|Non-Neoplastic Epithelial Proliferative Lesions ||Major Neoplastic Lesion(s) in the Clinical/Pathological Differential Diagnosis|
|• Polypoid-Papillary Cystitis |
• Nests of von Brunn, Cystitis Cystica, and Cystitis Glandularis
• Nephrogenic "Adenoma" (Metaplasia)
• Squamous Metaplasia and Related Lesions
|• Papillary Neoplasm|
• Deceptively Benign-appearing Transitional Cell Carcinoma (TCC) (tubular/nested, microcystic, inverted)
• Clear Cell Carcinoma
• Signet Ring Cell Carcinoma
• Squamous Cell Carcinoma
|Treatment Effect and Unusual Forms of Cystitis|
|• Treatment Effect: Radiation Injury & Chemotherapy |
• Unusual Forms of Cystitis
|• Transitional Cell Carcinoma|
|Reactive Mesenchymal Spindle Cell Lesions|
|• Inflammatory Pseudotumor Post-operative Spindle Cell Nodule ||• Myosarcoma (& other Sarcoma types)|
• Sarcomatoid Carcinoma
• Carcinoma with atypical stromal cells
|Ectopic or Misplaced Tissue Within the Urinary Bladder|
|• Mullerian Lesions:|
• Fallopian Tube Prolapse
• Ectopic Prostatic Tissue
|• Adenocarcinoma primary versus secondary |
|Developmental and Related Abnormalities|
|• Fibroepithelial polyp |
• Urothelial, Urachal and mullerian duct cysts
|Normal Anatomical Structures|
|• Paraganglia ||• Paraganglioma,|
• Nested TCC
• (Sarcoma & Melanoma)
A wide range of epithelial and mesenchymal pseudoneoplastic disorders of the urinary bladder may
clinically mimic a malignant neoplasm. A tissue biopsy is usually required for a definitive diagnosis.
At times, the pathologic features may mimic a neoplasm, making their interpretation difficult. It is
obviously important to be aware of these lesions and their spectrum of morphological appearances to avoid
over-diagnosis and inappropriate therapy.
NON-NEOPLASTIC EPITHELIAL PROLIFERATIVE LESIONS
Papillary neoplasms are usually readily recognized, in spite of the controversies
regarding their exact classification , but they require careful evaluation to exclude the possibility
of polypoid/papillary cystitis. The latter is a non-neoplastic condition with exophytic mucosal folds
protruding into the bladder lumen mimicking a papillary neoplasm
. At the time of cystoscopy, a
biopsy of the mucosal folds of polypoid/papillary cystitis is often done because of suspicion for
transitional cell carcinoma .
Light microscopic examination reveals urothelial mucosa with a polypoid or papillary architecture,
with thick, broad-based and thinner stromal cores respectively
. The fronds are low-lying,
with a tendency to be thick and edematous. Even when thinner, they lack the more complex arborizing
pattern that is associated with papillary neoplasia
. The urothelium lining the mucosal folds
has a reactive appearance and may be hyperplastic. Cell polarity with orderly maturation is maintained,
with a surface layer of umbrella cells. There may be mild nucleomegaly with vesicular, smoothly
contoured nuclei, at times with prominent nucleoli; but there is an absence of notched nuclei, coarse
chromatin, marked hyperchromaticity or abnormal mitotic activity
. Metaplastic urothelium may
be present . Usually there is some degree of acute or chronic mucosal inflammation with vascular
congestion in the lamina propria . The urothelium adjacent to the exophytic structures notably lacks
any evidence of in-situ neoplasia. Recognition of the reactive or hyperplastic nature of the urothelium
in the context of inflammatory and metaplastic mucosal features allows for avoidance of over-diagnosis.
Clinicopathological correlation is often helpful and necessary for a definitive diagnosis of
polypoid-papillary cystitis. This lesion occurs most often in a patient with an indwelling urinary
catheter, vesical fistula, or other form of chronic bladder irritation
. Polypoid cystitis
may be found in up to 80% of patients with an indwelling catheter, at times with grossly visible lesions
up to .5 cm in size, most often involving the dome or posterior wall . Vesical fistulae, three times
more common in men than in women
, are most often associated with diverticulitis, Crohn's disease,
colorectal cancer, and appendiceal inflammation . Uncommonly, the bladder involvement is the initial
presentation of extra-vesical disease, with non-specific symptoms such as frequency, dysuria and urgency
. The catheter associated lesions may be detectable with ultrasonographic examination .
Polypoid-papillary cystitis can be expected to resolve once the injurious stimulus is removed. In a
study of catheterized patients, the mucosal abnormality disappeared in 87% of cases within 28 weeks
following the removal of the urinary catheter .
Polypoid-papillary cystitis may be a herald lesion that portends a neoplastic or inflammaotry process
elsewhere in the urinary tract or neighbouring organs . Focal papillary hyperplasia of the
transitional cell epithelium, with grossly inconspicuous low-lying mucosal folds, may be found
microscopically overlying any abnormality within the bladder wall, including lesions related to secondary
involvement of the bladder by extravesical disease . Very rarely a diffuse papillomatosis of the
urinary bladder mucosa may occur, producing a "velvety" appearance . The exact nature of
papillomatosis is unclear; it may be a pre-neoplastic or neoplastic lesion.
