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Bladder Cancer BJUI Mini Reviews - Pathological Variants of Invasive Bladder Cancer According to Their Suggested Clinical Significance
Bladder Cancer BJUI Mini Reviews - Pathological Variants of Invasive Bladder Cancer According to Their Suggested Clinical Significance | BJUI Mini Reviews - Pathological Variants of Invasive Bladder Cancer According to Their Suggested Clinical Significance |
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BJUI Mini Reviews - In this review, the most common pathological variants of urothelial carcinoma are summarized, with an emphasis on clinical implications.
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![Pathological variants of invasive bladder cancer according
to their suggested clinical significance
Antonio Lopez-Beltran, Maria J. Requena*, Liang Cheng†‡ and Rodolfo Montironi¶
Departments of Pathology and *Urology, Reina Sofia University Hospital and Cordoba University Medical School,
Cordoba, Spain, †Pathology and ‡Urology, Indiana University School of Medicine, Indianapolis, USA, and ¶Institute of
Pathological Anatomy and Histopathology, Polytechnic University of the Marche Region, Ancona, Italy
Accepted for publication 27 July 2007
pathologists and urologists to be aware of the
diverse morphological patterns in invasive
bladder cancer, as they might be relevant in
patient management and prognosis, mainly
because they can mimic benign lesions,
secondary tumours or might require a specific
therapeutic approach
KEYWORDS
bladder, neoplasms, pathological variant,
urothelial carcinoma
Several pathological variants of bladder
cancer, reflecting tumour heterogeneity in
urothelial carcinoma, have been recently
recognized. In this review we summarize the
most common pathological variants of
urothelial carcinoma, with an emphasis on
clinical implications. It is important for both
INTRODUCTION
Urothelial carcinoma (UC) is a heterogeneous
tumour with a great propensity for divergent
differentiation, resulting in a urothelial
carcinoma admixed with other
morphologically recognisable components [1].
The most common mixed differentiation is
squamous, in
≈
20% of urothelial bladder
carcinomas, followed by glandular, that can
reach up to 6% of cases in some series [1–5].
As seen in Table 1, virtually the whole
spectrum of bladder carcinoma variants can
be seen in variable proportions from an
otherwise typical UC, but most importantly,
these variants can be relevant in clinical
practice, as they might simulate benign
lesions, secondary tumours, or necessitate a
more complex therapeutic approach beyond
surgery [1,6]. Recent studies suggest an
increasing likelihood of lymph node
metastases associated with the finding of
pathological variants in the primary tumour
[7]. Recognising these variants is therefore
clinically relevant in patient management.
UC WITH DECEPTIVELY
BENIGN APPEARANCE
NESTED VARIANT
The nested variant of UC is an aggressive
neoplasm with fewer than 50 reported cases
[1,8–10]. There is a male predominance, and
70% of patients died 4–40 months after
diagnosis, despite therapy [9,11]. This rare
pattern of UC was first described as a tumour
with a ‘deceptively benign’ appearance that
closely resembles Brunn’s nests infiltrating
the lamina propria [8,12–14]. Nuclei generally
show little or no atypia, but the invariable
presence of an infiltrative growth should
facilitate an accurate diagnosis. In terms of
biology, there is high p53 accumulation and
tumour cell proliferation, findings that are
useful in difficult cases [1]. Despite the
deceptively benign appearance of the tumour,
recently it was proposed to grade this as
high-grade, to assist the urologist in selecting
the appropriated therapy [1].
UC WITH ENDOPHYTIC GROWTH (INVERTED
PAPILLOMA-LIKE CARCINOMA)
The recent interest in UC with endophytic
growth arose because they can be
misdiagnosed as a benign inverted papilloma
[1,15–18]. This is because inverted papillomalike
carcinoma can show variable-to-minimal
cytological and architectural abnormalities,
but invariably has a higher mitotic count and
cell proliferation, as seen by Ki67, high p53
accumulation, aberrant cytokeratin 20
expression, and frequent polysomies at
chromosome 3, 9 and 17 [19]. This profile has
been very useful in the differential diagnosis
with inverted papilloma [18,19]. In some
instances, both inverted papilloma and
inverted papilloma-like carcinoma are
intimately mixed [18]. The other important
feature in papillary tumours with endophytic
growth is that they invade the lamina propria
with a ‘pushing’ border [20]. Unless this
pattern is accompanied by true destructive
stromal invasion, the likelihood of metastasis
is minimal because the basement membrane
is not truly breached [15].
