Histopathology 2019, 74, 97–111. DOI: 10.1111/his.
13719
REVIEW
Non-urothelial carcinomas of the bladder
Sanghui Park,1 Victor E Reuter2 & Donna E Hansel3
1
Department of Pathology, Ewha Womans University College of Medicine, Seoul, Korea, 2Department of Pathology,
Memorial Sloan Kettering Cancer Institute, New York, NY, and 3Department of Pathology, University of California at
San Diego, La Jolla, CA, USA
Park S, Reuter V E & Hansel D E
(2019) Histopathology 74, 97–111. https://doi.org/10.1111/his.13719
Non-urothelial carcinomas of the bladder
Non-urothelial carcinomas involving the bladder are
uncommon and often diagnostically challenging.
These carcinomas may show squamous, adenocarci-
nomatous or neuroendocrine features, with immuno-
histochemical stains aiding the diagnosis in only a
subset of cases. The clinical history in non-urothelial
bladder carcinomas is important, given that the differ-
ential diagnosis often includes secondary involvement
of the bladder by direct extension or metastasis from
carcinomas at other sites. This paper will review non-
urothelial carcinomas in each of these three morpho-
logical categories, emphasising recent changes in
diagnostic grouping and challenges in the
Keywords: non-urothelial carcinoma, urinary bladder
Introduction
Non-urothelial carcinomas of the bladder are rela-
tively rare, accounting for approximately 5% of car-
cinomas arising at this location. However, there is
an increased risk of these less frequent forms of car-
cinoma arising within diverticula of the bladder.1
The most common subtypes of non-urothelial carci-
nomas involving the bladder include squamous cell
carcinoma, adenocarcinoma and neuroendocrine
tumours,2 which can be further subdivided into dis-
tinct subtypes (Table 1). Given their relative infre-
quency, the diagnosis of these entities in routine
Address for correspondence: D E Hansel, 9500 Gilman Drive, MC
0612, La Jolla, CA 92093, USA. e-mail: dhansel@ucsd.edu
© 2018 John Wiley & Sons Ltd.
histopathological diagnosis. Review of bladder cancers
with squamous morphology will include discussion of
conventional squamous cell carcinoma and verrucous
carcinoma and their distinction from urothelial carci-
noma with extensive squamous differentiation. Blad-
der carcinomas with adenocarcinomatous change
will include primary bladder adenocarcinoma, ura-
chal adenocarcinoma and tumours of M€ ullerian type.
Finally, neuroendocrine neoplasms of the bladder,
including well-differentiated neuroendocrine tumour
and neuroendocrine carcinomas, will be discussed.
Associated surface findings, risk factors and prognos-
tic features will be described.
practice may pose challenges. For example, the dis-
tinction between ‘pure’ squamous cell carcinoma or
adenocarcinoma from urothelial carcinoma with
extensive divergent differentiation relies not only on
histopathological features, but also knowledge of
precedent pathology and clinical history. Staging
may be also challenging in the setting of adenocarci-
noma, in which diagnosis of urachal carcinoma
necessitates use of a specific staging system. Finally,
non-urothelial forms of bladder carcinoma may be
associated with unique risk factors, molecular
alterations and therapeutic response differences from
conventional agents. Given the complexity of non-
urothelial carcinoma of the bladder, we address a
stepwise approach to the diagnosis of these entities
and highlight key properties that are unique to each
of the subtypes.
98 S Park et al.

Table 1. Non-urothelial carcinomas of the bladder

Carcinoma categories Definition Diagnostic considerations

Squamous cell features

Squamous cell carcinoma Pure invasive squamous cell Well-, moderately or poorly differentiated should be
carcinoma that shows irregular specified
invasive nests and frequent
desmoplasia

Verrucous carcinoma Well-differentiated squamous cell Entire lesion should be submitted to exclude a
carcinoma with broad, pushing conventional SCC
invasive front with frequent HPV
association

Adenocarcinomatous features

Adenocarcinoma Invasive carcinoma with glandular Subtypes include enteric, mucinous, mixed and NOS;
features intracellular mucin within single cells may indicate
plasmacytoid urothelial carcinoma

Urachal carcinoma
Carcinoma arising in the dome or
anterior wall of the bladder and not
associated with glandular changes
in the surface urothelial lining of the
bladder
Carcinomas may be cystic or solid and encompass
mucinous, enteric and other forms of
adenocarcinoma

€llerian type tumours

Mu Tumours that arise in association with Subtypes include clear cell adenocarcinoma and
M€ullerian remnants such as endometrioid adenocarcinoma
endometriosis and M€ ullerianosis

Neuroendocrine tumours

Well-differentiated Neuroendocrine lesion with limited Relatively favourable prognosis

neuroendocrine tumour atypia, often small in size

Large-cell neuroendocrine Neuroendocrine carcinoma with Shows similar immunohistochemical findings and
carcinoma abundant cytoplasm clinical outcomes as small-cell carcinoma