Nests of von Brunn, Cystitis Cystica, and Cystitis Glandularis
Nests of von Brunn and cystitis cystica are two of the most common lesions encountered, and there are
several metaplastic lesions that may occur, including glandular differentiation in cystitis cystica, the
latter being referred to as cystitis glandularis. Nests of von Brunn are usually an incidental
microscopic finding, often present in the trigone region. They may be found in association with mucosal
inflammation or with no apparent underlying abnormality. In several autopsy studies, nests of von Brunn
were present in 86 to 94 percent of cases, occurring over a wide age range, commonly without inflammation
of the bladder mucosa
. These nests are not considered to be a risk factor for the development
Usually nests of von Brunn are not a diagnostic challenge. The nests are just beneath, and typically
separate from, the urothelium, with an orderly non-invasive arrangement of smoothly contoured, round,
islands of cytologically bland transitional cell epithelial cells surrounded by a basal lamina.
Prominent aggregates of nests of von Brunn may resemble an inverted papilloma . When these nests
are very numerous with deeper than usual placement in the lamina propria they may have a worrisome
microscopic appearance. Florid, hyperplastic collections of nests of von Brunn must be distinguished
from the "deceptively bland" or "nested" variant of transitional cell carcinoma
Hyperplastic nests of von Brunn have a non-infiltrative base with the nests extending to the same
horizontal level . Typically, transitional cell carcinoma has infiltrative, irregularly
distributed, variably sized and shaped nests with angular, pointed contours, set within a reactive
stroma, often associated with infiltration by single cells or 2 to 3 cell clusters . It is
important to note that nests of von Brunn may have reactive epithelial atypia. In addition they may be
secondarily involved by in-situ neoplasia and this must not be mistaken for invasive disease.
Carcinomatous nests have a higher proliferation rate, as indicated by MIB-1 immunostaining, and may more
often be positive for p53, but the variability of staining precludes relying solely on these markers for
a definitive diagnosis in this circumstance .
Nests of von Brunn may develop central degenerative changes with microcystic lumina, referred to as
cystitis cystica. This is a less common finding, but some have found it in up to 60 percent of bladders
upon close inspection . Cystitis cystica may be evident grossly as discrete nodular mucosal
elevations ranging in size from 2 to 5 mm. Florid examples may produce a worrisome polypoid fleshy
lesion . The cysts typically contain clear or yellowish fluid that appears pink in hematoxylin and
eosin stained tissue. The epithelium lining the cysts is cuboidal to flattened, cytologically bland, and
often mixed with inflammatory cells. Cystitis glandularis occurs when this epithelium undergoes
glandular differentiation with an inner lining of cuboidal to columnar cells that contain abundant mucin.
It is readily recognized when there are tall columnar mucinous cells with interspersed goblet cells,
closely resembling intestinal epithelium
. The intestinal-type epithelium may be extensive,
especially in patients with non-functional bladders, and the metaplasia may be complete with Paneth cells
and argyrophil-positive endocrine cells . Mucinous metaplasia of the overlying urothelial surface
epithelium may be present.
Cystitis glandularis may have a worrisome gross appearance, particularly when it produces a polypoid
mass . In most cases, the microscopic distinction of cystitis glandularis from adenocarcinoma is
easily achieved as the epithelial structures are mucosal based and arranged just beneath the urothelial
surface in an orderly fashion, and the glandular epithelium lacks significant cytological atypia.
Occasionally, it may have an appearance that makes this distinction more difficult
glandularis can be an extensive lesion, and mucous extravasation into the stroma can occur, but this
should not be taken as presumptive evidence of a malignant tumor
. Rarely, cystitis glandularis
extends to involve the superficial muscularis propria, potentially leading to misinterpretation as an
invasive carcinoma . Of course, any degree of atypia, particularly in the intestinal-type of
cystitis glandularis, should lead to a thorough evaluation for the possibility of an adenocarcinoma. In
the vast majority of cases, the degree of atypicality found in adenocarcinoma of the bladder is far
greater than what might be encountered in cystitis glandularis .
It appears that, in some cases, there may be a progression of cystitis glandularis to carcinoma.
There are reports of close juxtaposition or merging between areas of glandular metaplasia with
intestinal-type adenocarcinoma  and with the rarely encountered villous adenoma of the bladder
. Several cases of prolonged cystitis glandularis of intestinal type with subsequent
development of adenocarcinoma have been described
, and this has been associated with chronic
indwelling catheterization . Similarities of mucin types of secretions found in intestinal-type
cystitis glandularis, villous adenoma of the bladder, and adenocarcinoma of the bladder support the
concept of a metaplasia to dysplasia to carcinoma progressive sequence or continuum
concept has been reinforced with the finding of nuclear localization of beta-catenin in intestinal type
cystitis glandularis, in association with increased levels of TNFalpha expression, similar to that found
in Barrett's esophagus where these molecular events have been shown to be part of the signalling pathway
in the progression to adenocarcinoma .
Nephrogenic "Adenoma" (Metaplasia)
Nephrogenic adenoma is a distinctive benign lesion typically found in areas of urothelial mucosal
trauma, irritation, or inflammation
. Most patients will have a history of previous urinary
. It may be an incidental finding or the patient may present with
hematuria, dysuria or frequency . The lesion usually occurs in the urinary bladder of adults, more
often in men than in women
. Uncommonly, it is found in children . It typically involves
a single site, but may occur at multiple sites. Most lesions are less than 1 cm in size, but sizes of 1
to 4 cm and greater have been reported
. The cystoscopic appearance of nephrogenic adenoma may
simulate a papillary, sessile or in-situ carcinoma, or have the appearance of cystitis
. In one
study, 17/31 (55%) cases were polypoid at endoscopy . The diagnosis is rarely suspected clinically
and histopathological examination is required for the diagnosis . One or more recurrences of the
lesion can occur. In two recent studies, the lesion recurred in 7 of 31(23%) patients  and 5 of
8(63%) patients .