UC WITH FEATURES SUGGESTING
SECONDARY INVOLVEMENT TO
THE BLADDER
MICROPAPILLARY UC
This variant of UC was initially described
because it resembles papillary serous
carcinoma of the ovary [1,21]. This
morphology has been further recognized in
other organs such as lung, colon, breast, renal
pelvis or salivary glands [1,22]. A recent report
based on 100 consecutive cases treated by
cystectomy showed a mean patient age of
64.7 years, with a male: female ratio of 10 : 1
[22]. The stage at the time of presentation was
Ta in five patients, carcinoma
in situ
in four, T1
in 35, T2 in 26, T3 in seven, T4 in six; N
+
in
nine and M
+
in eight. The 5- and 10-year
overall survival rates were 51% and 24%,
respectively. Intravesical BCG therapy was
attempted in 27 of 44 patients with nonmuscle-
invasive disease; 18 (67%) developed
disease progression (
≥
cT2), including 22%
who developed metastatic disease [22]. Of 55
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patients undergoing radical cystectomy for
surgically resectable disease (
≤
cT4a), 23
received neoadjuvant chemotherapy and 32
were treated with initial cystectomy, with no
significant difference in stage distribution
between the groups. For the 23 patients
treated with neoadjuvant chemotherapy, the
median overall survival was 43.2 months, with
32% of patients still alive at 5 years [22].
For the 32 patients treated with initial
cystectomy, the median survival had not been
reached at the time of the last follow-up, with
71% still alive at 5 years. It was concluded
that micropapillary bladder cancer is
associated with a poor prognosis, that
intravesical therapy appears to be ineffective
in this disease, and patients with surgically
resectable disease should be offered early
radical cystectomy [22]. Also, increased lymph
node positivity was associated with the
presence of micropapillary carcinoma in
a recent study [7,23].
At histology, the micropapillary component
is found in association with noninvasive
papillary or invasive UC in 80% of
reported cases [1]; 25% show glandular
differentiation, and some authors consider
it as a variant of adenocarcinoma.
Vascular and lymphatic invasion is common,
and most cases show invasion into
muscularis propria or deeper, often with
metastases at the time of diagnosis [24].
Immunohistochemical studies show
immunoreactivity for epithelial markers,
similar to conventional UC in all, and CA125
staining in 43% of cases [25]. The presence
of a surface micropapillary component in
bladder biopsy specimens is a useful clue for
further investigation, and an indication for
deeper biopsies to determine the level of
invasion. In addition to stage, the prognosis
seems to be related to the proportion and
location of the micropapillary component
[10,25]. Cases with a moderate or extensive
micropapillary component are at high risk of
having an advanced stage at presentation.
Cases with
<
10% micropapillary component
have a high chance of detection at an early
stage.
PLASMACYTOID UC
This is an unusual variant in which the
tumour cells show eosinophilic cytoplasm and
eccentric nuclei, producing a plasmacytoid
appearance, thus suggesting multiple
myeloma/lymphoma [1,6,10,26]. The epithelial
nature of the malignancy is confirmed
by positive immunohistochemistry of
cytokeratin and negativity for lymphoma/
plasmacytoma markers. This tumour is an
aggressive neoplasm with a stage-related
outcome and frequent lymph node positivity
at diagnosis [27]. In a series report of six cases,
the male-to female ratio was 2 : 1, and the
mean age at presentation was 58 years. Five
of six patients died from disease (mean
survival 23 months) [27]. Some of these cases
were recorded in older reports as lymphomalike
carcinoma [28,29].
