Article

Urothelial lesions with inverted growth patterns: histogenesis, molecular genetic findings, differential diagnosis and clinical management

Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
BJU International (Impact Factor: 3.53). 02/2011; 107(4):532-7. DOI: 10.1111/j.1464-410X.2010.09853.x
Source: PubMed
ABSTRACT
What’s known on the subject? and What does the study add?
Inverted lesions of the urinary bladder comprise a spectrum of changes ranging from von Brunn’s nests to inverted urothelial carcinoma. Differentiating these lesions is important because their proper clinical management and their expected clinical outcomes are distinctly different.
In this article, we review the spectrum of inverted urothelial lesions of the bladder, including current morphological criteria, key differential diagnosis, molecular genetic findings and histogenesis. We have refined the diagnostic criteria for various bladder lesions with inverted growth patterns.
A number of well-recognized urothelial lesions with inverted morphology occur in the urinary bladder. Some are so common that they are considered normal variants of urothelium, whereas others are rare. It is important for the surgical pathologist to recognize these lesions and their overlapping morphological features, because in some cases establishing an accurate diagnosis is challenging. In this article, we review the spectrum of inverted urothelial lesions of the bladder. Emphasis is placed on differential diagnosis, molecular genetic findings, morphology and histogenesis.

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2010 BJU INTERNATIONAL | 107, 532–537 | doi:10.1111/j.1464-410X.2010.09853.x
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THE
AUTHORS;
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Mini Reviews
INVERTED UROTHELIAL LESIONS
HODGES
ET AL.
Urothelial lesions with inverted growth patterns:
histogenesis, molecular genetic findings,
differential diagnosis and clinical management
Kurt B. Hodges*, Antonio Lopez-Beltran
, Gregory T. MacLennan
,
Rodolfo Montironi
§
and Liang Cheng*
*Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN,
Department of Pathology, Case Western Reserve University, Cleveland, OH,
Department of Urology, Indiana
University School of Medicine, Indianapolis, IN, USA,
Department of Pathology, Cordoba University, Cordoba, Spain,
and
§
Institute of Pathological Anatomy and Histopathology, Polytechnic University of the Marche Region (Ancona),
United Hospitals, Ancona, Italy
Accepted for publication 25 May 2010
KEYWORDS
urinary bladder, transitional cell (urothelial)
carcinoma, urothelial papilloma, molecular
pathology, precursor lesions, inverted
and nested TCC urothelial carcinoma,
tumourigenesis(carcinogenesis), molecular
genetics, fibroblast growth factor receptor 3
(FGFR3), histological variant, differential
diagnosis
What’s known on the subject? and What does the study add?
Inverted lesions of the urinary bladder comprise a spectrum of changes ranging from von
Brunn’s nests to inverted urothelial carcinoma. Differentiating these lesions is important
because their proper clinical management and their expected clinical outcomes are
distinctly different.
In this article, we review the spectrum of inverted urothelial lesions of the bladder,
including current morphological criteria, key differential diagnosis, molecular genetic
findings and histogenesis. We have refined the diagnostic criteria for various bladder
lesions with inverted growth patterns.
A number of well-recognized urothelial
lesions with inverted morphology occur
in the urinary bladder. Some are so
common that they are considered normal
variants of urothelium, whereas others
are rare. It is important for the surgical
pathologist to recognize these lesions and
their overlapping morphological features,
because in some cases establishing an
accurate diagnosis is challenging. In this
article, we review the spectrum of inverted
urothelial lesions of the bladder. Emphasis is
placed on differential diagnosis, molecular
genetic findings, morphology and
histogenesis.
INTRODUCTION
Except for von Brunn’s nests, inverted
urothelial lesions of the bladder are
uncommon. Familiarity with these lesions
is important if the surgical pathologist is
to avoid misdiagnoses. In the present review
we will discuss the differential diagnosis,
molecular genetic findings, morphology
and histogenesis of benign and malignant
lesions of the urinary bladder with endophytic
(or inverted) growth pattern (Table 1).
Von Brunn’s nests, cystitis cystica/cystitis
glandularis and inverted papilloma represent
a spectrum of proliferative lesions, which
are histogenetically related. Inverted
papilloma and urothelial carcinoma
with inverted growth pattern are distinct
clinicopathological entities with overlapping
morphological features. These represent
particularly challenging lesions that if
misinterpreted, could result in serious errors
in patient care. While most of these lesions
can be diagnosed on morphological findings,
some might require ancillary studies to
establish a definitive diagnosis [1].
