
Parwani AV, Husain AN, Epstein JI, et al. Low-grade myxoid
renal epithelial neoplasms with distal nephron differential. Hum
Pathol. 2001;32:506–512.
Rakozy C, Schmahl GE, Bagner S, et al. Low-grade tubularmucinous renal neoplasms: morphologic, immunohistochemical,
and genetic features. Mod Pathol. 2002;15:1162–1171.
1488 | www.ajsp.com
Am J Surg Pathol
Volume 37, Number 10, October 2013
161. Hes I, Hora M, Perez-Montiel DM, et al. Spindle and cuboidal
renal cell carcinoma, a tumour having frequent association with
nephrolithiasis: report on 11 cases including a case with hybrid
conventional renal cell carcinoma/spindle and cuboidal renal cell
carcinoma components. Histopathology. 2002;41:549–555.
162. Paner GP, Srigley JR, Radhakrishnan A, et al. Immunohistochemical analysis of mucinous tubular and spindle cell carcinoma and
papillary renal cell carcinoma of the kidney. Am J Surg Pathol.
2006;30:13–19.
163. Fine SW, Argani P, DeMarzo AM, et al. Expanding the histologic
spectrum of mucinous tubular and spindle cell carcinoma of the
kidney. Am J Surg Pathol. 2006;30:1554–1560.
164. Farghaly H. Mucin poor mucinous tubular and spindle cell
carcinoma of the kidney, with nonclassic morphologic variant of
spindle cell predominance and psammomatous calcification. Ann
Diagn Pathol. 2012;16:59–62.
165. Shen SS, Ro JY, Tamboli P, et al. Mucinous tubular and spindle
cell carcinoma of kidney is probably a variant of papillary renal cell
carcinoma with spindle cell features. Ann Diagn Pathol. 2007;11:
13–21.
166. Cossu-Rocca P, Eble JN, Delahunt B, et al. Renal mucinous
tubular and spindle carcinoma lacks the gains of chromosomes 7
and 17 and losses of chromosome Y that are prevalent in papillary
renal cell carcinoma. Mod Pathol. 2006;19:488–493.
167. Kuroda N, Naroda T, Tamura M, et al. High-grade mucinous
tubular and spindle cell carcinoma: comparative genomic
hybridization study. Ann Diagn Pathol. 2011;15:472–475.
168. Ursani NA, Robertson R, Schieman SM, et al. Mucinous tubular
and spindle cell carcinoma of kidney without sarcomatoid change
showing metastases to liver and retroperitoneal lymph node. Hum
Pathol. 2011;42:444–448.
169. Pillay N, Ramdial PK, Cooper K, et al. Mucinous tubular and
spindle cell carcinoma with aggressive histomorphology a
sarcomatoid variant. Hum Pathol. 2008;39:966–969.
170. Simon RA, di Sant’agnese PA, Palaputtu GS, et al. Mucinous
tubular and spindle cell carcinoma of the kidney with sarcomatoid
differentiation. Int J Clin Exp Pathol. 2008;1:180–184.
171. Dhillon J, Amin MB, Selbs E, et al. Mucinous tubular and spindle
cell carcinoma of the kidney with sarcomatoid change. Am J Surg
Pathol. 2009;33:44–49.
172. Bulimbasic S, Sima R, Kuroda N. Aggressive high-grade mucinous
tubular and spindle cell carcinoma. Hum Pathol. 2009;906–907.
173. Larkin J, Fisher R, Pickering L, et al. Metastatic mucinous tubular
and spindle cell carcinoma of the kidney responding to Sunitinib.
J Clin Oncol. 2010;28:539–540.
174. Martignoni G, Bonetti F, Chilosi M, et al. Cathepsin K expression
in the spectrum of perivascular epithelioid cell (PEC) lesions of the
kidney. Mod Pathol. 2012;25:100–111.
175. Dickson BC, Brooks JS, Pasha TL, et al. TFE3 expression in
tumors of the microphthalmia-associated transcription factor
(MiTF) family. Int J Surg Pathol. 2011;19:26–30.
176. Nese N, Martignoni G, Fletcher CD, et al. Pure epithelioid
PEComas (so-called epithelioid angiomyolipoma) of the kidney:
a clinicopathologic study of 41 cases: detailed assessment of
morphology and risk stratification. Am J Surg Pathol. 2011;35:
161–176.
177. Brimo F, Robinson B, Guo C, et al. Renal epithelioid angiomyolipoma with atypia: a series of 40 cases with emphasis on
clinicopathologic prognostic indicators of malignancy. Am J Surg
Pathol. 2010;34:715–722.