Small-cell neuroendocrine Neuroendocrine carcinoma with May be admixed with other forms of bladder cancer or
carcinoma limited cytoplasm, identical to small- occur in pure form; exclude secondary spread from
cell carcinomas arising at other sites other sites

NOS, Not otherwise specified; HPV, Human papillomavirus; SCC, Squamous cell carcinoma.

forms of SCC and variants including sarcomatoid

Bladder cancers with squamous
SCC.5 Although there has been much debate regard-
morphology
ing the surface findings associated with SCC, the defi-
SQUAMOUS CELL CARCINOMA nition of invasive SCC should be based primarily on
the invasive component, which has been shown to
Squamous cell carcinoma (SCC) occurs most com-
correlate with the presence of squamous carcinoma
monly in the conventional form, as distinguished
morphology in metastasis.5 Furthermore, given the
from verrucous carcinoma. Among non-urothelial
morphological overlap between urothelial carcinoma
carcinomas, squamous cell carcinoma (SCC) is the
in situ and squamous cell carcinoma in situ, surface
most common variant of bladder cancer, comprising
urothelial changes may not always be a reliable sur-
2.1–6.7% of all bladder malignancies.3–7 The conven-
rogate in the differential diagnosis.
tional form is highlighted by a pure invasive squa-
Risk factors associated with the development of
mous cell phenotype characterised by the presence of
bladder SCC include smoking,8 long-term catheterisa-
keratin pearls and intercellular bridges in many
tion in patients with a spinal cord injury9,10 and
instances of well- to moderately differentiated carci-
chronic inflammation due to bacterial infections, for-
noma,2 but can also include poorly differentiated
eign bodies and bladder calculi. In addition, there are
© 2018 John Wiley & Sons Ltd, Histopathology, 74, 97–111.
 Non-urothelial carcinomas of the bladder 99

several other potential aetiological agents causing A

SCC in the bladder, including cyclophosphamide ther-
apy11 and human papillomavirus (HPV) infec-
tion.5,12,13 Specifically, extensive condylomatous
colonisation of the bladder may pose some risk in the
development of SCC.5,13 Schistosomiasis is an addi-
tional risk factor in the development of SCC in some
parts of the world, including Egypt, Iraq, the Jizan
region in southern Saudi Arabia, Yemen and
Sudan.14 However, the declining incidence of this
infection may result in a reduction in the frequency
of SCC.15.
At gross evaluation, SCC may appear exophytic,
ulcerated, solid or nodular.5,7 Necrotic material and
flaky keratin debris on the surface are relatively com-
mon.2,5 Microscopic analysis of SCC in the bladder
B
shows that most tumours are moderately to poorly
differentiated.5 Areas of keratinisation and glassy pink
cytoplasm are recognisable within the carcinoma in
many cases, although poorly differentiated forms may
lack these features (Figure 1A–C). Variations in mor-
phology can occur and include large nest formation,
clear cell change, pseudocyst formation, bizarre aty-
pia and spindled morphology, consistent with sarco-
matoid change (Figure 2A–C).5 In cases associated
with schistosomal infection, parasite eggs may be
identified (Figure 3). A basaloid SCC phenotype has
been reported and is often associated with HPV.16,17
Stromal reactions may include a giant cell reaction to
keratin, prominent desmoplasia and inflammation,
including the presence of neutrophils.5
Surface changes that occur in the presence of SCC C
are varied and include squamous and non-squamous
alterations. Squamous changes are the most common
and include keratinising squamous metaplasia, verru-
cous squamous hyperplasia, extensive condyloma
acuminata and squamous cell carcinoma in situ.18,19
Squamous cell carcinoma in situ shows marked aty-
pia of squamous cells lining the surface of the bladder
(Figure 4A). Condyloma acuminatum resembles its
counterpart at other sites, including an exophytic,
papillary appearance and a lining consisting of hyper-
plastic squamous epithelium with cells showing koilo-
cytosis (Figure 4B).18 Verrucous squamous
hyperplasia contains repetitive upward tenting of
atypical squamous epithelium associated with hyperk-
eratosis and represents a risk factor for the develop- Figure 1. Squamous cell carcinoma of the bladder shows a range
ment of invasive squamous cell carcinoma of differentiation that includes (A) well-differentiated, (B) moder-
ately differentiated and (C) poorly differentiated features, with mod-
(Figure 4C).18 With the exception of condyloma
erately and poorly differentiated carcinomas being most common.
acuminatum, these changes in isolation should
prompt a comment raising the risk of development of show non-squamous surface changes that include
subsequent SCC in these patients. A small subset of urothelial carcinoma in situ and adenocarcinoma
patients with invasive squamous cell carcinoma also in situ.5
© 2018 John Wiley & Sons Ltd, Histopathology, 74, 97–111.
100 S Park et al.
B Figure 3. Schistosome eggs involving the bladder wall.
C sive SCC morphology who lack either precedent
Figure 2. Bladder squamous cell carcinoma can show a variation
in morphology including (A) clear cell features, (B) large invasive
nests with central debris and (C) sarcomatoid transformation.
Potentially the greatest challenge in the diagnosis
of invasive SCC is its distinction from invasive urothe-
lial carcinoma with squamous differentiation.
Unfortunately, immunohistochemical markers do not
aid in the differential diagnosis and the approach is
based primarily on histological assessment and
knowledge of patient history. In instances in which
clear-cut urothelial carcinoma nests or other forms of
divergent differentiation are present, the best diagno-
sis is ‘urothelial carcinoma with divergent differentia-
tion’, specifying the variants and their percentages.
In patients with invasive SCC morphology, but a prior
history of urothelial carcinoma, the best diagnosis is
also ‘urothelial carcinoma with divergent (squamous)
differentiation’ with a comment acknowledging prior
pathology of the patient. In patients with pure inva-
pathology or recognisable urothelial carcinoma com-
ponents, the diagnosis is more complex. Although
some advocate for diagnosis that incorporates surface
findings, the most reliable indicator of squamous car-
cinoma metastasis appears to be the presence of pure
invasive SCC morphology.5 The second major entity
in the differential diagnosis includes secondary
involvement of the bladder by SCC from other sites,
either by direct extension or metastasis. In many
cases, a prior history of squamous carcinoma arising
in an adjacent location, such as the cervix or anorec-
tal regions, may be available upon re-review of the
medical records.
SCC of the bladder shows immunoreactivity for
cytokeratin (CK)5/6, CK7, CK14, desmoglein-3, p63
and p40, which is shared in common with squamous
carcinomas arising from other sites.5,20–22 In general,
the role of immunohistochemical markers in distin-
guishing SCC from urothelial is not helpful.23 Some
studies that evaluated a panel-type approach to dis-
tinguish urothelial carcinoma with extensive
© 2018 John Wiley & Sons Ltd, Histopathology, 74, 97–111.