INVERTED UROTHELIAL PAPILLOMA
Inverted papilloma of the urinary bladder
accounts for less than 1% of all urothelial
neoplasms [2,3]. The age range of affected
patients is broad, but most are in their
sixth or seventh decade of life [2,4].
Inverted papilloma is far more common
in men than in women (7.3:1 ratio). Most
patients present with haematuria and/or
irritative voiding symptoms [2]. Rarely,
patients might present with obstructive
voiding symptoms.
Cystoscopically, inverted papilloma
characteristically appears as a sessile or
pedunculated lesion with a smooth surface.
Most arise in the trigone or bladder neck [2].
They are usually small (
<
3 cm) but can be
as large as 8 cm. Most lesions are single,
although the incidence of multiple lesions
ranges from 1.3 to 4.4% [2,5,6]. Inverted
papilloma is associated with a low risk of
recurrence (
<
5%), in marked contrast to the
high recurrence rates of papillary urothelial
neoplasms [2,6].
Morphologically, there are two main subtypes
of inverted papillomas: trabecular and
glandular. The trabecular subtype is the classic
lesion composed of irregularly ramifying
cords and sheets of urothelium arranged at
various angles to the surface mucosa and
arising directly from the overlying urothelium
(Fig. 1A). The trabeculae are thin and orderly
with a relatively uniform width. The cords of
urothelium have characteristic peripheral
palisading of basaloid cells. The neoplastic
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cells within the nests and cords of urothelium
often have a spindled appearance. The
intervening stroma is variable in amount and
can be fibrotic. Urothelial buds are frequently
present at various points along the
undersurface of the urothelium, protruding
down into the loose stroma of the lamina
propria. It is thought that these urothelial
buds are the source of new tumour cords. The
overlying surface urothelium can be normal,
attenuated or hyperplastic, and by definition
an exophytic component is either absent or
minimal. Some inverted papillomas of the
trabecular type are punctuated by cystic
spaces lined by flattened urothelial cells and
containing eosinophilic material, producing
an appearance reminiscent of cystitis
cystica. Foci of non-keratinizing squamous
metaplasia are often present, and rare cases
can show neuroendocrine differentiation [7].
Marked cytological atypia and mitotic activity
are absent. An uncommon variant, designated
inverted papilloma with atypia, exhibits focal
mild cytological atypia, with prominent
nucleoli, atypical squamous features and
degenerate-appearing multinucleated giant
cells. These features are not known to have
any clinical significance [4,8].
The glandular subtype has morphological
overlap with cystitis glandularis. It is
composed of nests of mature urothelium
with either pseudoglandular spaces lined
by urothelium or true glandular spaces
containing mucus-secreting goblet cells. The
luminal secretions stain with mucicarmine.
Some inverted urothelial papillomas exhibit
vacuolizated or foamy cytoplasm, which
might make them difficult to distinguish
from urothelial carcinoma [9]. Recently,
inverted papillomas with focal papillary
features have been described, broadening
the morphological spectrum of inverted
papillomas [10]. The key diagnostic features of
inverted papilloma are listed in Table 2.
Histogenetically, the trabecular subtype is
thought to develop by proliferation of the
basal cells of the overlying urothelium [4].
Supporting this hypothesis is the presence of
bud-like basal proliferations overlying the
tumor and the close resemblance between
trabecular cells and normal basal cells.
Microcysts, which are frequently present in
the trabecular type, are pseudoglandular
structures that are incapable of mucin
production. Microcyst formation is most
probably the result of cell necrosis within the
core of the trabeculae. The glandular subtype
is thought to arise from cystitis cystica and
cystitis glandularis in a multi-step process [4].
This involves formation of von Brunn’s nests,
which undergo cystic degeneration and
pseudoglandular metaplasia, resulting in
cystitis cystica and cystitis glandularis,
respectively, followed eventually by neoplastic
transformation.
While inverted papillomas are generally
considered to be benign neoplasms, there are
conflicting data in the literature regarding
their biological behavior [5,11,12]. Previous
TABLE 1
Main urothelial lesions with inverted
growth patterns
Benign lesions
Inverted urothelial papilloma
von Brunn’s nests and florid von Brunn’s
nest proliferations
Cystitis cystica and cystitis glandularis
Malignant lesions
Inverted urothelial carcinoma
Nested variant of urothelial carcinoma
Verrucous squamous cell carcinoma
FIG1.