CLEAR CELL (GLYCOGEN-RICH) UC
Up to two-thirds of cases of UC have foci of
clear-cell change resulting from abundant
TABLE 1
Proposed classification of pathological variants of UC of the bladder according to their suggested clinical significance
Pathological variants of invasive bladder cancer and their
potential pitfalls Main lesions and tumours in differential diagnosis
Deceptively benign features
UC, nested variant Von Brunn’s hyperplasia
UC, inverted papilloma-like variant Inverted papilloma
Differential diagnosis with metastases to the bladder
UC, micropapillary variant Serous carcinoma of the ovary; micropapillary carcinomas from other sites
UC, plasmacytoid variant Plasmacytoma
UC, clear cell (glycogen-rich) variant Clear cell carcinomas from kidney, prostate and others
Large-cell undifferentiated carcinoma Large-cell undifferentiated carcinoma of lung
Misdiagnosis as benign proliferative lesions
UC, microcystic variant Cystitis cystica et glandularis, rarely adenocarcinoma
Complex therapeutic approach
UC, lymphoepithelioma-like variant Chemotherapy, metastases from other sites
SCC Chemotherapy, metastases from lung
Misdiagnosis as choriocarcinoma either 1ry/ 2ry
UC with syncitiotrophoblastic giant cells Choriocarcinoma either primary or secondary
Misdiagnosis as myofibroblastic proliferation
Sarcomatoid UC (carcinosarcoma) Inflammatory myofibroblastic tumour (inflammatory pseudotumour)
Misdiagnosis as squamous-cell carcinoma or adenocarcinoma, either 1ry or 2ry
UC with squamous and/or glandular differentiation Squamous cell carcinoma, adenocarcinoma
Misdiagnosis as other tumour types
UC, lipoid-cell variant Carcinosarcoma/sarcomatoid carcinoma of heterologous type
UC with peudosarcomatous stroma Sarcomatoid carcinoma
UC with stromal osseous or cartilaginous metaplasia Carcinosarcoma/sarcomatoid carcinoma heterologous type
UC with osteoclast-type giant cells Reactive granulomatous lesion
UC with prominent lymphoid infiltrate Lymphoma
Rare UCs with discohesive, prostate-like or endometrioid-like
morphologies
Lobular carcinoma of breast, endometrial carcinoma or Gleason 3
+
3
prostate cancer
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glycogen, but the glycogen-rich clear-cell
‘variant’ of UC, recently described [30],
appears to represent the extreme end of
the morphological spectrum, consisting
predominantly or exclusively of cells with
abundant clear cytoplasm that stains for
cytokeratin 7, thus confirming a urothelial
origin [30,31]. Recognising this pattern avoids
confusion with clear-cell adenocarcinoma
of the bladder and metastatic clear-cell
carcinoma of the kidney and other sites.
Recent data relates this morphology with
lymph node metastases [7].
LARGE CELL UNDIFFERENTIATED CARCINOMA
This is a poorly defined category that contains
large-cell type carcinoma that cannot be
otherwise classified [1,6]. They are extremely
rare in the urinary tract, aggressive, and of
high stage at presentation, including frequent
lymph node metastases [7]. One reported
case showed increased
α
-fetoprotein
production in the patient’s serum, and by
immunohistochemistry in the tumour cells
[32]. Some might contain abundant epithelial
tumour giant cells resembling giant cell
carcinoma of the lung (so called pleomorphic
giant cell carcinoma of the bladder) [1,6,33];
this is a very infrequent and aggressive
variant with poor prognosis, similar to that
associated with giant cell carcinoma in
the lung or prostate. The giant cells have
cytokeratin immunoreactivity. We think that
this should be considered in the spectrum of
the large-cell undifferentiated carcinoma of
the bladder instead of a different pathological
variant, until more experience is available [1].
The spectrum of neuroendocrine carcinomas
of the urinary bladder might include rare
examples of large-cell neuroendocrine
carcinomas, similar to the more common
counterpart in the lung. The experience
with these cases suggests that they are at
advanced stage at presentation [34,35].
