Difference between revisions of "Urothelium"

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The '''urothelium''' lines the upper portion of the genitourinary tract... and a bit of the lower part.
The '''urothelium''' lines the upper portion of the genitourinary tract, i.e. [[ureter]]s, [[urinary bladder]]), and a bit of the lower part.


=Normal histology=
=Normal urothelium=
===Gross===
====Extent of urothelium====
*[[Ureters]].
*Renal pelvis.
*[[Urinary bladder]].
*Part of the urethra.
=====Urethra in males=====
{{Main|Urethra}}
*Pre-prostatic urethra - transitional epithelium.
*[[Prostate gland|Prostatic]] urethra - transitional epithelium.
**Cancer arising at this site is ''[[prostatic urothelial carcinoma]]''.
*Membranous urethra (from apex of prostate to bulb of penis (bulb of the corpus spongiosusm)) - pseudostratified columnar epithelium.
*Spongy urethra - pseudostratified columnar epithelium (proximal) & stratified squamous (distal).
 
===Microscopic===
Features:
*Maturation (cuboidal at base - squamoid at surface).
*Maturation (cuboidal at base - squamoid at surface).
**Surface cells called 'umbrella cells' (umbrella cells CK20+).
**Surface cells called 'umbrella cells' (umbrella cells CK20 +ve).
*Urothelium should be 4-5 cell layers thick.
*Urothelium should be 4-5 cell layers thick.
*+/-Prominent nucleoli.
*+/-Prominent [[nucleoli]].


*Should NOT have papillary architecture -- if it does it is likely [[cancer]]!
Note:
*Should '''not''' have a papillary architecture -- if it does it is likely [[cancer]]!
**If it is 'papillary' -- it must have fibrovascular cores.
**If it is 'papillary' -- it must have fibrovascular cores.


==Extent of urothelium==
===IHC===
*Ureters.
*Rare superficial [[CK20]] staining.
*Renal pelvis.
 
*Bladder.
====Image====
*Part of the urethra.
<gallery>
Image: Benign urothelium - CK20 -- high mag.jpg | Benign urothelium - CK20 - high mag. (WC)
===Urethra in males===
</gallery>
*Pre-prostatic urethra - transistional epithelium.
 
*Prostatic urethra - transistional epithelium.
===Sign out===
*Membranous urethra (from apex of prostate to bulb of penis (bulb of the corpus spongiosusm)) - pseudostrat. columnar epithelium.
<pre>
*Spony urethra - pseudostratified columnar epi. (proximal) & strat. squamous (distal).
URINARY BLADDER LESION, TRANSURETHRAL RESECTION:
- UROTHELIAL MUCOSA WITHIN NORMAL LIMITS.
- NEGATIVE FOR MALIGNANCY.
</pre>
 
====Micro====
The sections shows urothelium with underlying tissue.  The urothelium is 4-5 cells thick. Umbrella cells are present. Few mononuclear inflammatory cells are seen in the subepithelial tissue.
 
The urothelium has no nuclear hyperchromasia and no significant nuclear enlargement. Mitotic activity is not identified. No papillary structures are present.


=Approach=
=Approach=
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#* Normal is 4-5 cell layers.
#* Normal is 4-5 cell layers.
# Nests of glandular cells
# Nests of glandular cells
#* Consider ''cystitis cystica'', ''cystitis glandularis'', ''cystitis cystica et glandularis'', ''Brunn's nest'', ''inverted papilloma''.
#* Consider ''[[cystitis cystica]]'', ''[[cystitis glandularis]]'', ''cystitis cystica et glandularis'', ''[[von Brunn's nest]]'', ''[[inverted urothelial papilloma|inverted papilloma]]''.
# Inflammation?
# Inflammation?
#* Michaelis-Gutman bodies?
#* Michaelis-Gutman bodies?


Pitfalls:
Pitfalls:
*Urothelial carcinoma of the bladder may be confused with a ''paraganglioma of the bladder''.
*Urothelial carcinoma of the bladder may be confused with a ''[[paraganglioma]] of the bladder''.
**Way to differentiate: paraganglioma = ''stippled chromatin'', UCC = ''single nucleoli''.
**Way to differentiate: paraganglioma = ''stippled chromatin'', UCC = ''single nucleoli''.