Urothelial lesions with inverted growth pattern.
A
, Inverted papilloma, trabecular type, with anastomosing trabeculae of urothelium extending in to the lamina
propria.
B
, von Brunn's nests and florid von Brunn's nest proliferations (note the rounded and smooth contours).
C
, Cystitis glandularis of the typical type and florid
cystitis glandularis (note the irregularly spaced tubular glands lined by columnar epithelium; intestinal metaplasia is also present resembling colonic glands,
indicated by arrow).
D
, Inverted urothelial carcinoma mimicking inverted papilloma.
E
, Inverted urothelial carcinoma involving the renal pelvis (gross image).
F
, Panoramic view of the case (from image E).
G
, Nested variant of urothelial carcinoma growing as relatively uniform round nests.
H
, Verrucous squamous cell
carcinoma (note the blunt pushing architecture).
TABLE 2
Key features to recognition of inverted
papilloma
Relatively smooth surface with minimal to
absent exophytic component
Lesional circumscription with smooth base
and no obvious infiltration
Minimal to absent cytological atypia
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studies have reported an increased incidence
of urothelial carcinoma in some patients [13].
However, most of those patients had a
history of previous or concurrent urothelial
carcinoma. By contrast, Sung
et al
. [2]
reported on 75 patients with resected
inverted papilloma, none of whom had a
history of previous or concurrent urothelial
carcinoma. During a mean follow-up of 68
months, there was only one recurrence in
these patients [4]. Therefore, complete
transurethral resection of inverted papilloma
appears to be adequate surgical therapy, and
surveillance protocols as rigorous as those
employed in the management of urothelial
carcinoma seem unnecessary [5].
Molecular genetic studies, including X-
chromosome inactivation, have shown that
inverted papilloma is a clonal, usually diploid,
neoplasm that arises from a single progenitor
cell [14]. The low incidence of loss of
heterozygosity in inverted papilloma is similar
to normal urothelium [14,15,16]. Recently,
Lott
et al
. [17] conducted fibroblast growth
factor receptor 3 (FGFR3) and TP53 mutation
analysis in a number of inverted papillomas.
Point mutations of the FGFR3 gene were
identified in 45% (nine of 20) of cases. It is
notable that papillary urothelial neoplasms of
low malignant potential and most low-grade
urothelial carcinomas also are characterized
by the FGFR3 mutations seen in inverted
papilloma, and yet have substantial rates of
recurrence, as well as low but still significant
rates of progression to more aggressive forms
of urothelial carcinoma. The underlying
mechanisms that account for the different
biological behaviours of these neoplasms that
share a common set of mutations remain to
be elucidated. Lott
et al
. [17] also found no
TP53 mutations in the large cohort of inverted
papillomas they studied, indicating that
inverted papillomas do not harbour key
genetic abnormalities predisposing to
development of high-grade papillary
urothelial carcinoma. As will be discussed
in a later section, there are pronounced
differences between inverted papillomas
and inverted urothelial carcinomas, in their
immunohistochemical expression of Ki-67,
p53 and CD20, and in their frequency of
molecular alterations in chromosomes 3,
7, 17 and 9p21 as detected by UroVysion
fluorescence
in situ
hybridization (FISH)
analysis, supporting the notion that inverted
papillomas arise through entirely different
pathogenetic mechanisms from inverted
urothelial carcinoma.
The key differential diagnostic considerations
are limited. Cystitis cystica is characterized by
well-delineated, round nests of normal-
appearing urothelium, whereas inverted
papilloma shows cords with anastomosing
growth patterns. In contrast to inverted
papilloma, inverted urothelial carcinoma is, at
least in part, exophytic, the endophytic cords
and trabeculae are less uniform, and varying
degrees of cytological atypia are evident [18].
The presence of cytological atypia of a degree
seen in high-grade urothelial carcinoma is
unacceptable in inverted papilloma, and
warrants a diagnosis of inverted urothelial
carcinoma.