UC WITH FEATURES SUGGESTING BENIGN
PROLIFERATIVE LESIONS
MICROCYSTIC UC
This pathological variant is characterized
by the formation of cysts ranging from
microscopic to up to 1–2 cm in diameter
[13,36,37]. The cysts or small tubules might be
empty or contain necrotic debris or mucin.
This variant of cancer can be confused with
benign proliferations such as florid polypoid
cystitis cystica and glandularis, nephrogenic
adenoma, and rarely with adenocarcinoma
[13,36].
UC WITH A COMPLEX
THERAPEUTIC APPROACH
LYMPHO-EPITHELIOMA-LIKE UC
This tumour resembles lympho-epithelioma
of the nasopharynx [38,39]; the male-tofemale
ratio is 3 : 1, and occurs in late
adulthood (mean 69 years, range 52–81).
Most patients present with haematuria
[39–41]. The tumour is solitary and usually
involves the dome, posterior wall, or trigone,
often with a sessile growth pattern. At
histology, it can be pure, or mixed with typical
UC [42]. The epithelial tumour cells show
poorly defined cytoplasmic borders imparting
a characteristic syncytial appearance. The
background consists of a prominent lymphoid
stroma that includes T- and B-lymphocytes,
plasma cells, histiocytes, and occasional
neutrophils or eosinophils [39]. Epstein-Barr
virus infection has not been identified in
lympho-epithelioma-like carcinoma of the
bladder [43]. This tumour has been found
to be responsive to chemotherapy when it
is encountered in its pure form.
SMALL-CELL CARCINOMA (SCC)
A recent molecular study indicated that SCC
and UC are derived from the same clonal
population, and we consider SCC of the
urinary bladder as a variant of UC, with a
dismal prognosis [44,45]. In a recent series
of 64 such cases the mean age at diagnosis
was 66 years and the male : female ratio was
3.3 : 1; 88% presented with haematuria
[44,46,47]. All the patients except one had
muscle-invasive disease at presentation.
Thirty-eight patients (59%) had a cystectomy
and 66% of patients had lymph node
metastasis at the time of cystectomy, with
regional lymph nodes, bone, liver and lung
being the most common locations. Fortyfour
cases (68%) cases consisted of SCC
with other histological types (UC, 35;
adenocarcinoma four; sarcomatoid UC two;
and three with both adenocarcinoma and
UC) [44,47]. No clinicopathological variables
studied correlated with survival. There was
no significant survival difference between
patients who had a cystectomy and those
who did not. Patients with organ-confined
cancers had marginally better survival than
those with extravesical cancer (
P
=
0.06) [44].
Overall, the 1-year, 18-month, 3-year and
5-year cancer-specific survivals were 56%,
41%, 23%, and 16%, respectively. The
prognosis of SCC of the urinary bladder
remains poor, irrespective of therapy.
Hypercalcaemia or hypophosphataemia, and
ectopic secretion of adrenocorticotropic
hormone, have also been reported as part
of the paraneoplastic syndrome associated
with primary SCC of the bladder [46]. On
histological examination, they mimic
its pulmonary counterpart. The
immunohistochemical profile reveals
neuroendocrine markers at variable
frequency, but SCC can be diagnosed on
morphological grounds alone, even if
neuroendocrine differentiation cannot be
detected. The recent finding of c-kit and
epidermal growth factor receptor expression
by immunohistochemistry opens new
possibilities for targeted therapy in SCC of
the bladder [46,48,49].
UC MISDIAGNOSED AS
CHORIOCARCINOMA, EITHER PRIMARY
OR SECONDARY
UC WITH SYNCITIOTROPHOBLASTIC
GIANT CELLS
Up to 12% of cases of UC show
syncitiotrophoblastic giant cells producing
substantial amounts of
β
-hCG [50–53].
Secretion of hCG into the serum can be
associated with a poor response to radiation
therapy [53]. The most important differential
diagnostic consideration is choriocarcinoma;
most, but not all, cases previously reported
as primary choriocarcinoma of the bladder
represent UC with syncytiotrophoblasts
rather than pure choriocarcinoma, a lesion
that is very unusual in the bladder [1]. One
reported primary choriocarcinoma of the
bladder that occurred in a 19-year-old
man showed a high copy number of the
isochromosome 12p, supporting germ
cell differentiation [54].