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===Flat urothelial lesions===
===Flat urothelial lesions===
Comparison urothelial changes - flat epithelium - benign/premalignant/cancerous:<ref>{{Ref GUP|155-163}}</ref>
Comparison urothelial changes - flat epithelium - benign/premalignant/cancerous:<ref>{{Ref GUP|155-163}}</ref>
{| class="wikitable"
{| class="wikitable sortable"
| ||'''Normal'''||'''Reactive atypia'''||'''Flat urothelial hyperplasia'''||'''Urothelial dysplasia'''||'''UCC in situ'''||'''Invasive UCC'''
! Diagnosis
! Nuclear enlargement<br>(X stromal lymphocyte)
! Nucleoli
! size var., shape
! Polarity
! Mitoses
! Thickness
! Inflammation
! Other
|-
|-
|Nuclear enlargement<br>(X stromal lymphocyte) ||none (2x) ||moderate, prominent (3x) ||none (2x) ||moderate (3x) ||'''signif. (4-5x)'''|| signif. (4-5X)
| '''Normal'''
| none (2x)
| small
| none, round
| matures to surface
| none/minimal
| 4-5 cells
| none
| -
|-
|-
|Nucleoli ||small ||prominent ||small ||small, some multiple ||+/-large ||+/-large
|'''Reactive atypia'''
| moderate, prominent (3x)
| prominent  
| none, round
| as normal
| some, none atypical
| as normal
| '''severe, acute or chronic'''
| -
|-
|-
|size var., shape ||none, round ||none, round ||none, round ||mod. variation, some irregularity ||marked, irregular ||marked, irregular
| '''Flat urothelial hyperplasia'''
| none (2x)
| small
| none, round
| as normal
| as normal
| '''increased'''
| usu. none
| -
|-
|-
|Polarity ||matures to surface ||as normal ||as normal ||'''lost''' ||lost ||lost
| '''[[Urothelial dysplasia]]'''
| moderate (3x)
| small, some multiple
| mod. variation, some irregularity
| '''lost'''
| rare, none atypical
| as normal
| usu. none
| -
|-
|-
|Mitoses ||none/minimal ||some, none atypical ||as normal ||rare, none atypical ||common, atypical ||common, atypical
| '''[[Urothelial carcinoma in situ]]'''
| '''signif. (4-5x)'''
| +/-large
| marked, irregular
| lost
| common, atypical
| thin, thick or norm.
| +/-
| -
|-
|-
|Thickness ||4-5 cells ||as normal ||'''increased''' ||as normal ||thin, thick or norm. ||thin, thick or norm.
| '''[[Urothelial carcinoma|Invasive UCC]]'''
|-
| signif. (4-5X)
|Inflammation ||none ||'''severe, acute or chronic''' ||usu. none ||usu. none ||+/- ||+/-
| +/-large
|-
| marked, irregular
|Other ||- ||- ||- ||- ||- ||'''stromal invasion'''
| lost
| common, atypical
| thin, thick or norm.
| +/-
| '''stromal invasion'''
|-
|-
|}
|}
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===Papillary urothelial lesions===
===Papillary urothelial lesions===
Urothelial cells in papillae - benign/premalignant/cancerous:<ref>{{Ref GUP|166-175}}</ref><ref name=Ref_WMSP310>{{Ref WMSP|310}}</ref>
Urothelial cells in papillae - benign/premalignant/cancerous:<ref>{{Ref GUP|166-175}}</ref><ref name=Ref_WMSP310>{{Ref WMSP|310}}</ref>
{| class="wikitable"
{| class="wikitable sortable"
| ||'''Papilloma''' ||'''PUNLMP''' ||'''low grade PUCC''' ||'''high grade PUCC'''
! Diagnosis
! Papillae features
! Papillae branching
! Papillae fusion
! Nuclear size
! Mitoses
! DDx
! IHC
! Other
! Key feature
|-
| [[Urothelial papilloma|Papilloma]]
| '''fat papillae''', <br>'''thick FV core'''
| rare
| none
| normal (2x lymphocyte)
| very rare basal
| [[PUNLMP]], low gr. PUCC
| p53-, CK20+ umbrella cells
| cytologically normal
| normal cells,<br>fat papillae
|-
|-
|papillae features ||'''fat papillae''', <br>'''thick FV core''' ||'''slender FV core''' ||slender FV core, <br>'''thick epithelium''' ||mixed population
| [[PUNLMP]]
| '''slender FV core'''
| uncommon
| rare
| '''enlarged - uniform'''
| rare basal only
| papilloma, low gr.
| CK20+ umbrella
| low cellular density (@ low power) vs. low gr.<ref>GAG. 26 February 2009.</ref>
| uniformly enlarged cell pop., <br>slender papillae
|-
|-
|papillae branching ||rare ||uncommon ||frequent ||common
| [[Low grade papillary urothelial carcinoma|Low grade PUCC]]
| slender FV core, <br>'''thick epithelium'''
| frequent
| some
| '''enlarged with variation'''
| infreq., usually basal
| PUNLMP, high gr.
| -/+ p53, CK20+ umbrella
| +/- small nucleoli
| nuc. pleomorphism, <br> thick epithelium
|-
|-
|papillae fusion ||none ||rare ||some ||common
| [[High grade papillary urothelial carcinoma|High grade PUCC]]
|-
| mixed population
|nuclear size ||normal (2x lymphocyte) ||'''enlarged - uniform''' ||'''enlarged with variation''' ||'''4-5x lymphocyte,'''<br>'''marked pleomorphism'''
| common
|-
| common
|mitoses ||very rare basal || rare basal only ||infreq., usually basal ||common, everywhere
| '''4-5x lymphocyte,'''<br>'''marked pleomorphism'''
|-
| common, everywhere
|DDx ||PUNLMP, low gr. PUCC ||papilloma, low gr. ||PUNLMP, high gr. ||low gr., invasive UCC
| low gr., invasive UCC
|-
| '''diffuse CK20+''', p53+ in 50%
|IHC ||p53-, CK20+ umbrella cells ||CK20+ umbrella ||-/+ p53, CK20+ umbrella ||'''diffuse CK20+''', p53+ in 50%
| nucleoli prominent
|-
| marked nuclear pleomorphism
|Other ||cytologically normal ||low cellular density (@ low power) vs. low gr.<ref>GAG. 26 February 2009.</ref> ||+/- small nucleoli ||nucleoli prominent
|-
|Key feature ||normal cells,<br>fat papillae ||uniformly enlarged cell pop., <br>slender papillae ||nuc. pleomorphism, <br> thick epithelium ||marked nuclear pleomorphism
|-
|-
|}
|}
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*Toxins.
*Toxins.
*Drugs, e.g. cyclophosphamide.
*Drugs, e.g. cyclophosphamide.
*Marijuana.<ref name=pmid16413342>PMID 16413342.</ref>
*Marijuana.<ref name=pmid16413342>{{Cite journal  | last1 = Chacko | first1 = JA. | last2 = Heiner | first2 = JG. | last3 = Siu | first3 = W. | last4 = Macy | first4 = M. | last5 = Terris | first5 = MK. | title = Association between marijuana use and transitional cell carcinoma. | journal = Urology | volume = 67 | issue = 1 | pages = 100-4 | month = Jan | year = 2006 | doi = 10.1016/j.urology.2005.07.005 | PMID = 16413342 }}</ref>
*Chinese Herbs.<ref>URL: [http://content.nejm.org/cgi/content/full/343/17/1268 http://content.nejm.org/cgi/content/full/343/17/1268]. Accessed on: 27 May 2010.</ref>
*Chinese Herbs.<ref>URL: [http://content.nejm.org/cgi/content/full/343/17/1268 http://content.nejm.org/cgi/content/full/343/17/1268]. Accessed on: 27 May 2010.</ref>
Others:
*[[Lynch syndrome]].
**Should be considered in ureteral cancers.<ref name=pmid21419447>{{Cite journal  | last1 = Crockett | first1 = DG. | last2 = Wagner | first2 = DG. | last3 = Holmäng | first3 = S. | last4 = Johansson | first4 = SL. | last5 = Lynch | first5 = HT. | title = Upper urinary tract carcinoma in Lynch syndrome cases. | journal = J Urol | volume = 185 | issue = 5 | pages = 1627-30 | month = May | year = 2011 | doi = 10.1016/j.juro.2010.12.102 | PMID = 21419447 }}</ref>