Microscopically, nephrogenic adenoma is confined to the urothelial mucosa, at times with a band-like
growth. The lesion usually exhibits a range of patterns with variable proportions of each, including
tubular, microcystic, solid nested, and papillary patterns
. The tubular pattern often
predominates and it may be the only pattern present. The tubules are generally small and round, at times
closely packed, but often loosely distributed within an inflamed edematous stroma. Branched and
elongated tubules may be present. There may be a prominent peri-tubular basement membrane. Gradual
transition of the tubules, with progressive tubular dilatation, into microcysts often occurs; and the
cysts may be a prominent feature. When present, the papillae are small slender papillary structures
found on the mucosal surface. Solid nests of cells are almost always a focal finding, although a limited
area may have a diffusely solid pattern
. The cells lining the tubules, cysts, and papillae are
predominantly cuboidal to low columnar with a small amount of cytoplasm; flattened cells are found in the
larger cysts. Hobnail cells are also found in up to 70% of cases  and cells with clear cytoplasm may
be present. Transitional cell epithelium is absent. The cells are bland with nuclei that are small and
dark with a degenerative appearance, or open and vesicular with occasional nucleoli. Mitoses are rare to
absent. The lumina may contain eosinophilic material, but overt mucinous differentiation is typically
Although often referred to as a nephrogenic adenoma, this lesion is generally considered a
metaplastic epithelial lesion that has been misnamed. There has been some ongoing discussion of the
derivation and pathogenesis of this lesion. The immunohistochemical profile provides some support for
the urothelial origin of this lesion. The lesional cells are immunoreactive for cytokeratin 7 and 20,
and they show a membranous pattern of positivity with uroplakin immunostains
. However, one
recent study on nephrogenic adenoma of the urinary bladder in renal transplant recipients found
chromosomal evidence for derivation of the bladder lesion from renal tubular cells . Of interest, a
small number of cases are positive for CD10 and renal cell carcinoma antigen , and free PNA lectin
receptor sites are found in the epithelial lining of the tubular luminal surface in nephrogenic adenoma
and embryonic kidney .
One must be aware of the range of appearances of nephrogenic adenoma to avoid its misinterpretation.
Of note, the papillary growths are not lined with transitional cell epithelium, and usually
characteristic tubules are found in the stroma just beneath the papillae. At times nephrogenic adenoma
may have numerous tiny tubules with inspissated eosinophilic luminal contents surrounded by compressed
cells, giving an overall appearance that mimics a signet ring cell carcinoma . Uncommonly,
low-grade transitional cell carcinoma may form small nests and tubules
, requiring careful
scrutiny to avoid confusion with nephrogenic adenoma. The neoplastic tubules have a discernable rim of
transitional cells, in contrast to the cuboidal or low-columnar cells found in nephrogenic adenoma, and a
subtle but appreciable degree of atypia is present in the lining cells. This variant of transitional
cell carcinoma will not have a prominent peri-tubular basement membrane, and the mixture of patterns seen
in nephrogenic adenoma will not be present. The presence of hobnail cells and clear cells in nephrogenic
adenoma may suggest the possibility of clear cell carcinoma, a tumor that very rarely occurs in the
bladder . In contrast to nephrogenic adenoma, clear cell carcinoma occurs most frequently in
middle-aged to elderly females without a history of injury or inflammation . It typically forms a
sizeable destructive mass with a diffusely infiltrating pattern, and there is malignant cytological
atypia with increased mitotic activity
. There may be associated Mullerian remnant tissue or
foci of transitional cell carcinoma may be admixed with the clear cell carcinoma .
Squamous Metaplasia and Related LesionsTREATMENT EFFECT AND UNUSUAL FORMS OF CYSTITIS
Squamous metaplasia of the urothelium develops in response to injury and frequently is found next to
other metaplastic and reactive lesions such as polypoid cystitis or cystitis glandularis. It is reported
to be more common in women than men  and is commonly found in chronic cystitis, non-functional
bladders, and chronic schistosomiasis of the bladder . Typically a white or grey-white patch is
visualized at the time of cystoscopy , and dramatic examples of squamous metaplasia with marked
keratinization diffusely involving the bladder have been reported . Microscopic examination reveals
stratified squamous epithelium, with or without keratinization, that is cytologically bland with orderly
maturation. The mucosa often has an undulating or "corrugated" appearance; the metaplastic epithelium
may be thickened or thinned. Tangential sectioning with oblique orientation of the mucosal surface may
produce squamous epithelial islands and squamous metaplasia may involve nests of von Brunn , but the lack
of an infiltrative pattern and the bland cytology will indicate the benign nature of the process.
Invasive squamous cell carcinoma, including the extremely rare verrucous carcinoma of the bladder, are
usually large destructive masses unlikely to be confused with a metaplastic process
It is important to note that vaginal-type glycogenated non-keratinizing stratified
squamous epithelium is present in the trigone and bladder neck region in many women . Similar
epithelium has been reported involving the bladder trigone in men who have received estrogen therapy for
prostatic carcinoma .
Difficulties in interpretation may arise when varying degrees of atypia, including squamous cell
carcinoma-in-situ, are encountered. Any degree of atypia should be viewed with suspicion because it may
indicate the presence of squamous cell carcinoma elsewhere in the specimen or in adjacent unsampled
mucosa. The presence of squamous metaplasia itself may be an indicator of an increased risk for the
development of squamous cell carcinoma. With long-term follow-up of up to 30 years, up to 25% of
patients with squamous metaplasia subsequently develop squamous cell carcinoma of the urinary bladder
. When it occurs, the mean elapsed time from initial diagnosis of squamous metaplasia to the
development of carcinoma is 11 years . Rarely, an exophytic papillary squamous cell carcinoma
occurs. There is diffuse co-expression of epidermal growth factor receptor and transforming growth
factor alpha in hyperplastic keratinizing squamous metaplasia, similar to that found in verrucous
carcinoma and well differentiated squamous carcinoma . The presence of metaplastic urothelium in
association with superficial bladder carcinoma, be it squamous or glandular metaplasia, may be associated
with resistance to intravesical BCG therapy .