178. He W, Cheville JC, Sadow PM, et al. Pathologic characteristics and
clinical outcome of renal epithelioid angiomyolipoma: a multiinstitutional experience based on primary tumor resections. Mod
Pathol. 2011;24(S1):196A–197A.
179. Cho NH, Shim HS, Choi YD, et al. Estrogen receptor is
significantly associated with the epithelioid variants of renal
angiomyolipoma: a clinicopathological and immunohistochemical
study of 67 cases. Pathol Int. 2004;54:510–515.
180. Martignoni G, Pea M, Bonetti F, et al. Oncocytoma-like
angiomyolipoma. A clinicopathologic and immunohistochemical
study of 2 cases. Arch Pathol Lab Med. 2002;126:610–612.
r
2013 Lippincott Williams & Wilkins
Am J Surg Pathol
Volume 37, Number 10, October 2013
181. Chandrasoma S, Daneshmand S, Wilson S, et al. Renal angiomyolipoma with liposarcomatous transformation: a case report
and review of the literature. Urol Oncol. 2004;22:425–427.
182. Nikaido T, Nakano M, Kato M, et al. Characterization of smooth
muscle components in renal angiomyolipomas: histological and
immunohistochemical comparison with renal capsular leiomyomas.
Pathol Int. 2004;54:1–9.
183. Kilicaslan I, Gulluoglu MG, Dogan O, et al. Intraglomerular
microlesions in renal angiomyolipoma. Hum Pathol. 2000;31:
1325–1328.
184. Fine SW, Reuter VE, Epstein JI, et al. Angiomyolipoma with
epithelial cysts (AMLEC): a distinct cystic variant of angiomyolipoma. Am J Surg Pathol. 2006;30:593–599.
185. Buritica C, Serrano M, Zuluaga A, et al. Mixed epithelial and
stromal tumour of the kidney with luteinised ovarian stroma.
J Clin Pathol. 2007;60:98–100.
186. Michal M, Hes O, Bisceglia M, et al. Mixed epithelial and stromal
tumors of the kidney. A report of 22 cases. Virchows Arch.
2004;445:359–367.
187. Adsay NV, Eble JN, Srigley JR, et al. Mixed epithelial and stromal
tumor of the kidney. Am J Surg Pathol. 2000;24:958–970.
188. Yang Y, Ondrej H, Zhang L, et al. Mixed epithelial and stromal
tumor of the kidney with cervical and intestinal differentiation.
Virchows Arch. 2005;447:669–671.
189. Michal M, Syrucek M. Benign mixed epithelial and stromal tumor
of the kidney. Pathol Res Pract. 1998;194:445–448.
190. Pawade J, Soosay GN, Delprado W, et al. Cystic hamartoma of the
renal pelvis. Am J Surg Pathol. 1993;17:1169–1175.
191. Beiko DT, Nickel JC, Boag AH, et al. Benign mixed epithelial
stromal tumor of the kidney of possible mullerian origin. J Urol.
2001;166:1381–1382.
192. Karafin M, Parwani AV, Netto GJ, et al. Diffuse expression of
PAX2 and PAX8 in the cystic epithelium of mixed epithelial
stromal tumor, angiomyolipoma with epithelial cysts, and primary
renal synovial sarcoma: evidence supporting renal tubular differentiation. Am J Surg Pathol. 2011;35:1264–1273.
193. Kum JB, Grignon DJ, Wang M, et al. Mixed epithelial and stromal
tumors of the kidney: evidence for a single cell of origin with
capacity for epithelial and stromal differentiation. Am J Surg
Pathol. 2011;35:1114–1122.
194. Sukov WR, Cheville JC, Lager DJ, et al. Malignant mixed
epithelial and stromal tumor of the kidney with rhabdoid features:
report of a case including immunohistochemical, molecular genetic
studies and comparison to morphologically similar renal tumors.
Hum Pathol. 2007;38:1432–1437.
195. Svec A, Hes O, Michal M, et al. Malignant mixed epithelial
and stromal tumor of the kidney. Virchows Arch. 2001;439:
700–702.
196. Antic T, Perry KT, Harrison K, et al. Mixed epithelial and stromal
tumor of the kidney and cystic nephroma share overlapping
features: reappraisal of 15 lesions. Arch Pathol Lab Med.
2006;130:80–85.
197. Jevremovic D, Lager DJ, Lewin M. Cystic nephroma (multilocular
cyst) and mixed epithelial and stromal tumor of the kidney:
a spectrum of the same entity? Ann Diagn Pathol. 2006;10:
77–82.