UC MISDIAGNOSED AS MYOFIBROBLASTIC
PROLIFERATION OR SARCOMA
SARCOMATOID UC (CARCINOSARCOMA,
SPINDLE-CELL CARCINOMA)
The term ‘sarcomatoid variant of UC’ should
be used for all biphasic malignant neoplasms
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with morphological and/or
immunohistochemical evidence of epithelial
and mesenchymal differentiation (with the
presence or absence of heterologous elements
acknowledged in the pathology report) [55].
Some patients had a previous history of
radiation or cyclophosphamide therapy [56].
The most frequent presenting signs and
symptoms are haematuria, dysuria, nocturia,
acute urinary retention and lower abdominal
pain [56]. The mean (range) age is 66
(50–77) years. The pathological stage is the
best predictor of survival in sarcomatoid
carcinoma [56]. The tumours are often
polypoid with large intraluminal masses.
Microscopically, sarcomatoid carcinoma is
composed of a urothelial, glandular or smallcell
component showing variable degrees of
differentiation; carcinoma
in situ
is present in
30% of cases and occasionally is the only
apparent epithelial component [56]. A small
subset of sarcomatoid carcinoma of the
bladder and the renal pelvis might have a
prominent myxoid stroma, a finding that
misguides the pathologist to inflammatory
pseudotumour (inflammatory myofibroblastic
tumour), but this is characteristically positive
for anaplastic lymphoma kinase stains, unlike
sarcomatoid carcinoma, which is negative
[56–61]. The most common heterologous
element in a large series is osteosarcoma,
followed by chondrosarcoma,
rhabdomyosarcoma, leiomyosarcoma,
liposarcoma, or angiosarcoma, but multiple
types might be present [56]. By
immunohistochemistry, epithelial elements
react with cytokeratins, whereas stromal
elements react with specific markers
corresponding to the type of mesenchymal
differentiation. Recent molecular evidence
strongly argues for a monoclonal origin of
both components in sarcomatoid carcinoma
[62].
MISDIAGNOSIS AS SQUAMOUS CELL
CARCINOMA OR ADENOCARCINOMA,
EITHER PRIMARY OR SECONDARY
UC WITH SQUAMOUS AND/OR
GLANDULAR DIFFERENTIATION
Squamous differentiation, defined by
the presence of intercellular bridges or
keratinization, occurs in 21% of UCs of the
bladder [1,3,6,56]. Its frequency increases with
grade and stage [3]. The proportion of the
squamous component varies considerably,
with some cases having UC
in situ
as the only
urothelial component. These cases can have a
less favourable response to therapy (surgical,
radiation or systemic chemotherapy) than
pure UC. Of 91 patients with metastatic
carcinoma, 83% with mixed adenocarcinoma
and 46% with mixed squamous cell
carcinoma had disease progression despite
intense chemotherapy, whereas progression
occurred in
<
30% of patients with pure UC
[4,5]. Low-grade UC with focal squamous
differentiation also has a higher recurrence
rate. Tumours with any identifiable urothelial
element are classified as UC with squamous
differentiation [3]. Rare cases of squamous
differentiation in the bladder with basaloid
or clear cell features have been recognized
[3].
Glandular differentiation is less common than
squamous differentiation and can be present
in
≈
6% of UCs of the bladder [2]. Glandular
differentiation is defined as the presence of
true glandular spaces within the tumour.
These can be tubular or enteric glands with
mucin secretion. A colloid-mucinous pattern
characterized by nests of cells ‘floating’ in
extracellular mucin, occasionally with signetring
cells, can be present. Cytoplasmic mucincontaining
cells are present in 14–63% of
typical UC and are not considered to represent
glandular differentiation [1,6]. In rare cases,
the glandular component has the morphology
of hepatoid or clear cell adenocarcinoma [63].
A tumour with mixed glandular and urothelial
differentiation is best classified as UC with
glandular differentiation.