A cases may be limited, given immunohistochemical
B
C
Figure 4. Surface changes that accompany squamous cell carci-
noma include (A) squamous cell carcinoma in situ, (B) occasionally
condylomata and (C) verrucous squamous hyperplasia.
squamous differentiation from pure squamous cell
carcinoma have found a decreased frequency of uro-
plakin III, S100P and GATA-3 expression in SCC in
the bladder and elsewhere, although use in individual
© 2018 John Wiley & Sons Ltd, Histopathology, 74, 97–111.
Non-urothelial carcinomas of the bladder 101
overlap in a subset of cases and a disconnect between
morphology and immunohistochemical staining pat-
tern in another subset of cases.21,24 Although p16
has been applied in the context of HPV-related carci-
nomas of the genitourinary and gynaecological tract,
this marker is often expressed in both urothelial carci-
noma and SCC of the bladder irrespective of HPV
status.25
Patients with SCC of the bladder often show
advanced-stage disease at diagnosis, and approxi-
mately one-quarter of patients have lymph node
metastasis at cystectomy.5 In some analyses, the 5-
year disease-free survival rate following a radical cys-
tectomy is 43–57%,5,26,27 which is similar to that of
urothelial carcinoma of the bladder when controlling
for cancer stage.27 However, other studies have sug-
gested that bladder SCC may be more aggressive than
urothelial carcinoma after adjusting for stage and
other prognostic factors. Future studies that incorpo-
rate a larger number of patients treated in a similar
manner may be needed to define more clearly any
potential differences in outcome between SCC and
urothelial carcinoma of the bladder.
VERRUCOUS CARCINOMA
Verrucous carcinoma of the bladder is a rare, clinically
indolent form of bladder cancer. It has been associated
with schistosomal infection, but it can also occur in its
absence.15,28–31 Verrucous carcinoma is an exophytic
squamous malignant neoplasm with multiple filiform
projections lined by thick folds of well-differentiated
squamous epithelium, with a broad, pushing invasive
front.2 Its incidence accounts for 3–4.6% of bladder
carcinomas in areas of endemic schistosomiasis.15,29
However, occasional sporadic cases have been reported
in non-endemic areas.30,32–34 The aetiology is
unknown and the relationship with HPV is not certain,
although progression from condyloma acuminatum to
verrucous carcinoma has been reported.28,35 Clini-
cally, verrucous carcinoma is often observed in males
and in endemic areas of schistosomiasis. The tumour is
often detected in the fifth decade of life in endemic
areas,15,29,31 and a decade later in cases unrelated
with schistosomiasis.30,32,34 Grossly, verrucous carci-
noma is often a solitary lesion that appears exophytic,
fungating and filiform. Microscopically, the tumour is
characterised by papillary proliferation with epithelial
acanthosis and hyperkeratosis (Figure 5A).2 The deep
portions have broad, pushing, tongue-like borders
rather than the irregular invasive nests that define
conventional SCC (Figure 5B). Nuclear and
102 S Park et al.
A lined by bland, benign squamous epithelium, but lack
B or secondary in nature, with secondary adenocarci-
Figure 5. A, Verrucous squamous hyperplasia shows broad, push-
ing invasive borders. B, On occasion, invasion may be difficult to
assess on transurethral resection chips, although extensive large
squamous nests throughout the specimen may help in the differen-
tial diagnosis.
architectural atypia are minimal.2 Whereas stromal
desmoplasia is an uncommon finding, dense lympho-
cytic infiltration can be seen at the border between the
atypical squamous epithelium and stroma.
The differential diagnosis includes secondary
involvement of the bladder by well-differentiated SCC
from other sites and conventional SCC of the bladder.
To exclude conventional SCC, the entire lesion should
be completely resected and available for evaluation in
order to rule out the presence of irregular invasive
squamous nests that correspond to conventional SCC.
Several surface lesions may also mimic verrucous car-
cinoma, including verrucous squamous hyperplasia,
squamous papilloma and condyloma acuminatum.
Distinguishing features of verrucous squamous hyper-
plasia and condyloma acuminatum have been dis-
cussed in the previous section. Squamous papillomas
appear exophytic and contain thin fibrovascular cores
the deep pushing invasive front seen in verrucous
carcinoma.18
Verrucous carcinoma has a highly favourable prog-
nosis, although there are some limitations due to the
small number of cases reported and short-term fol-
low-up.32 The association with schistosomiasis does
not appear to alter the prognosis.15
Bladder carcinomas with
adenocarcinomatous features
PRIMARY ADENOCARCINOMA (NON-URACHAL)
Adenocarcinoma within the bladder may be primary
noma representing the most common form. Second-
ary adenocarcinomas involving the bladder may
originate from colon, prostate, breast, endometrium,
cervix, lung and other organs.36,37 Secondary carci-
nomas may co-exist with bladder neoplasia and may
also colonise the surface urothelium, thus mimicking
a primary bladder neoplasm. By contrast, primary
adenocarcinoma in the bladder is a pure glandular
malignancy derived from the urothelium.2 Therefore,
urachal adenocarcinoma is not included in this
category.
Primary adenocarcinoma is an uncommon malig-
nant neoplasm showing a pure glandular phenotype
that arises from the urothelial lining. Adenocarci-
noma accounts for 0.5–2.0% of all bladder cancers in
the United States.38–40 Although the pathogenesis is
unclear, several risk factors have been suggested.
Long-standing intestinal metaplasia, especially in
patients with exstrophy, chronic irritation and
obstruction due to non-functioning bladder or ende-
mic schistosomiasis have all been implicated as risk
factors.2,41 The lining of bladder diverticula has been
proposed to be a predisposing site for carcinogenesis
because of stasis of carcinogens.42 Historically, cystitis
cystica et glandularis and pelvic lipomatosis have
been considered as premalignant conditions. How-
ever, in a recent large study there seemed to be no
evidence of future risk of malignancy in these latter
entities.43
Grossly, the tumours are frequently solid or sessile
rather than papillary,44 and will occasionally show a
mucinous appearance.2 Microscopically, bladder ade-
nocarcinoma is subdivided into enteric type, muci-
nous type, mixed type and not otherwise specified
(NOS) adenocarcinoma.2 Additional morphological
patterns have been described, such as hepatoid
growth.45 Formerly, clear cell adenocarcinoma has
© 2018 John Wiley & Sons Ltd, Histopathology, 74, 97–111.
 Non-urothelial carcinomas of the bladder 103