=Flat urothelial lesions=
=Flat urothelial lesions=
==Overview==
==Overview==
Several different benign & pre-malignant diagnoses can be made:
Several different benign & pre-malignant diagnoses can be made.
*Reactive atypia.
 
The World Health Organization classification is:<ref name=pmid19762067>{{Cite journal  | last1 = Hodges | first1 = KB. | last2 = Lopez-Beltran | first2 = A. | last3 = Davidson | first3 = DD. | last4 = Montironi | first4 = R. | last5 = Cheng | first5 = L. | title = Urothelial dysplasia and other flat lesions of the urinary bladder: clinicopathologic and molecular features. | journal = Hum Pathol | volume = 41 | issue = 2 | pages = 155-62 | month = Feb | year = 2010 | doi = 10.1016/j.humpath.2009.07.002 | PMID = 19762067 }}</ref>
*Reactive urothelial atypia.
*Flat urothelial hyperplasia.
*Flat urothelial hyperplasia.
*Urothelial dysplasia.
*Urothelial atypia of unknown significance.
*Urothelial carcinoma in situ.
*[[Urothelial dysplasia]] (low-grade dysplasia).
*Urothelial carcinoma in situ (high-grade dysplasia).
*Invasive urothelial carcinoma.
*Invasive urothelial carcinoma.


==Urothelial carcinoma in situ==
==Mild urothelial atypia in normal urothelium==
===General===
===General===
*Lack papillae.
*May be confused with [[urothelial carcinoma in situ]].<ref name=Ref_Amin2-57>{{Ref Amin|2-57}}</ref>
*Uncommon.
*Considered to be [[normal urothelium]].


===Microscopic===
===Microscopic===
Features:
Features:<ref name=Ref_Amin2-57>{{Ref Amin|2-57}}</ref>
*Nuclear changes '''key feature'''.
*Umbrella cells have:
**Enlargement of nuclei (often 4-5x the size of stromal lymphocytes) -- diagnostic.<ref name=Ref_GUP161>{{Ref GUP|161}}</ref>
**Mild nuclear enlargement ~3-4x lymphocyte.
***Normal urothelium approx. 2x the size of stromal lymphocytes.
**Round/regular nuclear membranes.
**Nuclear pleomorphism - marked variation in size of nuclei.
**+/-Multi-nucleation.
*Disordered arrangement/crowding of cells.
**Focally clear cytoplasm with cobwebs.
**In normal urothelium the cell line-up on the basement membrane.
***Clear cytoplasm with eosinophilic reticulations.
*Umbrella cells often absent.
*+/-Inflammation.
*Mitoses present.
*No mitotic activity.
*+/-Enlarged nucleoli.


==Urothelial cell carcinoma==
DDx:<ref>URL: [http://pathology.jhu.edu/bladder/definitions.cfm http://pathology.jhu.edu/bladder/definitions.cfm]. Accessed on: 8 January 2014.</ref>
*Abbreviated ''UCC''.
*[[Urothelial carcinoma in situ]].
===General===
*[[Urothelial dysplasia]].
*These lesions lack papillae and are typical flat.
*Clinically, it may not be possible to differentiate renal pelvis urothelial carcinoma and [[renal cell carcinoma]].  


===Microscopic===
====Images====
Features:
<gallery>
*Nuclear pleomorphism - '''key feature'''.
Image: Benign urothelium with large superficial cells -- intermed mag.jpg | Benign large superf. cells - intermed. mag. (WC)
**Compare nuclei to one another.
Image: Benign urothelium with large superficial cells -- high mag.jpg | Benign large superf. cells - high mag. (WC)
*Increased N/C ratio.
Image: Benign urothelium with large superficial cells -- very high mag.jpg | Benign large superf. cells - very high mag. (WC)
*Lack of maturation to surface (important).
</gallery>


*Cells become dyscohesive.
===IHC===
**Mostly useless in my experience.
*Ki-67 low.
*p53 -ve.