MISDIAGNOSIS AS OTHER TUMOUR TYPES
LIPOID-CELL UC
The lipoid-cell variant is a rare neoplasm
defined by the WHO (1999, 2004) as a UC
which shows transition to a cell type
resembling signet-ring lipoblasts [1,6]. It is
currently considered to be an ill-defined
tumour variant. The clinicopathological
features in seven reported cases showed gross
haematuria as the initial symptom [64]. All
patients were elderly men (mean age 74 years,
range 63–94). On microscopic examination
the extent of the lipid cell pattern was
10–30% of the tumour specimen, with
associated micropapillary (one), plasmacytoid
(two), and grade 3/3 conventional UCs (four).
The immunohistochemical results showed an
epithelial phenotype of the lipoid cell
component. The reported cases were
pathological stage T2 in two, T3a in one, T3b
in three and T4 in one [64]. Patient follow-up
showed one dead and two alive with disease
at 58, 14 and 55 months, respectively; two
showed no evidence of disease at 11 and
29 months. Two additional patients died from
other causes at 10 and 15 months [64].
Primary or secondary carcinosarcoma with
a liposarcoma component is the main
differential consideration.
UC WITH STROMAL REACTIONS
(PEUDOSARCOMATOUS STROMA; STROMAL
OSSEOUS OR CARTILAGINOUS METAPLASIA;
OSTEOCLAST-TYPE GIANT CELLS; PROMINENT
LYMPHOID INFILTRATE)
Infiltrating UC can be associated with a
variety of stromal reactions, which are
occasionally pronounced. The finding of a
peudosarcomatous stroma raises serious
concern about sarcomatoid carcinoma or
true sarcoma of the bladder [65]. Tumourassociated
stromal osseous and/or chondroid
metaplasia is present in some cases of UC
and its metastases, and this should be
differentiated from osteosarcoma,
chondrosarcoma or heterologous type of
sarcomatoid carcinoma [66]. The presence of
osteoclast-like giant cells in cases of invasive
high-grade UC seems not to be related to
tumour prognosis [67]. An inflammatory cell
response in the stroma adjacent to the
invasive tumours is relatively common [68].
This response usually takes the form of a
lymphocytic infiltrate with a variable
admixture of plasma cells. Generally, this
cellular reaction is mild to moderate, but
occasionally it can be dense [69]. Intense
inflammation in bladder carcinoma was found
to be associated with tumour angiogenesis
and indicative of a good prognosis in one
study [68].
UC WITH RARE DISCOHESIVE, PROSTATE-LIKE
OR ENDOMETRIOID-LIKE MORPHOLOGY
Baldwin
et al.
[70] described a series of
10 cases of UC with a striking discohesive
growth pattern which showed
morphological features that mimicked
infiltrating lobular carcinoma of the breast
and diffuse carcinoma of the stomach. The
mean age of the patients was 67 years at
presentation. All cases had an advanced
stage at the time of diagnosis. It is
important to recognize this pattern to
avoid misdiagnosis of metastatic lobular
carcinoma of the breast or diffuse
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carcinoma of the stomach, especially in
small biopsies [70]. Gleason 3 prostate
cancer with a tubular pattern of growth,
which might be seen, is the main differential
consideration for bladder cancer with small
tubule formation [71]. A rare case of UC
simulating endometrioid carcinoma of the
endometrium was reported [1]. In these
cases a clinicopathological correlation is
mandatory.
CONCLUSIONS AND RECOMMENDATIONS
• Accurate diagnosis and classification of
unusual variants of urothelial tumours is
critical for patient management.
• Detailed pathological evaluation of UC
of the bladder remains of paramount
importance, as it provides useful information
to guide urologists in daily practice.
• The diagnosis of morphological clinically
relevant variants of bladder cancer relies
at present on the morphology, molecular
features and clinicopathological correlation.
CONFLICT OF INTEREST
None declared. Source of funding: Public.
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e-mail:
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Abbreviations: UC, urothelial carcinoma;
SCC, small-cell carcinoma.](http://urotoday.com/images/stories/bjui_feb2008_cover.gif)
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