Case 2 -
Atypical Urothelial Proliferation, Concerning for Nested Urothelial Carcinoma
Donna E. Hansel
The Cleveland Clinic
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Patient summary: The patient is a 72 year old male with a progressive history of
nocturia and urinary urgency. The patient has had no prior urinary tract history and no evidence of
gross or microscopic hematuria. His past medical history includes a diagnosis of benign prostatic
hyperplasia (BPH), which has been treated with Flomax. A prior prostate biopsy revealed only benign
glands and his current prostate specific antigen (PSA) is 1.62. The patient has been a long-time smoker,
with a 30 pack year history of cigarette use. A urinalysis performed at the urologist's office did not
reveal any abnormalities and a urine cytology was normal. A cystoscopy was performed, which revealed a
raised, reddened patch on the posterior wall of the bladder. No exophytic component was identified. The
remainder of the bladder, ureteral orifices, and urethra appeared unremarkable. A biopsy was performed,
which was superficial in nature and lacked muscularis propria.
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
pathology is presented in the accompanying powerpoint presentation. In brief, superficial portions of
bladder mucosa were available for analysis. In the majority of tissue fragments, a urothelial
proliferation was present in the lamina propria and was characterized by: 1) densely packed nests and
glandular structures, 2) mild nuclear atypia, with the majority of nuclei demonstrating open chromatin
and small nucleoli, 3) occasional cells with more abundant, eosinophilic cytoplasm – likely squamoid
differentiation - scattered throughout the lesion, 4) occasional dense eosinophilic secretions in von
Brunns-like structures, and 5) occasional vacuolization of the cytoplasm. The associated overlying
urothelium was not strikingly abnormal, but did contain similar large cells with abundant pink cytoplasm.
The differential diagnosis at this point includes a nested urothelial
carcinoma, as well as inverted papilloma, a florid proliferation of von Brunns nests and cystitis cystica
The final diagnosis in this case was "atypical urothelial proliferation, concerning
for nested urothelial carcinoma." Due to the lack of marked atypia and inability to survey the base of
the lesion, a definitive diagnosis of carcinoma cannot be definitely rendered. Although the p53
immunoreactivity is striking, a diagnosis should not be rendered solely on the basis of
Unfortunately, deeper levels of the lamina propria and the muscularis propria were
absent from the specimen, which would significantly aid in parsing the differential diagnosis. More
specifically, if the atypical proliferation extended deep into the lamina propria or the muscularis
propria, a diagnosis of nested urothelial carcinoma would be more likely. In contrast, if the lesion
were well-circumscribed and paralleled the urothelium, a benign diagnosis would be favored. In this
case, immunohistochemical stains for Ki67 and p53 were performed. Ki67 stains are non-specific, but are
typically increased in neoplastic proliferations. In this case, a mild increase in proliferation was
present. p53 nuclear immunoreactivity is a hallmark of p53 mutation and is frequent in urothelial
neoplasia. This lesion demonstrates an almost uniform, strong expression of nuclear p53 – a finding that
strongly favors a neoplastic process.
1. Florid proliferation of von Brunns
nests. von Brunn nests are invaginations of the surface urothelium into the underlying lamina propria and
may occur as a response to injury . von Brunn nests appear as smooth invaginations of the urothelium
located directly below – parallel to - the luminal surface. Occasionally, the presence of von Brunn
nests may be extensive, a condition termed florid proliferation of von Brunn nests. A marked
proliferation of von Brunns nests may appear as a submucosal nodule and are defined by urothelial nests
that closely approximate one another within the superficial lamina propria, but do extend into the deep
lamina propria or muscularis propria. The urothelial cells have minimal to no cytologic atypia, limited
to no mitotic activity, and generally contain open chromatin with occasional pinpoint nucleoli. Florid
proliferation of von Brunns nests is a benign diagnosis. The most common differential diagnosis
associated with a florid proliferation of von Brunn nests is nested urothelial carcinoma (below) .
Cystitis cystica et glandularis. Cystitis cystica and cystitis glandularis occur when von Brunns nests
undergo cystic dilation, with cystitis glandularis defined by glandular change of the urothelium
More specifically, in cystitis cystica, the urothelium is lined by an umbrella cell layer that may appear
reactive in nature, whereas the urothelium in cystitis glandularis may appear cuboidal or columnar in
nature. Cystitis cystica et glandularis is a benign condition and is often associated with proliferation
of von Brunns nests. Again, these lesions may appear as a submucosal nodule in the urothelium.
Microscopically, cystitis cystica et glandularis appears as rounded urothelial nests demonstrating cystic
dilation and present within the lamina propria, parallel to the urothelial surface. The cystically
dilated lumens often contain prominent eosinophilic secretions. Similar to florid proliferation of von
Brunns nests, the cells in cystitis cystica et glandularis maintain their polarity to the luminal surface
and have minimal to no atypia or mitotic activity.
3. Inverted papilloma. Inverted papillomas are well-
recognized entities that are defined by anastomosing cords of bland-appearing urothelial cells within the
lamina propria. Often, the cells show a prominent polarization to the exterior surface of the cords and
appear to demonstrate a "streaming" effect in the center of the urothelial cords. On rare occasions,
foamy or vacuolated cytoplasm may be present within the cells . Cystoscopically, these lesions appear as
submucosal nodules. Considered an indolent neoplasm, inverted papillomas typically lack mutations of the
p53 protein, making nuclear localization of this protein by immunohistochemistry unlikely . In addition,
Ki67 proliferation indices are minimal at most .
4. Nested urothelial carcinoma. Nested urothelial
carcinoma is an uncommon and diagnostically challenging variant of bladder cancer
Per its name, this
form of invasive carcinoma is defined by small, occasionally irregular, nests of bland urothelial cells.
The invasive nature of this entity is often only defined by the identification of nests infiltrating well
below the surface urothelium, often involving the muscularis propria. Atypia, if present, is often most
conspicuous in these deepest regions of the carcinoma. Nested urothelial carcinoma often pursues an
aggressive course and is likely due to the delay in diagnosis resulting from the bland morphology of this
entity. p53 immunoreactivity, however, is present in only approximately 25% of cases and is often not
diffusely present, making this case unusual
Limited biopsies often present significant challenges to the pathologist, especially
when a proliferative process is present. Systematic examination of the surface urothelium, organization
of the submucosal proliferation (nodular, infiltrative, confined immediately below the surface
urothelium), and careful review of the cytologic features is of primary importance. Although
immunohistochemical stains can provide some guidance, the final diagnosis ultimately rests on the H&E
features and comfort of the pathologist with the diagnosis.
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