Condyloma accuminatum has rarely been encountered in the urinary bladder, most often in the trigone
and bladder neck in a patient with ano-genital condylomata
. The lesion is identified by its
characteristic papillomatous thickened squamous epithelium with koilocytotic cells. As at other body
sites, condyloma of the urinary bladder may show varying degrees of atypia and transformation to squamous
cell carcinoma has been reported . Verrucous carcinoma of the bladder, a very rare tumor found
almost exclusively in regions where schistosomiasis of the bladder is endemic , is differentiated
from a condyloma by its larger downward expansion of invasive bulbous fronds of very well-differentiated
Treatment Effect: Radiation Therapy and Chemotherapy
There are a number of inflammatory conditions of the urinary bladder, some of them related to the
effects of treatment, that may cause intraepithelial atypia leading to an over-diagnosis of neoplasia,
although they do not necessarily produce a defined mass or localized lesion. As well, the damaged mucosa
may become ulcerated with adjacent regenerating atypical urothelium that shows a proliferative,
hyperplastic pattern. If the changes are treatment induced, knowledge of the prior treatment can be
crucial to arriving at the correct diagnosis.
Radiation injury of the urinary bladder often produces marked epithelial atypia, although the
constellation of abnormalities found in the urothelial mucosa may lead to at least the suspicion of
radiation effect. There is a recent report of 6 of 12 patients with radiation cystitis showing marked
epithelial proliferation that mimicked invasive carcinoma in the lamina propria . The transitional
epithelial cells may be hyperchromatic and pleomorphic but there are degenerative features with
cytoplasmic ballooning, smudged chromatin, nuclear and cytoplasmic vacuolation and karyorrhectic cellular
debris . Other features that suggest the effects of recent radiation include multiple
telangiectactic blood vessels within an inflamed edematous lamina propria, swollen endothelial cells,
microvessel thrombosis, and atypical, at times multinucleated, fibroblasts. These changes typically
develop within 4 to 6 weeks of injury and the effects of radiation can persist for years, in some cases
for longer than 6 years . The bladder may become contracted with ulcerated mucosa and an indurated,
thickened wall. In the chronic phase of radiation injury there are blood vessels with myointimal
proliferation and hyalinization, scattered atypical fibroblasts and intramural fibrosis with replacement
of smooth muscle by collagen. The atypical fibroblasts are similar to the atypical mesenchymal cells
found in giant cell cystitis . The latter condition is often but not invariably associated with
prior radiation or chemotherapy . It is characterized by mononuclear or multinucleated atypical
mesenchymal cells singly distributed, at times in prominent numbers, within the lamina propria .
Intravesical chemotherapy (eg. Mitomycin C, Thiotepa) or BCG treatment, commonly used to treat
transitional cell carcinoma-in-situ, often induces marked atypia of the urothelium
, although the
atypia may be less evident with BCG therapy. Chemotherapeutic agents used in the treatment of
non-urologic diseases (eg. alkylating agents such as cyclophosphamide or busulfan) may injure the
urothelium with subsequent severe regenerative atypia
. It can be very difficult to confidently
distinguish this atypia from carcinoma-in-situ, even for an experienced observer. As in radiation
injury, the urothelial atypia often has a degenerative appearance with smudged hyperchromatic
multilobated nuclei, nuclear and cytoplasmic vacuolization, and ballooning of the cytoplasm producing a
low nuclear to cytoplasmic ratio. The atypia associated with intravesical chemotherapy may be
predominantly found in the superficial cell layer of the urothelium. Chemotherapy can cause a widespread
denudation of the urothelium with a variably retained single cell layer of very atypical large cells,
mimicking one of the recognized patterns of transitional cell carcinoma-in-situ. The atypical urothelium
is commonly accompanied by an inflamed, edematous, at times hemorrhagic lamina propria that may have
atypical stromal cells.
When evaluating urothelial atypia following treatment with chemotherapy or pelvic irradiation,
transitional cell carcinoma should only be diagnosed when there is unequivocal evidence of in-situ
neoplasia or invasive tumor. If the distinction between treatment induced atypia and carcinoma is
uncertain, then a conservative approach with repeat cystoscopy and biopsy, preferably after the
inflammation has subsided, is the preferred approach.
Unusual Forms of Cystitis
Many forms of cystitis have been categorized in terms of their predominant pathological appearance.
The descriptive categories include eosinophilic , follicular , emphysematous , hemorrhagic
, encrusted , gangrenous , and granulomatous  cystitis: any of these forms of cystitis
may be associated with variable degrees of reactive urothelial atypia that can mimic dysplastic or
neoplastic epithelium, and they may have an appearance of a mass. Eosinophilic cystitis has been
reported to mimic invasive carcinoma, at times with a palpable mass, especially in children . Of
note, the reverse situation can occur: neoplasia may be associated with inflammation. For example,
transitional cell carcinoma-in-situ can mimic interstitial cystitis . Rarely, low-grade lymphoma of
the urinary bladder occurs and inflammatory infiltrates must always be evaluated with this possibility in
. A very unusual case of bladder involvement by a myeloproliferative disorder with dysplastic
megakaryocytes has been described .