Invasion vs. in situ:
===Sign out===
Useful features - present in invasion:<ref>Sternberg, H4P, P.2047.</ref>
<pre>
*Thin-walled vessels.
URINARY BLADDER, TRANSURETHRAL BIOPSY:
*Stromal reaction (hypercellularity).
- UROTHELIAL MUCOSA WITH MILD CHRONIC INFLAMMATION.
*Retraction artefact around the tumour cell nests.
- NO EVIDENCE OF MALIGNANCY.


====Staging====
COMMENT:
*T1 - lamina propria.
Levels were cut and show large benign umbrella cells.
**Several subdivisions of T1 exist:<ref>Sternberg, H4P 4th Ed., P.2048-9.</ref>
</pre>
***T1a - superficial or in muscularis mucosae.
***T1b - beyond muscularis mucosae - into submucosa.
*T2 - muscularis propria.


====Subtypes====
====Micro====
There are numerous subtypes:<ref>URL: [http://www.nature.com/modpathol/journal/v22/n2s/full/modpathol200926a.html http://www.nature.com/modpathol/journal/v22/n2s/full/modpathol200926a.html]. Accessed on: 19 August 2011.</ref>
The sections show small fragments of urothelial mucosa with enlarged benign superficial epithelial cells. The lamina propria has a mild lymphocytic infiltrate. No papillary structures are identified. There is no significant nuclear atypia. Superficial small blood vessels appear congested.
*Squamous differentiation.
*Clear cell.
*Plasmacytoid.
**Abundant gray cytoplasm, eccentric nucleus.
*Micropapillary.
**Small nests (< ~10 cells/nest).
*Many others...


===[[IHC]]===
==Urothelial dysplasia==
Features:
*[[AKA]] ''low-grade (urothelial) dysplasia''.
*CK7 +ve CK20 +ve.
{{Main|Urothelial dysplasia}}
**CK20 may be negative.


UCC vs. Prostate:
==Urothelial carcinoma in situ==
*UCC: p63+, PSA-, PSAP-, CK7+, CK20+.
*Abbreviated ''CIS''.
*Prostate: p63-, PSA+, PSAP+, CK7-, CK20-.
*[[AKA]] ''high-grade (urothelial) dysplasia''.
{{Main|Urothelial carcinoma in situ}}


UCC vs. RCC:
==Urothelial cell carcinoma==
*UCC: p63+.<ref>{{Cite journal  | last1 = Langner | first1 = C. | last2 = Ratschek | first2 = M. | last3 = Tsybrovskyy | first3 = O. | last4 = Schips | first4 = L. | last5 = Zigeuner | first5 = R. | title = P63 immunoreactivity distinguishes upper urinary tract transitional-cell carcinoma and renal-cell carcinoma even in poorly differentiated tumors. | journal = J Histochem Cytochem | volume = 51 | issue = 8 | pages = 1097-9 | month = Aug | year = 2003 | doi =  | PMID = 12871991 }}
:See ''[[Urine_cytopathology#Urothelial_cell_carcinoma|urine cytology]]'' for the [[cytopathology]].
</ref>
*Abbreviated ''UCC''.
*[[AKA]] ''urothelial carcinoma''.
{{Main|Urothelial carcinoma}}


=Papillary urothelial lesions=
=Papillary urothelial lesions=
Line 222: Line 334:


==Urothelial papilloma==
==Urothelial papilloma==
===General===
{{Main|Urothelial papilloma}}
*Very rare diagnosed.
**If the person has a history of a low grade papillary urothelial carcinoma... it is a low grade papillary urothelial carcinoma.
**These cases are a consensus diagnosis, i.e. you show it to a colleague... if they agree you can call it.
 
===Microscopic===
Features:<ref name=Ref_WMSP310>{{Ref WMSP|310}}</ref>
*Papillary fronds.
*Minimal branching or fusion.
*Cytological features of normal urothelium.
**Normal urothelium approx. 2x the size of stromal lymphocytes.<ref name=Ref_GUP161>{{Ref GUP|161}}</ref>
*No mitoses.


==Inverted urothelial papilloma==
==Inverted urothelial papilloma==
*[[AKA]] ''[[inverted papilloma]]''.
*[[AKA]] ''[[inverted papilloma]]''.
{{Main|Inverted urothelial papilloma}}
==Papillary urothelial neoplasm of low malignant potential==
*Abbreviated ''PUNLMP''.
**This is pronounced ''pun-lump''.
{{Main|Papillary urothelial neoplasm of low malignant potential}}
==Low-grade papillary urothelial carcinoma==
*Abbreviated ''LGPUC''.<ref name=pmid22857755>{{Cite journal  | last1 = Watts | first1 = KE. | last2 = Montironi | first2 = R. | last3 = Mazzucchelli | first3 = R. | last4 = van der Kwast | first4 = T. | last5 = Osunkoya | first5 = AO. | last6 = Stephenson | first6 = AJ. | last7 = Hansel | first7 = DE. | title = Clinicopathologic characteristics of 23 cases of invasive low-grade papillary urothelial carcinoma. | journal = Urology | volume = 80 | issue = 2 | pages = 361-6 | month = Aug | year = 2012 | doi = 10.1016/j.urology.2012.04.010 | PMID = 22857755 }}</ref>
*[[AKA]] ''low-grade papillary urothelial cell carcinoma''.
{{Main|Low-grade papillary urothelial carcinoma}}
==High-grade papillary urothelial carcinoma==
*Abbreviated ''HGPUC''.
*[[AKA]] ''high-grade papillary urothelial cell carcinoma'', abbreviated ''HGPUCC''.
{{Main|High-grade papillary urothelial carcinoma}}
==Papillary urothelial hyperplasia==
*[[AKA]] ''papillary hyperplasia''.
*[[AKA]] ''reactive papillary hyperplasia''.
{{Main|Papillary urothelial hyperplasia}}


===General===
=Benign urothelial lesions=
*May be confused with papillary urothelial carcinoma with an inverted growth pattern.
===Cystitis===
*Inflammation of the [[urinary bladder]]. 
*Comes in many forms (see below).
*Typically a [[clinical diagnosis]] under the more general term [[urinary tract infection]].
 