been included as a variant of bladder adenocarci- A

noma, but is now considered as a separate disease
entity within tumours of M€ ullerian type in the latest
World Health Organisation (WHO) classification.2
The enteric type is identical to its gastrointestinal
counterpart. This pattern contains pseudostratified
epithelium with atypia arranged in acinar, cribriform,
villous or solid architectural patterns (Figure 6A).
Necrosis is often present.2 The mucinous type is com-
posed of abundant extracellular mucin with floating
tumour cells that may appear signet-ring, gland-form-
ing or sheet-like (Figure 6B). The mixed type includes
a co-mixture of enteric and mucinous types (Fig-
ure 6C). In primary bladder adenocarcinomas in
which none of the above patterns apply, NOS is
applied. There is no uniformly accepted grading sys- B
tem for bladder adenocarcinoma.
Surface glandular changes may occur in the pres-
ence or absence of invasive adenocarcinoma, and
include villous adenoma and adenocarcinoma in situ.
Villous adenomas are histologically identical to their
colonic counterparts and contain thin exophytic vil-
lous structures lined by intestinal type epithelium
(Figure 7A). Villous adenomas may be associated
with extravasated mucin, and caution should be
taken to distinguish if an associated adenocarcinoma
may be present. Assessment of nuclear stratification
and degree of atypia separates these lesions into
those with low- and high-grade dysplasia. Adenocar-
cinoma in situ may occur in a background of flat or
villous architecture and is characterised by severe C
atypia and increasing complexity of the glandular
lining (Figure 7B). Both high-grade dysplasia and
adenocarcinoma in situ co-exist with invasive adeno-
carcinoma in up to 35% of cases.46 Adenocarcinoma
may occur in the absence of a recognisable in situ-
lesion and, conversely, secondary spread of adeno-
carcinoma to the bladder may colonise the urothelial
lining.
Primary bladder adenocarcinomas are usually posi-
tive for CK20 and CDX2.47,48 Variable immunoreac-
tivity has been reported for CK7, carcinoembryonic
antigen, thrombomodulin, b-catenin and CA125.48–
50
GATA-3 is rarely positive in bladder primary ade-
nocarcinoma and, when positive in cases that show
signet-ring like features, may actually reflect a plas-
macytoid urothelial carcinoma.51 In general, markers Figure 6. Primary adenocarcinoma of the bladder includes (A)
enteric-type, (B) mucinous and (C) mixed subtypes.
associated with prostatic adenocarcinoma are
negative.
The main differential diagnosis in primary bladder Knowledge of precedent clinical history and patient
adenocarcinoma is secondary spread of adenocarcino- imaging is helpful in refining the differential diagno-
mas from other sites that commonly include the gas- sis. Distinction from colorectal adenocarcinoma is dif-
trointestinal, prostate and female genital tract. ficult, especially given the substantial overlap of
© 2018 John Wiley & Sons Ltd, Histopathology, 74, 97–111.
104 S Park et al.
A A
B B
Figure 7. Superficial changes that may be seen in association with
primary bladder adenocarcinoma include (A) villous adenoma and
(B) adenocarcinoma in situ.
genomic alterations between bladder primary adeno-
carcinoma and colorectal adenocarcinoma.52 b-cate-
nin has been reported to demonstrate an increased
frequency of nuclear localisation in colorectal carci-
noma, although this is not often helpful in individual
cases.48 Additional sites of origin from the gastroin-
testinal site, including the stomach, should also be
considered (Figure 8A,B). The differential diagnosis
also includes urothelial carcinoma with extensive
glandular differentiation. In this setting, small foci of
urothelial carcinoma or squamous differentiation can
help in determining this diagnosis. Distinction from
prostatic adenocarcinoma may be often performed on
morphological grounds and, in challenging cases,
through the application of a panel of prostate mark-
ers. Breast carcinoma can metastasise to the bladder,
with invasive lobular carcinoma representing the
most common subtype.53 In this setting, markers that
distinguish breast origin may help resolve the
Figure 8. The bladder can be involved by direct extension or
metastasis from the gastrointestinal tract. A, In this case, a small
low-grade papillary urothelial carcinoma is present on the surface
of the bladder, but infiltrative cells are present in the lamina pro-
pria. B, Higher magnification shows a signet-ring cell like morphol-
ogy to these cells, which were positive for CK20, CDX2 and villin
and negative for urothelial markers. The patient had a known his-
tory of signet ring cell carcinoma of the stomach.
differential. There will be a subset of cases that can-
not be resolved; in these cases, a frank discussion of
the differential diagnosis and acknowledgement of
clinical history is essential.
The prognosis of primary bladder adenocarcinoma
has been considered to be poor, as tumour stage at
initial diagnosis is usually advanced.41 When
matched for stage, however, bladder primary adeno-
carcinoma may have similar outcomes to urothelial
carcinoma.54 The 5-year survival rate is reported to
be 30–50%,38,41,55 with prognosis influenced primar-
ily by stage.38,44,56 Histological type does not appear
to be a significant predictor of outcome in bladder pri-
mary adenocarcinoma.38
© 2018 John Wiley & Sons Ltd, Histopathology, 74, 97–111.