Xanthogranulomatous cystitis  and malakoplakia
are two very rare diseases of the
urinary bladder that may cause diagnostic problems because of the infiltrative appearance of large
aggregates of histiocytes. Both malakoplakia of the bladder and xanthogranulomatous cystitis typically
occur in a middle-aged adult, associated with gram negative urinary tract infection
Malakoplakia of the urinary tract is more common in women than men . Both diseases typically
produce multiple yellowish-brown, at times umbilicated, mucosal plaques that are usually less than 2 cm
in size. Occasionally, larger polypoid protrusions occur and there may be necrosis, giving a cystoscopic
appearance that suggests a neoplasm. Histological examination reveals an accumulation of cytologically
bland histiocytes with abundant, vacuolated, variably eosinophilic cytoplasm (von Hansemann cells),
typically within the lamina propria just beneath an intact urothelium. In addition to the sheets of
histiocytes, malakoplakia has cytoplasmic and extra-cellular targetoid eosinophilic bodies
(Michaelis-Gutmann bodies): these microscopic structures are a necessary feature for the diagnosis of
malakoplakia. Michaelis-Gutmann bodies are the result of an acquired macrophage defect that gives rise
to the accumulation of phagolysosomes containing fragments of bacterial wall that are inadequately and
. Michaelis-Gutmann bodies typically contain calcium and iron salts
and can be highlighted with special histochemical stains for these substances .
AmyloidosisREACTIVE MESENCHYMAL SPINDLE CELL LESIONS
Amyloidosis of the urinary bladder may occur as a primary disease or be the result of secondary
bladder involvement by systemic disease. The more common primary amyloidosis often presents with
hematuria and typically produces a nodular or polypoid tumor-like lesion that is potentially mistaken for
carcinoma at the time of cystoscopy
. Secondary involvement of the bladder by systemic amyloidosis
occurs less often, may cause massive hematuria and usually has more of a diffuse erythematous appearance
. Primary amyloidosis predominantly involves the stroma of the lamina propria, although vascular
involvement may also occur. There may be a foreign body giant cell reaction to the amyloid deposits.
Secondary amyloidosis of the bladder predominantly involves the blood vessel walls. Amyloid deposition
can be recognized microscopically by its amorphous pink colour and its presence can be confirmed with a
Congo red histochemical stain. Electron microscopic examination will reveal a characteristic feltwork of
non-branching amyloid fibres .
Spindle cell lesions of the urinary bladder occur infrequently, but they present some of the most
difficult diagnostic challenges in urinary bladder pathology. Nonneoplastic reactive mesenchymal
proliferations must be differentiated from spindle cell neoplasms that may be a benign or malignant
mesenchymal tumor, or an epithelial tumor with spindle cell morphology.
Inflammatory pseudotumor of the urinary bladder is a recently described but now well documented
benign proliferative mesenchymal spindle cell lesion that may be mistaken for a sarcoma
. It has also been referred to as a pseudosarcomatous fibromyxoid tumor
. It is a rare lesion that has a non-specific presentation, with painless gross hematuria being
the usual symptom. Typically, it arises in a patient with no recent history of urinary tract trauma or
infection. The majority of cases have occurred in children and young adults, with only a few cases
reported in patients over the age of 50 years
. The female:male ratio is about 2:1. Over
85 cases have now been reported and, to date, clinical follow-up of up to 180 months has been uneventful,
even in those patients who have been treated with curettage alone
. There is a
recent report of spontaneous regression of inflammatory pseudotumor of the urinary bladder .
Cystoscopy usually reveals an exophytic or polypoid mass. On gross examination the mass is
frequently soft and gelatinous
. Less commonly, it is a firm white submucosal or intramural
nodule . The lesions range in size from a few centimeters up to a reported size of 13 cm
On microscopic examination, the spindle cells are typically widely separated and haphazardly arranged
in a myxoid stroma
. There is a prominent network of fine blood vessels with scattered
lymphocytic and histiocytic inflammatory cells, giving a granulation tissue-like appearance. Neutrophils
and eosinophils may be present. Often there are extravasated red blood cells, and conspicuous large
aggregates of red blood cells may form. The cellularity is variable and areas with a vague fascicular
arrangement of the spindle cells may be found. In some lesions, areas with a more compact cellularity,
at times with a more fascicular arrangement and greater amounts of intercellular collagen, may
predominate . This second pattern often has a prominent lymphocytic and plasmacytic inflammatory
infiltrate. In both patterns, infiltration into the muscularis propria is common and the lesion may
extend through the bladder wall
The lesional spindle cells have the distinctive morphology of reactive myofibroblasts: bipolar cells
with eosinophilic, elongated, tapering cytoplasmic processes that lack striations, and central oval
nuclei with smooth nuclear contours, open chromatin pattern, and occasional nucleoli. Rounded and
stellate cells may be present. Anaplastic or pleomorphic features are absent. Occasional mitoses may be
found but the mitotic activity is typically low and there are no abnormal mitotic figures
Special studies may be needed to be confident of the diagnosis and to exclude other lesions
considered in the differential diagnosis. Procurement of additional tissue may be necessary for this
purpose. The spindle cells of an inflammatory pseudotumor are typically immunoreactive for vimentin and
muscle-specific actin and negative for epithelial markers. Of note, an occasional case has demonstrated
cytokeratin immunoreactivity in the spindle cells
, presumably due to cross-reactivity
of actin filaments with the cytokeratin antibodies. Cytokeratin positivity is not absolute evidence of
an epithelial tumor.
Recently, expression of anaplastic lymphoma kinase (ALK-1) has been detected in inflammatory
pseudotumor using immunohistochemical techniques
. One study found 5/6 inflammatory pseudotumors
immunoreactive for ALK-1  and another found ALK-1 positivity in 6/16 cases . However,
fluorescent in-situ hybridization did not detect chromosomal translocation involving the ALK gene in 4
cases that were positive for the ALK-1 immunostain . Sarcomatoid carcinoma and myosarcoma are
negative for ALK-1 .