198. Turbiner J, Amin MB, Humphrey PA, et al. Cystic nephroma and
mixed epithelial and stromal tumor of kidney: a detailed
clinicopathologic analysis of 34 cases and proposal for renal
epithelial and stromal tumor (REST) as a unifying term. Am J Surg
Pathol. 2007;31:489–500.
199. Zhou M, Kort E, Hoekstra P, et al. Adult cystic nephroma and
mixed epithelial and stromal tumor of the kidney are the same
disease entity: molecular and histologic evidence. Am J Surg
Pathol. 2009;33:72–80.
200. Lane BR, Campbell SC, Remer EM, et al. Adult cystic nephroma
and mixed epithelial and stromal tumor of the kidney: clinical,
r
2013 Lippincott Williams & Wilkins
Classification of Renal Neoplasia
radiographic, and pathologic characteristics. Urology. 2008;71:
1142–1148.
201. Montironi R, Mazzucchelli R, Lopez-Beltran A, et al. Cystic
nephroma and mixed epithelial and stromal tumour of the kidney:
opposite ends of the spectrum of the same entity? Eur Urol.
2008;54:1237–1246.
202. Argani P, Faria PA, Epstein JI, et al. Primary renal synovial
sarcoma: molecular and morphologic delineation of an entity
previously included among embryonal sarcomas of the kidney . Am
J Surg Pathol. 2000;24:1087–1096.
APPENDIX
The members of the ISUP Renal Tumor Panel are
the following:
Anila Abraham, Adebowale Adeniran, Khalid
Ahmed, Hikmat Al Ahmadie, Ferran Algaba, Robert
Allan, Mahul Amin, Pedram Argani, Ulrika Axcrona,
Marc Barry, Dilek Baydar, Louis Bégin, Dan Berney,
Peter Bethwaite, Athanase Billis, Ruth Birbe, Stephen
Bonsib, David Bostwick, Fadi Brimo, Helen Cathro,
Ying-Bei Chen, Liang Cheng, John Cheville, Yong Mee
Cho, Ai-Ying Chuang, Cynthia Cohen, Henry Crist,
Brett Delahunt, Warick Delprado, Fang-Ming Deng,
Lars Egevad, Jonathan Epstein, Andrew Evans, Oluwole
Fadare, Daniel Fajardo, Sara Falzarano, Samson Fine,
Stewart Fleming, Eddie Fridman, Bungo Furusato, Masoud Ganji, Masoumeh Ghayouri, Giovanna Giannico,
Neriman Gokden, David Griffiths, David Grignon, Nilesh Gupta, Omar Hameed, Ondrej Hes, Michelle Hirsch,
Jiaoti Huang, Wei Huang, Christina Hulsbergen-van de
Kaa, Peter Humphrey, Sundus Hussein, Kenneth Iczkowski, Rafael Jimenez, Edward Jones, Laura Irene Jufe,
James Kench, Masatoshi Kida, Glen Kristiansen,
Lakshmi Priya Kunju, Zhaoli Lane, Mathieu Latour,
Claudio Lewin, Kathrine Lie, Josep Lloreta, Barbara
Loftus, Antonio Lopez-Beltran, Fiona Maclean, Cristina
Magi-Galluzzi, Guido Martignoni, Teresa McHale, Jesse
McKenney, Maria Merino, Rose Miller, Hiroshi Miyamoto, Holger Moch, Rodolfo Montironi, Hedwig Murphy, John Nacey, Tipu Nazeer, Gabriella Nesi, George
Netto, Peter Nichols, Marie O’Donnell, Semra Olgac,
Roberto Orozco, Adeboye Osunkoya, Aysim Ozagari,
Chin-Chen Pan, Anil Parwani, Joanna Perry-Keene,
Constantina Petraki, Maria Picken, Maria Pyda-Karwicka, Victor Reuter, Katayoon Rezaei, Nathalie RiouxLeclercq, Brian Robinson, Stephen Rohan, Ruben Ronchetti, Laurie Russell, Hemamali Samaratunga, Marina
Scarpelli, Ahmed Shabaik, Rajal Shah, Jonathan Shanks,
Steven Shen, Maria Shevchuk, Mathilde Sibony, John
Srigley, Bhuvana Srinivasan, Martin Susani, Sueli Suzigan, Joan Sweet, Hiroyuki Takahashi, Pheroze Tamboli,
Puay Hoon Tan, Satish Tickoo, Isabel Trias, Kiril
Trpkov, Larry True, Toyonori Tsuzuki, Funda VakarLopez, Theo Van der Kwast, Cheng Wang, Anne Warren, Jorge Yao, Asli Yilmaz, Jin Zhao, Ming Zhou,
Debra Zynger.
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