URACHAL ADENOCARCINOMA
Urachal carcinomas are malignant epithelial tumours
arising from urachal remnants.2 Urachal carcinoma
is extremely rare, ranging from 0.01% to 0.7% of
bladder cancers in North America and Europe.57–59
Although the aetiology is still unknown, urachal car-
cinomas usually develop in the remnants of the ura-
chus and may be associated with intestinal
metaplasia or adenomatous change.60 Mucosuria is
present in approximately 17–25% of patients. One
major challenge in the diagnosis of urachal carci-
noma is the distinction from primary adenocarcinoma
of the bladder with mucinous features, especially in
large tumours in which multiple regions of the blad-
der are involved.
When based in the bladder, urachal carcinomas
are located primarily in the bladder dome and ante-
rior wall of the bladder, and often are seen invading
the deeper layers of the bladder wall and perivesical
tissue.60 However, tumours may originate at any site
between the umbilicus and the dome of the bladder.61
Given the origin in deeper layers of the bladder wall,
a distinct staging system (called the ‘Sheldon staging
system’) has been proposed for use in this subset of
bladder carcinomas.
At gross examination, the tumours may appear as
firm, white or grey infiltrative masses. Occasional cys-
tic lumens may be seen and mucin is often abun-
dant.62 Microscopic evaluation can show a range of
features. A urachal remnant may be identified in a
subset of cases that is lined by urothelial or cuboidal
epithelium and may show intestinal metaplasia or
adenomatous changes (Figure 9).63 The associated
Figure 9. Urachal remnant in the dome of the bladder.
© 2018 John Wiley & Sons Ltd, Histopathology, 74, 97–111.
Non-urothelial carcinomas of the bladder 105
neoplasms that arise in this region can have a pre-
dominantly cystic component and these are subdi-
vided based on cellular atypia into mucinous
cystadenoma, mucinous cystic tumour of low malig-
nant potential and mucinous cystadenocarci-
noma.2,62 Non-cystic adenocarcinomas arising in
association with the urachus encompass the spectrum
described for non-urachal bladder primary adenocar-
cinomas, with the explicit distinction that these ade-
nocarcinomas have their epicentre in the dome or
anterior wall of the bladder and are not associated
with other glandular alterations of the bladder
urothelium, thus suggesting a probably urachal ori-
gin.60 These carcinomas include enteric type, muci-
nous, mixed or NOS morphology, with mucinous
representing the most common subtype.53,62 There
are no specific guidelines surrounding grading of
these lesions. Finally, a variety of non-glandular car-
cinomas including urothelial carcinoma, squamous
cell carcinoma, neuroendocrine neoplasms and other
carcinomas can arise in this setting.62
Immunohistochemistry in urachal carcinomas
shows expression of CK20 and CDX2; fewer than half
of urachal carcinoma cases express CK7 and Claudin-
18.64 Additional studies have evaluated markers such
as E48, CA125 and nuclear b-catenin, although
these appear to be of limited use.50,64 Immunohisto-
chemistry therefore plays a limited role in resolving
the differential diagnosis, which includes primary
bladder adenocarcinomas and secondary involvement
of the bladder by adenocarcinomas originating at
other sites. The distinction from primary bladder ade-
nocarcinoma is often difficult, especially in large car-
cinomas, and would involve exclusion of in situ
lesions in the urothelium elsewhere in the bladder. A
subset of secondary adenocarcinomas involving the
bladder can be diagnosed through immunohistochem-
istry, although distinction of colorectal carcinoma
retains the same difficulties as described for primary
bladder adenocarcinoma.
Urachal adenocarcinoma usually presents at an
advanced stage at the time of diagnosis and has a 5-
year survival rate ranging from 40% to 70%.38,59,65–
70
Although one study showed that patients with ura-
chal adenocarcinoma had an improved overall and dis-
ease-specific mortality relative to non-urachal
adenocarcinoma,70 more recent studies suggest that
outcomes may be similar. An improved prognosis has
been associated with low stage,57–60,68 confinement of
the tumour to the urachus with complete resec-
tion,57,67,71 low histological grade,59,71 absence of
lymph node involvement and distant metastasis57 and
mucinous cystic tumour type.62
106 S Park et al.