Ultrastructural examination reveals myofibroblastic differentiation with abundant rough endoplasmic
reticulum and sub-plasmalemmal bundles of thin filaments with focal densities . There is no evidence
of fully developed smooth muscle or skeletal muscle differentiation. Flow cytometric analysis of DNA
content has generally demonstrated a lack of aneuploidy
, although there is one report of an
aneuploid cell population in 1 of 2 cases studied . This same study found an abnormality in
chromosome 2 (2del(2)p23) in a karyotypic analysis of one case . An inflammatory pseudotumor of the
bladder with a chromosomal abnormality involving chromosome 12 has been recently reported .
Postoperative Spindle Cell Nodule
Unlike inflammatory pseudotumor, postoperative spindle cell nodule (PSCN) is associated with a recent
history of urinary tract trauma, typically within three months of presentation
. In one study,
the mean age of a patient with PSCN was 65 years, presumably reflecting the greater likelihood of urinary
tract instrumentation in the older male population . PSCN, like inflammatory pseudotumor, may
simulate a bladder neoplasm clinically and pathologically. Grossly, it may be friable or nodular and
firm and it may involve the muscularis propria. PSCN also has a distinctive proliferative
myofibroblastic spindle cell phenotype. It is often immunoreactive for vimentin, muscle-specific actin,
and desmin. It may be immunoreactive for cytokeratin . Ultrastructural examination reveals
myofibroblastic and fibroblastic differentiation . In contrast to inflammatory pseudotumor, PSCN is
usually less myxoid, more cellular, and more mitotically active. PSCN and inflammatory pseudotumor may
represent the same proliferative pseudosarcomatous spindle cell response at different stages of
Differential Diagnosis of Proliferative Reactive Mesenchymal
LesionsECTOPIC OR MISPLACED TISSUE WITHIN THE URINARY BLADDER
The major differential diagnosis of inflammatory pseudotumor and PSCN is with sarcoma,
sarcomatoid transitional cell carcinoma, and transitional cell carcinoma with pseudosarcomatous stromal
reaction. Myosarcomas, such as leiomyosarcoma in an adult or rhabdomyosarcoma in a child, are frequent
diagnostic considerations that must be confidently excluded before rendering a diagnosis of inflammatory
pseudotumor. Of note, up to 60% of leiomyosarcomas of the urinary bladder have myxoid areas .
Inflammatory pseudotumor differs from a leiomyosarcoma by having more variable cellularity, a greater
inflammatory component, and a distinct vascularity resembling granulation tissue
addition, it has myofibroblastic differentiation rather than fully developed features of smooth muscle
cells . A rhabdomyosarcoma can be excluded by the lack of a uniform population of small
hyperchromatic cells, an absence of a cambium cell layer and a lack of rhabdomyoblasts. Less often,
other sarcomas that may involve the bladder such as a liposarcoma or malignant fibrous histiocytoma may
be considered, but the diagnostic features of these tumors are not found. The presence of necrosis at
the tumor-detrusor muscle interface, along with significant nuclear atypicality, are good indications of
a malignant mesenchymal neoplasm . Of note, sarcomas of the urinary bladder are ALK-1 negative,
contrasting with the ALK-1 positivity that may be found in inflammatory pseudotumor . Moderate p53
protein nuclear immunostaining may be found in sarcoma whereas there is rare to absent p53 immunostaing
in inflammatory pseudotumor of the bladder .
Sarcomatoid carcinoma is much more common than sarcoma in the urinary bladder and, if a biopsy
reveals an overtly malignant spindle cell lesion, sarcomatoid carcinoma is the most likely diagnosis
. It usually occurs in an older patient, and anaplastic malignant cellular features with
increased mitotic activity are commonly present
. However, these tumors may have myxoid areas
with less cytologic atypia, and this is occasionally a conspicuous feature, leading to possible confusion
with inflammatory pseudotumor
. A thorough examination of all available tissue will often reveal
more typical areas of invasive or in-situ transitional cell carcinoma . Immunohistochemical evidence
of epithelial differentiation may be helpful in the context of overtly malignant cytological features,
and the cytokeratin immunostain can be useful to highlight nests of epithelial tumor cells that may be
otherwise overlooked on routine light microscopy . As noted above, if the lesion is not obviously
neoplastic, cytokeratin immunoreactivity should be interpreted cautiously. ALK-1 positivity would be
supportive evidence for a diagnosis of inflammatory pseudotumor
. Ultrastructural examination for
evidence of epithelial differentiation may be helpful.
Pseudosarcomatous stroma may occur next to transitional cell carcinoma, and a superficial biopsy may
only contain the reactive stromal component, possibly leading to a misdiagnosis of inflammatory
pseudotumor . Additional biopsy tissue may be needed, particularly if there is a history of bladder
carcinoma. When atypical hyperchromatic stromal cells, sometimes with bizarrely shaped nuclei and a
moderate amount of eosinophilic cytoplasm, are identified next to a carcinoma, the lesion may be
misdiagnosed as a sarcomatoid carcinoma or carcinosarcoma: a potentially serious diagnostic error as
either of these diagnoses indicates a very poor prognosis. A diagnosis of rhabdomyosarcoma may be
suggested when these atypical stromal cells occur within a fibroepithelial polyp . It is important
to be aware of these atypical stromal cells that can also occur as individually distributed cells within
the lamina propria of a bladder without tumor, sometimes but not invariably associated with inflammation
or previous chemotherapy or radiation. These atypical stromal cells are vimentin positive and
A number of different tissue types related to adjacent or nearby pelvic organs may be found within
the urinary bladder with formation of a palpable mass.