Note:
*So called "[[giant cell cystitis]]" is dealt with separately; it is a benign non-pathologic change that may or may not be associated with inflammation.<ref name=Ref_Amin2_6>{{Ref Amin|2:6}}</ref>
 
===The big table of cystitis===
{| class="wikitable sortable"
! Type
! Key feature
! DDx
! Reference
|-
|Florid proliferative cystitis
| expanded lamina propria with [[von Brunn's nests]], [[cystitis cystica et glandularis]]
| [[von Brunn's nests]], [[cystitis cystica et glandularis]], low-grade urothelial carcinoma
| <ref name=Ref_GUP113>{{Ref GUP|113}}</ref>
|-
|[[Polypoid cystitis]]
| wide base, height > base
| papillary cystitis, bullous cystitis
| <ref name=Ref_GUP120>{{Ref GUP|120}}</ref>
|-
|Bullous cystitis
| wide base, height < base
| papillary cystitis, polypoid cystitis
| <ref name=Ref_GUP120>{{Ref GUP|120}}</ref>
|-
|Papillary cystitis
| narrow base, height > base
| polypoid cystitis, bullous cystitis
| <ref name=Ref_GUP120>{{Ref GUP|120}}</ref>
|-
|[[Interstitial cystitis]]
| +/-ulceration (uncommon) - requires clinical correlation
| urothelial CIS
| <ref name=Ref_GUP124>{{Ref GUP|124}}</ref>
|-
|Follicular cystitis
| lymphoid follicles
| non-Hodgkin [[lymphoma]]
| <ref name=Ref_GUP122>{{Ref GUP|122}}</ref>
|-
|Infectious cystitis
| dependent cause (bacterial, viral, fungal)
|
| <ref name=Ref_GUP127>{{Ref GUP|127}}</ref>
|-
|Granulomatous cystitis
| [[granuloma]]s
| [[tuberculosis]], [[schistosomiasis]], [[fungi|fungal infection]], post-BCG
| <ref name=Ref_GUP127>{{Ref GUP|127}}</ref>
|-
|Radiation cystitis
| edema, vascular congestion, +/- [[erosion]]s -- acute; fibrosis in LP and detrusor -- chronic
|
| <ref name=Ref_GUP138>{{Ref GUP|138}}</ref>
|}
 
==Interstitial cystitis==
{{Main|Interstitial cystitis}}


==Follicular cystitis==
===Microscopic===
===Microscopic===
Features:
Features:<ref name=Ref_GUP122>{{Ref GUP|122}}</ref>
*Like papillomas... but grow downward.<ref name=Ref_WMSP310>{{Ref WMSP|310}}</ref>
*Lymphoid follicles in the lamina propria.
*According to THvdK,<ref>THvdK. 21 June 2010.</ref> ''inverted papillomas'' '''never''' have an exophytic component; if an exophytic component is present it is urothelial carcinoma.  This is disputed by one paper from Mexico that examines two cases.<ref name=pmid19433293>{{cite journal |author=Albores-Saavedra J, Chable-Montero F, Hernández-Rodríguez OX, Montante-Montes de Oca D, Angeles-Angeles A |title=Inverted urothelial papilloma of the urinary bladder with focal papillary pattern: a previously undescribed feature |journal=Ann Diagn Pathol |volume=13 |issue=3 |pages=158–61 |year=2009 |month=June |pmid=19433293 |doi=10.1016/j.anndiagpath.2009.02.009 |url=}}</ref>


Images:
DDx:
*[http://commons.wikimedia.org/wiki/File:Inverted_papilloma_high_mag.jpg Inverted papilloma - high mag. (WC)].
*Non-Hodgkin [[lymphoma]].
*[http://commons.wikimedia.org/wiki/File:Inverted_papilloma_intermed_mag.jpg Inverted papilloma - intermed. mag. (WC)].


==Papillary urothelial neoplasm of low malignant potential==
===Sign out===
*Abbreviated ''PUNLMP''.
<pre>
URINARY BLADDER, BIOPSY:
- UROTHELIAL MUCOSA WITH CHRONIC INFLAMMATION AND BENIGN LYMPHOID NODULES WITH GERMINAL CENTRE FORMATION.
- MUSCULARIS PROPRIA PRESENT.
- NEGATIVE FOR UROTHELIAL CARCINOMA IN SITU AND NEGATIVE FOR MALIGNANCY.
</pre>


==Polypoid cystitis==
===General===
===General===
*Uncommon: prevalence ~ 0-3.5%.<ref name=pmid19346063>{{cite journal |author=May M, Brookman-Amissah S, Roigas J, ''et al.'' |title=Prognostic Accuracy of Individual Uropathologists in Noninvasive Urinary Bladder Carcinoma: A Multicentre Study Comparing the 1973 and 2004 World Health Organisation Classifications |journal=Eur. Urol. |volume= 57|issue= 5|pages= 850|year=2009 |month=March |pmid=19346063 |doi=10.1016/j.eururo.2009.03.052 |url=}}</ref>
*Uncommon.
*PUNLMP vs. [[low grade papillary urothelial carcinoma]] has a poor inter-rater reliability.<ref name=pmid17095142>{{cite journal |author=MacLennan GT, Kirkali Z, Cheng L |title=Histologic grading of noninvasive papillary urothelial neoplasms |journal=Eur. Urol. |volume=51 |issue=4 |pages=889–97; discussion 897–8 |year=2007 |month=April |pmid=17095142 |doi=10.1016/j.eururo.2006.10.037 |url=}}</ref>
*Wide age range.
*Benign.