€llerian type
Tumours of Mu
M€ ullerian type tumours arise from pre-existing M€ ulle-
rian precursors within deeper layers of the bladder
wall, including endometriosis and M€ ullerianosis.
These carcinomas resemble their M€ ullerian-type
counterparts in the female genital tract, such as clear
cell adenocarcinoma and endometrioid adenocarci-
noma.2 Their incidence is very low, with fewer than
50 cases reported.72,73 The origin of these carcinomas
is unclear. Several hypotheses include derivation from
a M€ ullerian origin,74 derivation from a urothelial ori-
gin due to shared genetic alterations75,76 and poten-
tially a non-M€ ullerian origin.75,77 In contrast to other
non-urothelial bladder carcinomas, there is a female
predominance in this category of tumours.73
The major subtypes within this category include clear
cell adenocarcinoma and endometrioid adenocarcinoma.
At gross examination, clear cell adenocarcinoma occurs
most commonly at the bladder neck and appears as a
large, solitary mass that is papillary or sessile.73 The ori-
gin is often within the submucosal layers of the bladder,
including the lamina propria and muscularis propria.
Endometrioid adenocarcinoma may also appear solid,
but may be less likely to be polypoid given its origin
within the serosal layer of the bladder wall.
Clear cell adenocarcinoma is the more common of
the two carcinoma types and shows a variety of mor-
phologies, including tubulocystic, papillary or solid
sheet-like growth patterns. The tubulocystic pattern is
the most common and is characterised by tubules of
different sizes containing basophilic or eosinophilic
secretions within the lumens (Figure 10). By con-
trast, the papillary pattern shows small and rounded
Figure 10. Clear cell carcinoma represents the more common of
the M€ullerian type tumours originating in the bladder.
papillae with fibrovascular cores that may be hyali-
nised. Carcinoma cells may be flat, cuboidal or
columnar, with clear or eosinophilic cytoplasm. A
‘hobnail’ appearance can be seen. Cytological atypia
is moderate to severe, with frequent mitotic activity,
haemorrhage and necrosis. Endometrioid adenocarci-
noma resembles its counterparts in the ovary and
endometrium and often contains endometrioid-type
glands with squamous metaplasia or other metaplas-
tic changes.
By immunohistochemistry, clear cell adenocarci-
noma is frequently immunoreactive for CAM5.2,
EMA, CK7, PAX8, CA-125, napsin A, AMACR (race-
mase), hepatocyte nuclear factor-1b (HNF-1b) and
nuclear p53 and variably positive for CK20, CD10,
uroplakin and CEA.72,78 p63, GATA-3, oestrogen
receptor (ER) and progesterone receptor (PR) are neg-
ative. A high proliferative index is evident with Ki67
immunostain. The main differential diagnosis of clear
cell adenocarcinoma includes nephrogenic adenoma,
which often shows tubules lined by hobnail cells.
Although nephrogenic adenomas are often small and
superficially situated in the bladder wall, some lesions
may be quite large.77 Morphological distinction of
clear cell adenocarcinoma is based on the finding of
clear cell predominance, severe cytological atypia,
high mitotic rate and necrosis. Frequent Ki67 expres-
sion and strong nuclear p53 expression by immuno-
histochemistry supports a diagnosis of clear cell
adenocarcinoma over nephrogenic adenoma. Urothe-
lial carcinoma with glandular differentiation and
metastatic renal cell carcinoma may also be in the
differential diagnosis, although immunohistochemical
markers can readily distinguish these entities.
Endometrioid adenocarcinomas are often immunore-
active for ER, PR, PAX8 and b-catenin, occasionally
positive for p16, and show wild-type p53 immunore-
activity. A subset of these carcinomas may lose PTEN
and ARID1a expression. Distinction of endometrioid
adenocarcinoma from urothelial carcinoma with
glandular differentiation can be undertaken through
application of urothelial-specific markers, absence of
concurrent or precedent urothelial neoplasia, and
clinical history of endometriosis.
Given the limited number of cases of clear cell ade-
nocarcinoma and endometrioid carcinoma arising in
the bladder wall, long-term follow-up is limited and
tumour prognosis is unclear.
Neuroendocrine neoplasms
Neuroendocrine tumours are classified into well-differ-
entiated neuroendocrine tumour and neuroendocrine
© 2018 John Wiley & Sons Ltd, Histopathology, 74, 97–111.