There is a spectrum of non-neoplastic lesions of mullerian differentiation that are known to involve
the female urinary tract or pelvic peritoneum . Catamenial urinary bladder symptoms indicates a
significant likelihood of ectopic or misplaced mullerian tissue, such as endometrial-type or
endocervical-type glands within the bladder
. It appears that these lesions may either be
misplaced tissues related to a previous surgical procedure or arise spontaneously as metaplastic tissue
. The presence of 0C125 immunoreactivity in these lesions, along with co-expression of
vimentin, cytokeratin, oestrogen and progesterone receptors, is consistent their mullerian derivation.
. Rarely, Mullerian lesions such as endometriosis and endocervicosis may undergo malignant
transformation to clear cell adenocarcinoma of the bladder .
The most common and well recognized Mullerian lesion is endometriosis: a condition that involves the
bladder in about 1 to 2 percent of women with pelvic endometriosis
. The bladder is the
most common site in the urinary tract to be involved by endometriosis and, although it may be the only
apparent site of involvement, most often it is associated with endometriosis elsewhere in the pelvis
. It typically presents in a middle-aged woman and uncommonly occurs in post-menopausal
women . Vesical endometriosis has been described in men receiving estrogen therapy for prostatic
carcinoma . The bladder symptoms are often non-specific, but may be catamenial and associated with
symptoms related to other sites of involvement in the female pelvis. Occasionally the condition may
clinically mimic interstitial cystitis . Laproscopic segmental bladder resection of endometriosis
has been performed .
Cystoscopy typically reveals congested, edematous mucosa that may be intact or eroded, often with a
dark blue or reddish brown color, although involvement of the deeper regions of the bladder wall by
endometriosis may produce little or no mucosal abnormality. The lesions are usually 1 to 4 cm in size;
lesions up to 8 cm in size have been reported
. Most often endometriosis is found in the
posterior wall or the trigone. Light microscopy reveals the typical appearance of endometriosis with
scattered areas of mature endometrial glands, occasionally with focal mucinous metaplasia, surrounded by
variable amounts of endometrial stroma
, often with hemosiderin deposition. Usually these
lesions do not produce diagnostic difficulties. Some foci may have inflamed attenuated epithelium or may
lack stroma, making their recognition more difficult, but they are unlikely to be confused with a
Endocervicosis, the mucinous analogue of endometriosis, has only recently been reported in the
. Diffuse mucinous glands are present, in contrast to endometriosis with
mucinous metaplasia where the mucinous change is only a focal finding . Endocervicosis predominantly
occurs in the reproductive age group with a peak age frequency in the fourth decade
, but it has
been reported in women up to 65 years of age
. To date, within the urinary tract, endocervicosis
has only been identified in the bladder and all of the reported cases have occurred in isolation except
for two associated with pelvic endometriosis
. One case of a mucin-containing bladder
sinus, lined by benign mucinous cells and occasional ciliated cells, has been reported in a 19-year-old
woman, possibly representing ectopic cervical tissue . A lesion in the posterior wall of the
bladder, containing glands resembling endocervical, endometrial and "hobnail glands", referred to as a
paramesonephric remnant with prominent mucinous secretion, has been reported in a 52-year-old woman .
Three women, aged 37, 44 and 46 years of age, have recently been reported with a mass in the posterior
bladder wall that proved to be a benign mullerian lesion consisting predominantly of endosalpingiosis
with minor components of endometriosis and endocervicosis: the term "mullerianosis" was proposed as a
unifying term for these lesions . A case of "mullerianosis" of the urinary bladder, associated with
tubo-ovarian endometriosis, has been described in a 27-year-old woman who had no previous surgery .
Endocervicosis of the bladder may present with a variety of non-specific symptoms including pain,
hematuria, frequency, dysuria, urgency and dyspareunia
. The symptoms may be severe and
persistent, and catamenial exacerbation has been reported . In one report, three of the seven
patients had a history of Caesarean section . The lesion may be palpable on bimanual pelvic
examination and, at cystoscopy, an intramural mass is seen with overlying intact urothelial mucosa. It
lacks the red-blue color of endometriosis, and a mucous discharge may be appreciated at the time of
curettage or biopsy. Like endometriosis, endocervicosis is usually found in the posterior bladder wall,
and it also may be found in the trigone and posterior bladder dome
. There is one reported case
of vesical endocervicosis with involvement of the adjacent extravesical pelvic soft tissue .
Laproscopic segmental bladder resection of endocervicosis has been reported . Clinical follow-up of
up to 14 years in patients with endocervicosis of the bladder has been uneventful
Gross examination of curettings or biopsy tissue may be unremarkable, but the partial cystectomy
specimen usually reveals an ill-defined, intra-mural gray spongy soft tissue mass with mucoid areas and
small cysts. The lesion is usually a few centimeters in size, but it may be up to 5 cm in greatest
.Light microscopy reveals loosely distributed benign endocervical-type
mucin-secreting glands, predominantly in the muscularis propria with, at times, focal extension into the
deep lamina propria or the sub-serosal connective tissue
. The glands vary in size with
irregular shapes ranging from elongated to round and cystic. They lack a confluent growth pattern.
There is abundant luminal mucous surrounded by a lining of simple cuboidal to columnar mucous cells with
basally located nuclei and prominent apical eosinophilic and vacuolated cytoplasm. Occasional goblet
cells may be present and cystic glands may be lined by flattened epithelium. The cells are generally
bland; there may be occasional foci of mild to moderate cytological atypia. Mitotic figures are absent
in most cases but rarely may be found in the glandular epithelium. The glands are surrounded by smooth
muscle or fibrous, at times edematous, tissue. Peri-glandular elastotic stroma is found in some cases.
Ruptured glands occur with extravasated stromal mucous that is surrounded by reactive fibroblasts and
chronic inflammatory cells with mucin laden macrophages
. There may be a prominent neutrophil
infiltrate within the mucous. In about one-half of the cases, a careful search reveals a range of
mullerian differentiation with focally ciliated tubal-type epithelium, and an occasional endometrial-type
gland with a small amount of endometrial periglandular stroma
. The overlying urothelium is
usually unremarkable, although focal replacement of the transitional epithelium by mucinous epithelium
has been observed .