Treatment:
===Microscopic===
*Excision and on-going follow-up - like non-invasive [[low grade papillary urothelial carcinoma]].<ref name=pmid16697785>{{cite journal |author=Jones TD, Cheng L |title=Papillary urothelial neoplasm of low malignant potential: evolving terminology and concepts |journal=J. Urol. |volume=175 |issue=6 |pages=1995–2003 |year=2006 |month=June |pmid=16697785 |doi=10.1016/S0022-5347(06)00267-9 |url=}}</ref>
Features:<ref name=Ref_GUP120>{{Ref GUP|120}}</ref>
*Polypoid urothelium-covered projections with:
*#Broad bases.
*#Height > base.
*#Extensive edema.


===Microscopic===
DDx:
Features:<ref name=Ref_WMSP310>{{Ref WMSP|310}}</ref>
*Papillary cystitis - not a broad base.
*Rare fused papillae.
*Bullous cystitis.
*Infrequent mitoses.
*Nuclei larger than papilloma - but monotonous.<ref name=Ref_GUP170>{{Ref GUP|170}}</ref>


Images:
Image:
*[http://en.wikipedia.org/wiki/File:Punlmp1.jpg PUNLMP - low mag. (WC)].
*[http://www.webpathology.com/image.asp?case=51&n=3 Polypoid cystitis (webpathology.com)].
*[http://en.wikipedia.org/wiki/File:Punlmp2.jpg PUNLMP - high mag. (WC)].


==Low grade papillary urothelial carcinoma==
==von Brunn nests==
*[[AKA]] ''low grade urothelial cell carcinoma''.
===General===
**Abbreviated ''low grade UCC''.
*Benign.


===Microscopic===
===Microscopic===
Features:<ref name=Ref_WMSP310>{{Ref WMSP|310}}</ref>
Features:<ref name=Ref_PBoD1028>{{Ref PBoD|1028}}</ref>
*Fused papillae.
*Nests of (benign) urothelium budding into the lamina propria.
*Papillae branch.
*Larger nuclei than PUNLMPs.


==High grade papillary urothelial carcinoma==
Note:
*[[AKA]] ''high grade urothelial cell carcinoma''.
*Nests should '''not''' extend into the muscularis propria.
**Abbreviated ''high grade UCC''.


===Microscopic===
DDx:
Features:<ref name=Ref_WMSP310>{{Ref WMSP|310}}</ref>
*[[Nested urothelial cell carcinoma]].<ref name=pmid12960809>{{Cite journal  | last1 = Volmar | first1 = KE. | last2 = Chan | first2 = TY. | last3 = De Marzo | first3 = AM. | last4 = Epstein | first4 = JI. | title = Florid von Brunn nests mimicking urothelial carcinoma: a morphologic and immunohistochemical comparison to the nested variant of urothelial carcinoma. | journal = Am J Surg Pathol | volume = 27 | issue = 9 | pages = 1243-52 | month = Sep | year = 2003 | doi = | PMID = 12960809 }}</ref>
*"High grade nuclear features":
*[[Inverted urothelial papilloma|Inverted papilloma]].
**Nuclear pleomorphism - often 4-5x the size of stromal lymphocytes.<ref name=Ref_GUP161>{{Ref GUP|161}}</ref>
*[[Cystitis cystica]] - have lumens, may be focal.
*Architectural complexity.
**Fused papillary common.
**Papillae branch.
*Mitoses common.


=Benign urothelial lesions=
===IHC===
==Brunn nests==
Features:<ref name=pmid12960809/>
Microscopic:<ref name=Ref_PBoD1028>{{Ref PBoD|1028}}</ref>
*p53 -ve.
*Benign inbudding nests of urothelium.
*MIB-1 <3%.
**Should lead to consideration of "inverted papilloma".


==Cystitis cystica==
==Cystitis cystica==
Microscopic:<ref name=Ref_PBoD1028>{{Ref PBoD|1028}}</ref>
{{Main|Cystitis cystica}}
*Brunn nests with urothelium.


==Cystitis glandularis==
==Cystitis glandularis==
Microscopic:<ref name=Ref_PBoD1028>{{Ref PBoD|1028}}</ref>
{{Main|Cystitis glandularis}}
*Brunn nests with cuboidal and columnar epithelium.


==Malakoplakia==
==Malakoplakia==
{{Main|Malakoplakia}}
{{Main|Malakoplakia}}


==Nephrogenic metaplasia==
==Nephrogenic adenoma==
*[[AKA]] ''mesonephric adenoma'',<ref name=pmid21716880>{{Cite journal  | last1 = Singh | first1 = KJ. | title = Mesonephric adenoma in remnant ureteric stump: A rare entity. | journal = Indian J Urol | volume = 27 | issue = 1 | pages = 140-1 | month = Jan | year = 2011 | doi = 10.4103/0970-1591.78414 | PMID = 21716880 }}</ref> [[AKA]] ''nephrogenic adenoma''.
*[[AKA]] ''mesonephric adenoma''.
 