VON BRUNN’S NESTS AND FLORID VON
BRUNN’S NEST PROLIFERATIONS
Von Brunn’s nests are well-circumscribed
clusters of urothelial cells in the lamina
propria. The nests appear to arise by the
process of invagination of the overlying
urothelium. The nests may or may not be
demonstrably attached to the overlying
urothelium [19]. Although some investigators
hypothesize that von Brunn’s nests arise
secondary to inflammatory injury, autopsy
studies have documented their presence in
85–95% of bladders, suggesting that they
could be part of the spectrum of normal
bladder histology [20,21]. Cystoscopically,
they characteristically appear as small
mucosal nodules with smooth surfaces.
Microscopically, the nests typically have
smooth, rounded contours but they can be
slightly irregular. They are usually regularly
spaced. They usually occupy the superficial
lamina propria and typically are at a uniform
depth, but occasionally are found deeper in
the lamina propria. Cell nuclei in von Brunn’s
nests are bland and lack substantial atypia,
although they can show reactive and
metaplastic changes. Carcinoma
in situ
of
the surface urothelium can extend into von
Brunn’s nests, but this should not be mistaken
for invasion into the lamina propria.
Florid von Brunn’s nests are characterized by
larger nests with regular spacing (Fig. 1B)
[22]. They frequently have lobular or linear
configurations. Components of cystitis cystica
and cystitis glandularis can be present in such
proliferations. The key differential diagnostic
consideration of von Brunn’s nests, florid or
otherwise, is the nested variant of urothelial
carcinoma (see later discussion). In contrast
to florid von Brunn’s nests, the nested
variant of urothelial carcinoma is generally
characterized by smaller, crowded, irregularly
spaced nests of tumour cells that appear to
infiltrate deeply and haphazardly, and that
usually do not exhibit a marked degree of cyst
formation within the cell clusters.
CYSTITIS CYSTICA AND CYSTITIS
GLANDULARIS
Cystitis cystica and cystitis glandularis
represent a continuum of proliferative and
presumed reactive changes that evolve from
von Brunn’s nests. Cystitis cystica represents
von Brunn’s nests in which the central cells
are absent, resulting in the formation of
small cystic cavities (Fig. 1C). Cystitis cystica
is demonstrable in up to 60% of bladders.
Cystitis cystica manifests as translucent,
submucosal cysts containing clear yellow
fluid. Microscopically, the cysts contain
eosinophilic fluid and are lined by a few layers
of urothelium or cuboidal epithelium.
Two subtypes of cystitis glandularis exist
[4]. The typical (non-intestinal) subtype is
characterized by glands lined by cuboidal
to low columnar cells surrounded by
transitional cells. The intestinal subtype has
similar architecture to the typical subtype
of cystitis glandularis; however, the cells
lining the glands of the intestinal subtype
are tall and columnar, with abundant
mucin-secreting goblet cells closely
resembling intestinal epithelium (we prefer
the term cystitis glandularis with intestinal
metaplasia when goblet cells are present;
Fig. 1C, indicated by arrow). The two types
of cystitis glandularis can coexist, but one
form usually predominates. Although the
overall incidences of the two types are not
well documented, the intestinal type is
much less common than the typical type
of cystitis glandularis. Rare cases of florid
cystitis glandularis with extensive intestinal
metaplasia and mucin extravasation have
been reported, and such cases can be difficult
to distinguish from adenocarcinoma [23,24].
However, the degree of cytological and
architectural atypicality of adenocarcinoma
far exceeds that seen in florid cystitis
glandularis. Adenocarcinomas usually exhibits
obvious destruction of the lamina propria,
and in the colloid variant, clusters of
malignant cells are seen floating in pools of
mucin, a feature that excludes a diagnosis
of extensive intestinal metaplasia with mucin
extravasation. Although cystitis glandularis
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with intestinal metaplasia has been proposed
by some investigators as a precursor to
adenocarcinoma, clear-cut evidence for this
association is not well documented [25–27].