Endocervicosis has a pseudoinfiltrative growth pattern, at times with a reactive periglandular
stroma, extravasated mucous and focal epithelial atypia, possibly leading to its misinterpretation as a
well-differentiated adenocarcinoma . Whenever an unusual bland or low-grade glandular proliferative
lesion is encountered in the bladder of a woman, particularly in the reproductive age group, the
possibility of a mullerian lesion such as endocervicosis should be considered. The recognition of a
range of mullerian differentiation can be a helpful distinguishing feature. The major differential
diagnosis includes either a deceptively bland primary adenocarcinoma, or secondary spread of adenoma
malignum of the uterine cervix. A primary carcinoma of the bladder can have a very low-grade appearance
with a small tubular pattern
, but a pattern resembling adenoma malignum, with its distinctive
array of irregular glands , would be extremely unusual. Secondary spread of adenoma malignum from
the uterine cervix can usually be excluded by the absence of a mass in the uterine cervix or by obtaining
a negative history in the patient who has had a previous hysterectomy. Usually adenoma malignum has
some areas of greater atypia than that found in endocervicosis . Most mucin-secreting
adenocarcinomas that involve the urinary bladder, such as primary adenocarcinoma of signet-ring cell or
intestinal type, urachal adenocarcinoma, or metastatic adenocarcinoma arising from the gastrointestinal
tract, female genital tract, or elsewhere, are overtly infiltrative and cytologically malignant with
significantly greater tissue destruction.
Fallopian Tube Prolapse
A case of fallopian tube prolapse into the base of the urinary bladder has been reported, producing a
polypoid mass that was clinically interpreted to be carcinoma . It occurred several months following
a hysterectomy that was complicated by a vesicovaginal fistula.
Ectopic Prostatic TissueDEVELOPMENTAL and RELATED ABNORMALITIES
Ectopic glandular tissue also occurs in men, in the form of polypoid prostatic tissue. It may be an
incidental finding or it may present with hematuria
. It usually is found in the trigone,
peri-ureteral orifice or interureteric ridge regions
. Immunostaining reveals prostatic-specific
antigen and prostatic acid phosphatase positivity in the glandular epithelium. Possibly such tissue is a
type of metaplasia within altered urothelial mucosa. The prostatic tissue is usually never as extensive
in its distribution as can occur with the various forms of mullerian lesions in the female bladder.
Although spread of prostatic adenocarcinoma to the bladder may be a consideration, such tumors are
usually overtly malignant, and often large, in contrast to the small and obviously bland appearance of
ectopic prostate tissue. Benign prostatic hyperplasia can occasionally produce massive intravesical
enlargement of the prostate .
Fibroepithelial polyps of the bladder are very rare lesions that can occur in adults or children and
may mimic either a carcinoma or sarcoma
. Cystoscopic and gross examination reveals a cluster of
"grape-like" excrescences. Microscopy reveals fronds with a fibrous core lined by benign urothelium that
is thrown into folds with irregular clefts of epithelium extending into the fibrous tissue . When
atypical mesenchymal cells are encountered in the fibrous core of the lesion, a diagnosis of sarcoma
botryoides may be suggested, particularly if the lesion is present in a child . When there is a
marked disorderly admixture of benign epithelial and stromal elements that are normally found in the
bladder, the designation of hamartoma is an appropriate one . Such bladder hamartomas have occurred
in children and have shown epithelial changes resembling von Brunn's nests, cystitis glandularis, and
cystitis cystica mixed with a stroma that varies from fibrous tissue to smooth muscle .
Cysts of the bladder may produce a mucosal elevation, possibly suggesting a neoplastic tumor. Cysts
of urothelial origin have been described in the trigone region . In men, mullerian duct cysts,
although usually found in the midline between the bladder and the rectum, have been found in the
posterior bladder wall . A cystic lesion in the dome of the bladder may be due to a cystically
dilated urachal remnant
. Urachal remnants are typically localized to the apex or anterior of
the dome, often situated within the muscularis propria, and usually lined by transitional cell epithelium
or occasionally by cuboidal cells, although they may be lined by columnar epithelium with mucous cells
. Large urachal cysts may be lined by flattened, atrophic epithelium . The urachal remnants
have an investment of fibromuscular tissue surrounding the epithelial lined structure. Both benign and
malignant epithelial and stromal elements may develop in a urachal remnant and the pathologist must
examine the lesion thoroughly to exclude these possibilities .
NORMAL ANATOMICAL STRUCTURES
Paraganglia are a normal structure of the urinary bladder that may be found in all regions of the
bladder wall . These structures may be misinterpreted if such a finding is unexpected. They can be
recognized by their characteristic nested groups of small cells with bland dark nuclei, moderately
abundant "dusky" amphophilic cytoplasm, sinusoidal fine vascular pattern, and lack of surrounding stromal
reaction . They are typically small and not usually mistaken for a paraganglioma, although this is a
consideration in the differential diagnosis. An oncocytic variant of paraganglioma in the urinary
bladder has been reported . When there is an appearance of a tumor, the differential diagnosis also
includes transitional cell carcinoma, particularly the nested variant, and possibly sarcoma and melanoma.
Appropriate clinicopathological correlation and investigations, including immunohistochemical studies,
may be needed.
Intramural ganglia are found in the dome and lateral walls of the bladder . Ganglion cells, with
their large polygonal shape, abundant amphophilic cytoplasm, and distinct prominent nucleolus are easily
recognized unless crushed or otherwise distorted in a small biopsy specimen.
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