carcinoma, which includes both large- and small-cell
neuroendocrine carcinoma. Whereas well-differen-
tiated neuroendocrine tumours occur in pure form,
neuroendocrine carcinomas are often admixed with
some form of non-neuroendocrine carcinoma that is
most frequently urothelial carcinoma.79 In some
instances, neuroendocrine carcinoma may be ‘pure’,
although it is unclear if this represents an over-
growth of this component within an otherwise mixed
cancer.
WELL-DIFFERENTIATED NEUROENDOCRINE
TUMOUR
Well-differentiated neuroendocrine tumour is a rare
neuroendocrine neoplasm arising from isolated neu-
roendocrine cells located in the basal layer of the
urothelium.2,80,81 Associated carcinoid syndrome has
not been reported.80 Grossly, the tumours are small,
round or polypoid nodules, usually located in the sub-
mucosa of the trigone or bladder neck.80,81
Microscopically, these tumours are morphologically
identical to well-differentiated neuroendocrine
tumours occurring at other sites. Pseudoglandular,
solid and cribriform patterns may be seen. Tumour
cells are uniform in size and may be cuboidal or
columnar in nature. The cytoplasm is abundant and
nuclei are small, round and uniform with stippled
chromatin and inconspicuous nucleoli. Mitotic activ-
ity is an uncommon finding and necrosis is generally
absent. The overlying urothelium may be unremark-
able or show cystitis cystica, cystitis glandularis or
Paneth cell metaplasia.80
Tumour cells are immunoreactive for neuroen-
docrine markers such as synaptophysin, chromogranin
and CD56, and periodically show immunoreactivity for
CK7, TTF-1, and b-hCG. CK20 and most prostatic
markers except prostate-specific acid phosphatase are
negative.80,82 The differential diagnosis includes the
nested variant of urothelial carcinoma, inverted
urothelial papilloma, paraganglioma, metastatic
well-differentiated neuroendocrine tumour, metastatic
adenocarcinoma and small-cell neuroendocrine carci-
noma containing well-differentiated neuroendocrine
components. Whereas immunohistochemistry can
distinguish urothelial from neuroendocrine lesions in
this setting, differentiating well-differentiated neuroen-
docrine tumours requires careful histological assess-
ment and knowledge of patient history.
Although metastasis has been reported in some
cases, pure well-differentiated neuroendocrine
tumours are associated with a favourable clinical out-
come.80,81
© 2018 John Wiley & Sons Ltd, Histopathology, 74, 97–111.
Non-urothelial carcinomas of the bladder 107
NEUROENDOCRINE CARCINOMAS
Both large- and small-cell neuroendocrine carcinomas
can arise within the bladder, although large-cell neu-
roendocrine carcinoma is extremely uncommon, with
fewer than 20 sporadic reported cases in the litera-
ture.83–86 The incidence of small-cell neuroendocrine
carcinoma is somewhat higher, but still accounts for
only 0.5–1.0% of all bladder cancers.87,88 Similar to
most other bladder cancers, smoking may be a signifi-
cant risk factor.2,89 The cell of origin is unclear, and
several theories include origin from urothelial stem
cells, neuroendocrine cells in normal or metaplastic
urothelium and transformation of urothelial carci-
noma cells.90 Grossly, neuroendocrine carcinomas
may be evident as a submucosal nodule or may
ulcerate through the surface. Tumours may be large
and appear polypoid or nodular.2 Many cases of
small-cell neuroendocrine carcinomas may even show
extension into the perivesical fat, adjacent organ
involvement and distant metastasis.
Microscopically, large-cell neuroendocrine carcino-
mas are usually high-grade and poorly differentiated,
with a sheet-like, trabecular or nested growth pat-
tern. Tumour cells are large and polygonal with
abundant cytoplasm. Nuclei show a salt-and-pepper-
like chromatin pattern with or without prominent
nucleoli (Figure 11A). Frequent mitotic figures and
apoptotic bodies are noted, with occasionally necrosis
and bizarre giant cells. By contrast, small-cell neu-
roendocrine carcinomas are composed of sheets of