INVERTED UROTHELIAL CARCINOMA
Urothelial carcinoma with inverted growth
pattern can be difficult to distinguish from
inverted papilloma [18,28]. Distinction
between these two neoplasms requires strict
attention to architectural and cytological
features (Table 3). Amin
et al
. [18] reported 18
cases of urothelial carcinoma with endophytic
growth pattern. The mean (range) age of
patients was 68 (32–94) years with a male
preponderance (3.5:1 ratio). Some cases
had architectural features similar to inverted
papilloma (inverted papilloma-like pattern),
while others had broad-pushing bulbous
invaginations into the lamina propria (broad-
front pattern; Fig. 1D). In some cases, both
patterns coexisted. In general, the trabeculae
of inverted urothelial carcinomas are wider
and more variable than those of inverted
papillomas. Inverted urothelial carcinoma,
by definition, has substantial nuclear
pleomorphism, readily apparent mitotic
figures and architectural abnormalities
consistent with low- or high-grade urothelial
carcinoma [3]. These features are not seen in
inverted papilloma. Frequently, components
of otherwise typical exophytic or invasive
urothelial carcinoma accompany inverted
urothelial carcinoma. This raises the question
of what constitutes the bona fide inverted
urothelial carcinoma. We require at least
25% of the tumour to have an inverted
component to be considered inverted
urothelial carcinoma. Urothelial carcinoma
in situ
, if present in the surface urothelium,
provides further support for a diagnosis of
inverted urothelial carcinoma. Inverted
urothelial carcinoma may also occur in the
renal pelvis (Fig. 1E and 1F).
Immunohistochemical stains as well as FISH
can further aid in making the distinction
between inverted papilloma and inverted
urothelial carcinoma. Jones
et al
. [29]
compared specimens from 15 patients
with classic inverted papillomas and
specimens from 29 patients with urothelial
carcinomas exhibiting an inverted growth
pattern. The cases were analysed for
immunohistochemical expression of Ki-67,
p53 and CD20. In addition, UroVysion FISH
analysis was performed to assess the tumours
for alterations in chromosomes 3, 7, 17 and
9p21, which are commonly seen in bladder
cancer. Inverted papillomas usually did not
show immunoreactivity for Ki-67, p53 or
CD20, whereas the urothelial carcinomas
frequently expressed one or more of
these biomarkers. In addition, the inverted
papillomas did not show the classic molecular
alterations typically seen in urothelial
carcinomas using UroVysion FISH analysis.
These findings further support the notion that
inverted papillomas are benign and arise from
a different pathogenetic mechanism from
urothelial carcinoma.
One of the most challenging aspects when
dealing with an inverted urothelial carcinoma
is determining the presence or absence of
invasion (Table 4). This is particularly true
when there is tangential sectioning or
when tumour is intermingled with delicate
muscle bundles of the lamina propria. The
smoothness of the epithelial–lamina propria
interface is an important feature. Irregularly
shaped nests with disruption or absence of
the basement membrane are features of
invasion. In these situations, the lamina
propria can elicit a brisk inflammatory
response, which could obscure the
invading edge of the tumor. Desmoplasia
and/or a fibrotic stromal response are
reliable indicators of invasion. Paradoxical
differentiation can aid in the diagnosis of
early invasion. It is important to note that
microinvasion usually does not elicit a
stromal reaction, making its identification
more difficult. In these cases, cytokeratin
immunostaining can be helpful. The reason
why some urothelial carcinomas develop
an inverted growth pattern is not known;
however, it can be related to a propensity to
involve and expand von Brunn’s nests.
TABLE 3
Morphological, immunological and molecular genetic features of urothelial carcinoma with inverted pattern and inverted papilloma
Characteristic Urothelial carcinoma with inverted growth Inverted papilloma
Surface Usually exophytic papillary lesions present Smooth, dome-shaped, usually intact cytologically normal
Growth pattern Endophytic, lesional circumscription variable Endophytic, expansive, sharply delineated, anastomosing cords
and trabeculae
Cytological features Variable, nuclear pleomorphism and atypia present Orderly polarized cells, some with spindling and palisading at
the periphery. No marked atypia, mitoses rare
Biological potential Recurrences and progression can occur Benign, rare recurrences*
Immunohistochemistry Variable, usually high p53 and Ki-67 proliferation index Low p53 expression and Ki-67 proliferation index
Molecular analysis Frequent FGFR3 mutation, chromosome 9 and 17 deletions Rare deletions at chromosome 9 or 17, rare FGFR3 mutations,
low rate of LOH
*Rare recurrences related to incomplete excision. LOH, loss of heterozygosity.
TABLE 4
Urothelial carcinoma with inverted pattern criteria for invasion
Features Non-invasive Invasive
Contours of neoplastic nests/cords Regular Irregular
Size and shape of nests Similar, rounded edges Variable, irregular
and jagged edges
Inflammatory and desmoplastic stroma Absent Present
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An entity that must also be distinguished
from inverted urothelial carcinoma is inverted
papilloma with atypia [8]. In contrast to
inverted urothelial carcinoma, inverted
papilloma with atypia has only rare mitotic
figures and exhibits a very low proliferation
rate as estimated by Ki-67 immunostaining.