*[[AKA]] ''nephrogenic metaplasia''.
===General===
{{Main|Nephrogenic adenoma}}
Features:<ref name=pmid12118115>{{Cite journal  | last1 = Gokaslan | first1 = ST. | last2 = Krueger | first2 = JE. | last3 = Albores-Saavedra | first3 = J. | title = Symptomatic nephrogenic metaplasia of ureter: a morphologic and immunohistochemical study of four cases. | journal = Mod Pathol | volume = 15 | issue = 7 | pages = 765-70 | month = Jul | year = 2002 | doi = 10.1097/01.MP.0000019578.51568.24 | PMID = 12118115 | url = http://www.nature.com/modpathol/journal/v15/n7/full/3880603a.html }}</ref>
*Benign.
*Classic location is the [[urinary bladder]].
**Also reported in ureter and prostatic urethra.
*May mimic adenocarcinoma
 
===Microscopic===
Features:<ref name=pmid12118115>{{Cite journal  | last1 = Gokaslan | first1 = ST. | last2 = Krueger | first2 = JE. | last3 = Albores-Saavedra | first3 = J. | title = Symptomatic nephrogenic metaplasia of ureter: a morphologic and immunohistochemical study of four cases. | journal = Mod Pathol | volume = 15 | issue = 7 | pages = 765-70 | month = Jul | year = 2002 | doi = 10.1097/01.MP.0000019578.51568.24 | PMID = 12118115 | url = http://www.nature.com/modpathol/journal/v15/n7/full/3880603a.html }}</ref>
*Tubular structures - '''key feature'''.
**Hobnailed cells.
**+/-Thick eosinophilic basement membrane.
**Microcystic appearance.
*Usu. assoc. with chronic inflammation.
 
Notes:
*May mimic vascular/lymphatic channels - can be sorted-out with IHC.
 
Images:
*[http://www.archivesofpathology.org/action/showFullPopup?id=i1543-2165-134-10-1455-f01&doi=10.1043%2F2010-0226-CR.1 NA (archivesofpathology.org)].<ref name=pmid20923300>{{Cite journal  | last1 = Kunju | first1 = LP. | title = Nephrogenic adenoma: report of a case and review of morphologic mimics. | journal = Arch Pathol Lab Med | volume = 134 | issue = 10 | pages = 1455-9 | month = Oct | year = 2010 | doi = 10.1043/2010-0226-CR.1 | PMID = 20923300 }}</ref>


=See also=
=See also=
Line 342: Line 504:
{{reflist|2}}
{{reflist|2}}


[[Category:Uropathology]]
[[Category:Genitourinary pathology]]

Latest revision as of 21:35, 2 November 2016

The urothelium lines the upper portion of the genitourinary tract, i.e. ureters, urinary bladder), and a bit of the lower part.

Normal urothelium

Gross

Extent of urothelium

Urethra in males
Main article: Urethra
  • Pre-prostatic urethra - transitional epithelium.
  • Prostatic urethra - transitional epithelium.
  • Membranous urethra (from apex of prostate to bulb of penis (bulb of the corpus spongiosusm)) - pseudostratified columnar epithelium.
  • Spongy urethra - pseudostratified columnar epithelium (proximal) & stratified squamous (distal).

Microscopic

Features:

  • Maturation (cuboidal at base - squamoid at surface).
    • Surface cells called 'umbrella cells' (umbrella cells CK20 +ve).
  • Urothelium should be 4-5 cell layers thick.
  • +/-Prominent nucleoli.

Note:

  • Should not have a papillary architecture -- if it does it is likely cancer!
    • If it is 'papillary' -- it must have fibrovascular cores.

IHC

  • Rare superficial CK20 staining.

Image

  • Benign urothelium - CK20 - high mag. (WC)

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URINARY BLADDER LESION, TRANSURETHRAL RESECTION:
- UROTHELIAL MUCOSA WITHIN NORMAL LIMITS.
- NEGATIVE FOR MALIGNANCY.

Micro

The sections shows urothelium with underlying tissue. The urothelium is 4-5 cells thick. Umbrella cells are present. Few mononuclear inflammatory cells are seen in the subepithelial tissue.

The urothelium has no nuclear hyperchromasia and no significant nuclear enlargement. Mitotic activity is not identified. No papillary structures are present.

Approach

Where to start

July 1st PGY-2:

  1. Urothelial carcinoma - essentially defined by increased nuclear size +/- irreg. nuclear contour.
    • Nucleoli are common in urothelium.
      • This can be confusing... prostate carcinoma has nucleoli.
    • Mitosis - these are key if the nuclear enlargement is not present.[1]
    • Cell-depleted urothelium, where the cells have shed-off--but a few remain, should raise suspicions to cancer.
      • Thickness of the urothelium, otherwise, isn't very useful for diagnosing cancer.
  2. Round structures should make you think of papillae and prompt looking for fibrovascular cores.
  3. Fibrovascular cores = papillae... may be cancer!

A checklist-like approach

  1. Papillary structure - with fibrovascular cores?
    • Nuclear pleomorphism?
      • Yes - high grade (4-5x lymphocyte) --> Dx: high grade papillary urothelial carcinoma
      • No - low grade or normal (2-3x lymphocyte) --> DDx: low grade papillary urothelial carcinoma, PUNLMP, papilloma
  2. Flat lesions?
    • Nuclear pleomorphism?
  3. Maturation to surface?
    • No --> Dx: sectioning artefact vs. flat UCC.
    • Yes --> likely benign.
  4. Normal thickness?
    • Normal is 4-5 cell layers.
  5. Nests of glandular cells
  6. Inflammation?
    • Michaelis-Gutman bodies?

Pitfalls:

  • Urothelial carcinoma of the bladder may be confused with a paraganglioma of the bladder.
    • Way to differentiate: paraganglioma = stippled chromatin, UCC = single nucleoli.