small cells with scant cytoplasm showing a ‘pattern-
less’ pattern of growth, occasionally focal nesting pat-
tern (Figure 11B). Due to their scanty cytoplasm,
nuclear crowding, moulding and overlap is often
appreciated. Nucleoli are not prominent and chro-
matin is dispersed. Frequent mitotic figures with
apoptotic bodies and extensive necrosis are common
findings. Approximately 50% of cases show an
admixture of small-cell neuroendocrine carcinoma
with non-small-cell carcinoma components.79,91,92
The ratio of neuroendocrine carcinoma and non-neu-
roendocrine carcinoma components may vary, and
the amount of the neuroendocrine carcinoma compo-
nent may be important to outcomes. To use the term
‘small-cell neuroendocrine carcinoma’, the majority
of the tumour should demonstrate small-cell morphol-
ogy; tumours with a lesser amount of small-cell carci-
noma are considered mixed tumours, and a
description of the neuroendocrine component present
and its percentage should be reported.
By immunohistochemistry, both large- and small-
cell neuroendocrine carcinomas show similar
108 S Park et al.
A
B
Figure 11. Neuroendocrine carcinoma of the bladder can be subdi-
vided into (A) the less common large-cell neuroendocrine carci-
noma, which co-exists with urothelial carcinoma in situ in this
case, and (B) small-cell neuroendocrine carcinoma.
immunohistochemical staining patterns, although
large-scale comparisons have been lacking. Neuroen-
docrine carcinomas show immunoreactivity for neu-
roendocrine markers including synaptophysin,
chromogranin and CD56, and can often show
immunoreactivity for epithelial markers such as pan-
cytokeratin, CAM5.2 and high molecular weight
cytokeratin.87 TTF-1 is expressed in approximately
half the cases.93 GATA-3 expression is variable and
p63 expression is negative.94
The differential diagnoses of neuroendocrine carcino-
mas in the bladder include poorly differentiated high-
grade urothelial carcinoma, secondary involvement of
the bladder by neuroendocrine carcinoma from other
sites, malignant lymphoma, malignant melanoma, para-
ganglioma, lymphoepithelioma-like carcinoma, neurob-
lastoma, alveolar rhabdomyosarcoma and metastatic
Merkel cell carcinoma. Immunohistochemistry can be
used to distinguish poorly differentiated urothelial carci-
noma from neuroendocrine carcinoma, which repre-
sents the most common differential diagnosis.
Immunohistochemistry can also be used to differentiate
neuroendocrine carcinoma from lymphoma, melanoma,
Merkel cell carcinoma and alveolar rhabdomyosarcoma.
However, distinction from other lesions expressing neu-
roendocrine markers is more difficult, and relies on
knowledge of the clinical history and morphology. Care-
ful assessment of prior prostate cancer history and
involvement of the prostate gland is important in raising
the possibility that the neuroendocrine carcinoma may
be arising from the prostate.
The prognosis of small-cell neuroendocrine carci-
noma in the bladder is poor due to locally advance
disease and frequent metastasis.2 The median overall
survival is 11 months using analysis of the Surveil-
lance, Epidemiology and End Results (SEER) data-
base, but other studies report a 5-year survival rate
of 38–78%.95,96 In a recent study of 625 patients
with localised/locally advanced bladder small-cell
neuroendocrine carcinoma, the 3-year overall sur-
vival rate was 33%.97 However, outcomes analysis
in this disease is complicated, considering different
treatment modalities and enrolment into clinical tri-
als. Neoadjuvant platinum-based chemotherapy com-
bined with radical cystectomy has been associated
with the best outcomes.97 The biological behaviour
of large-cell neuroendocrine carcinoma remains to be
clarified because of limited cases, but a few cases
have been reported to have distant metastasis.86,98,99
Therefore, large-cell neuroendocrine carcinoma may
have similar outcomes to that of its small-cell
counterpart.
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