NESTED VARIANT OF UROTHELIAL
CARCINOMA
The nested variant of urothelial carcinoma is a
rare, aggressive neoplasm that, particularly in
limited biopsy specimens, can be notoriously
difficult to distinguish from aggregates of von
Brunn’s nests. This cancer typically occurs
in men in the fifth and sixth decades of life
[28,30]. Most patients die from disease
from 4 to 40 months after diagnosis despite
aggressive treatment [31,32]. Although it
has an innocuous appearance, it invariably
contains cells with enlarged nucleoli and
coarse chromatin, indicative of urothelial
carcinoma, particularly in the deeper portions
of the tumour (Fig. 1G). In addition, the nests
have an infiltrative pattern and often fuse
with one another.
Volmer
et al
. [22] compared 21 cases of florid
von Brunn’s nests and 11 cases of nested
variant of urothelial carcinoma for biomarker
expression. They found that nested urothelial
carcinomas had significantly higher MIB-1
and p53 expression parameters than florid
von Brunn’s nests, suggesting that these
immunohistochemical stains might be useful
in making the distinction between these two
lesions in difficult cases. Features helpful in
distinguishing the nested variant of urothelial
carcinoma from florid von Brunn’s nests are
summarized in Table 5.
VERRUCOUS SQUAMOUS CELL
CARCINOMA
This is an uncommon entity that must be
included in the group of bladder lesions
that display an inverted growth pattern.
Verrucous squamous cell carcinoma of the
urinary bladder is a non-invasive neoplasm
regarded as a distinct variant of squamous
cell carcinoma [33,34]. Predisposing factors
include recurrent cystitis, bladder diverticula
and, in particular, schistosomiasis [35]. It is
morphologically identical to its counterparts
at other sites, including the oral cavity. It can
appear grossly exophytic, papillary or warty.
Histologically, the neoplasm is composed of
well-differentiated keratinizing squamous
epithelium with broad-based pushing deep
margin (Fig. 1H). Its morphological features
overlap to some degree with those of
squamous papilloma and condyloma
acuminatum, although both of the latter
entities are predominantly exophytic
lesions. Condyloma acuminatum is a
squamous epithelial papillary growth that
often displays koilocytosis characteristic
of human papillomavirus infection. Cheng
et al
. [36] compared three cases of verrucous
carcinoma to three cases of condyloma
acuminatum and found that condyloma
acuminatum contained HPV DNA. All cases of
verrucous carcinoma were negative for HPV
DNA, indicating that HPV infection does not
play a role in the pathogenesis of verrucous
carcinoma. The clinical history is helpful
because condyloma acuminatum of the
bladder is almost always associated with
external genitalia lesions.
CONCLUSIONS
Inverted lesions of the urinary bladder
comprise a spectrum of changes ranging from
von Brunn’s nests to inverted urothelial
carcinoma. Differentiating these lesions
is important because their proper clinical
management and their expected clinical
outcomes are distinctly different. Diagnostic
difficulties can generally be resolved by
close attention to architectural and
cytological criteria. In some cases, such
as differentiating the nested variant of
urothelial carcinoma from von Brunn’s
nests, immunohistochemical stains, including
MIB-1 and p53, can be helpful. Inverted
papillomas are characterized by FGFR3
mutations similar to those seen in low-grade
urothelial neoplasms, but overall they show a
low frequency of genetic abnormalities. These
findings probably account for their benign
clinical behaviour and, in conjunction with a
demonstrable absence of p53 mutations in
inverted papillomas, support the concept
that inverted papillomas arise through
molecular mechanisms distinctly different
from those that give rise to high-grade
urothelial carcinomas. Considering the
evidence gathered so far, it appears quite
unlikely that inverted papilloma is a precursor
of inverted urothelial carcinoma.
The most challenging aspect of assessing
inverted urothelial carcinoma is the
determination of the presence or absence of
stromal invasion. We consider the following
morphological findings to be indicators of
invasion: variably sized and shaped cords and
nests of tumour cells with irregular contours,
particularly irregular and jagged edges, and a
desmoplastic stromal response. Currently,
there are insufficient data in the literature to
indicate whether, on a stage-for-stage basis,
patients with urothelial carcinomas with
endophytic growth patterns have a better
prognosis than those whose tumours are
exclusively exophytic.
CONFLICT OF INTEREST
None declared.
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Press, 2004
TABLE 5
Key morphological features distinguishing nested variant of urothelial carcinoma from florid
von Brunn’s nests
Organization Lumen formation
Cytologic
atypia Muscle invasion
Nested variant Crowded, irregular glands Yes, variable Present Yes, frequent
Florid von Brunn’s
nests
Large, regularly spaced,
rounded nests
Yes, variable Absent No
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Correspondence: Liang Cheng, MD, Chief of
Genitourinary Pathology Division, Director of
Molecular Diagnostics, Indiana University
School of Medicine, 350 West 11
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Street,
Clarian Pathology Laboratory Room 4010,
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    • "In that regard, it should be noted that none of the previous studies defined the percentage of tumor exhibiting endophytic pattern of invasion for a tumor to be labeled as " inverted invasive UC " or " large nested variant of UC. " In one review article, Hodges et al [10] state that at least 25% of the tumor having an inverted component was considered inverted UC. We required a cutoff of 50% in the present study [10]. From the above discussion, several observations can be made. "
    [Show abstract] [Hide abstract] ABSTRACT: The current series presents 12 cases of invasive urothelial carcinoma (UC) with inverted growth pattern that fulfill the architectural criteria of the recently described "large nested" variant of UC, but which display a wider spectrum of morphologic and cytologic changes. All cases had an associated component of usual invasive UC, and 10 had an associated surface papillary component. Although many areas within the tumors were indistinguishable from a noninvasive endophytic growth pattern, at least some had an irregular ragged contour, and all showed haphazard arrangement with variable amount of intervening stroma at least focally. Inflammatory stromal reaction was noted in 11 cases, and desmoplasia and retraction artifact were present in 8 cases each. Although major areas showed mild atypia, many tumors showed marked hyperchromasia, prominent nucleoli, marked irregular nuclear membranes, and brisk mitotic activity. Final pathological stage on cystectomy specimens was T2 in 4 cases, T3 in 2 cases, and T4 in 3 cases. In 3 cases, lymph node metastases were documented histologically. Review of the literature shows that the "large nested," "inverted," "endophytic," and "inverted papilloma-like" variants of invasive UC are interrelated entities and should probably be considered as one variant with a wide spectrum of cytoarchitectural features. They should also be separated from the "nested" variant with which they rarely coexist and which shows different characteristics at the morphologic level. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jun 2015 · Human pathology
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    • "This is not fully recognized in the current literature, in which, besides inverted 189 190 191 192 193 194 195 196 197 198 199 E U R O P E A N U R O L O G Y X X X ( 2 0 1 0 ) X X X – X X X urothelial papilloma, only one form of neoplasms is reported, namely, urothelial carcinoma with an inverted growth pattern. Scant molecular and clinical studies on the urothelial carcinoma with an inverted growth pattern have been published [28], and those that have focus mainly on differences with the inverted urothelial papilloma. Classification and terminology consistent with those of flat and papillary urothelial lesions and neoplasms should be adopted.Table 3 – Proposed subgrouping of the noninvasive urothelial neoplasms with an inverted growth pattern Group No 1., Flat Urothelial hyperplasia Urothelial dysplasia Urothelial carcinoma in situ Group No 2., Papillary Papillary urothelial neoplasm of low malignant potential Low-grade papillary carcinoma High-grade papillary carcinoma Group No 3., Inverted Inverted urothelial neoplasm of low malignant potential Low-grade inverted urothelial carcinoma High-grade inverted urothelial carcinoma E U R O P E A N U R O L O G Y X X X ( 2 0 1 0 ) X X X – X X "
    Full-text · Article · Nov 2010 · European Urology
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    [Show abstract] [Hide abstract] ABSTRACT: The aim of this essay is the self assessment of the level of knowledge of the 2004 WHO classification of bladder neoplasms through a series of MCQs, each associated a short commentary. This paper is directed to all who are involved with the application of this classification at the anticancer research, diagnostic, prognostic and therapeutic levels, in particular to uropathologists, urologists and oncologists.
    Full-text · Article · Apr 2011 · Diagnostic Pathology
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