Note about terminology

  • The bladder is rather unique in that "carcinoma" is a label used for things that are non-invasive.
    • It has been suggested that many things that are called papillary urothelial carcinoma, would be better described as papillary intraurothelial neoplasia.[2]
    • If the terminology in the urinary bladder were applied to the colon, we'd call all adenomas, i.e. pre-malignant lesions, carcinomas.

Overview in tables

General categorization

Urothelial lesions can broadly be divided into:

  1. Flat lesions.
    • Lack papillae.
    • Tend to be more aggressive.
  2. Papillary lesions.
    • Must have true papillae.
    • Very common.
    • More often benign/indolent.

Flat urothelial lesions

Comparison urothelial changes - flat epithelium - benign/premalignant/cancerous:[3]

Diagnosis Nuclear enlargement
(X stromal lymphocyte) 		Nucleoli size var., shape Polarity Mitoses Thickness Inflammation Other
Normal none (2x) small none, round matures to surface none/minimal 4-5 cells none -
Reactive atypia moderate, prominent (3x) prominent none, round as normal some, none atypical as normal severe, acute or chronic -
Flat urothelial hyperplasia none (2x) small none, round as normal as normal increased usu. none -
Urothelial dysplasia moderate (3x) small, some multiple mod. variation, some irregularity lost rare, none atypical as normal usu. none -
Urothelial carcinoma in situ signif. (4-5x) +/-large marked, irregular lost common, atypical thin, thick or norm. +/- -
Invasive UCC signif. (4-5X) +/-large marked, irregular lost common, atypical thin, thick or norm. +/- stromal invasion

The bold entry is considered the key feature.

Papillary urothelial lesions

Urothelial cells in papillae - benign/premalignant/cancerous:[4][5]

Diagnosis Papillae features Papillae branching Papillae fusion Nuclear size Mitoses DDx IHC Other Key feature
Papilloma fat papillae,
thick FV core 		rare none normal (2x lymphocyte) very rare basal PUNLMP, low gr. PUCC p53-, CK20+ umbrella cells cytologically normal normal cells,
fat papillae
PUNLMP slender FV core uncommon rare enlarged - uniform rare basal only papilloma, low gr. CK20+ umbrella low cellular density (@ low power) vs. low gr.[6] uniformly enlarged cell pop.,
slender papillae
Low grade PUCC slender FV core,
thick epithelium 		frequent some enlarged with variation infreq., usually basal PUNLMP, high gr. -/+ p53, CK20+ umbrella +/- small nucleoli nuc. pleomorphism,
thick epithelium
High grade PUCC mixed population common common 4-5x lymphocyte,
marked pleomorphism 		common, everywhere low gr., invasive UCC diffuse CK20+, p53+ in 50% nucleoli prominent marked nuclear pleomorphism

Notes:

  • FV core = fibrovascular core.
  • PUCC = papillary urothelial carcinoma.

Risk factors for urothelial carcinoma

  • Smoking.
  • Toxins.
  • Drugs, e.g. cyclophosphamide.
  • Marijuana.[7]
  • Chinese Herbs.[8]

Others:

Flat urothelial lesions

Overview

Several different benign & pre-malignant diagnoses can be made.

The World Health Organization classification is:[10]

  • Reactive urothelial atypia.
  • Flat urothelial hyperplasia.
  • Urothelial atypia of unknown significance.
  • Urothelial dysplasia (low-grade dysplasia).
  • Urothelial carcinoma in situ (high-grade dysplasia).
  • Invasive urothelial carcinoma.

Mild urothelial atypia in normal urothelium

General

Microscopic

Features:[11]

  • Umbrella cells have:
    • Mild nuclear enlargement ~3-4x lymphocyte.
    • Round/regular nuclear membranes.
    • +/-Multi-nucleation.
    • Focally clear cytoplasm with cobwebs.
      • Clear cytoplasm with eosinophilic reticulations.
  • +/-Inflammation.
  • No mitotic activity.

DDx:[12]

Images

  • Benign large superf. cells - intermed. mag. (WC)

  • Benign large superf. cells - high mag. (WC)

  • Benign large superf. cells - very high mag. (WC)

IHC

  • Ki-67 low.
  • p53 -ve.

Sign out

URINARY BLADDER, TRANSURETHRAL BIOPSY:
- UROTHELIAL MUCOSA WITH MILD CHRONIC INFLAMMATION.
- NO EVIDENCE OF MALIGNANCY.

COMMENT:
Levels were cut and show large benign umbrella cells.

Micro

The sections show small fragments of urothelial mucosa with enlarged benign superficial epithelial cells. The lamina propria has a mild lymphocytic infiltrate. No papillary structures are identified. There is no significant nuclear atypia. Superficial small blood vessels appear congested.

Urothelial dysplasia

  • AKA low-grade (urothelial) dysplasia.
Main article: Urothelial dysplasia

Urothelial carcinoma in situ

  • Abbreviated CIS.
  • AKA high-grade (urothelial) dysplasia.
Main article: Urothelial carcinoma in situ

Urothelial cell carcinoma

See urine cytology for the cytopathology.
  • Abbreviated UCC.
  • AKA urothelial carcinoma.
Main article: Urothelial carcinoma

Papillary urothelial lesions

Papillary urothelial lesions are grouped into one of five categories (listed from good to bad prognosis):[5]

  1. Urothelial papilloma.
  2. Inverted papilloma.
  3. Papillary urothelial neoplasm of low malignant potential (PUNLMP).
    • PUNLMP is pronouced "pun-lump".
  4. Low grade papillary urothelial carcinoma.
  5. High grade papillary urothelial carcinoma.

Key characteristics:

  1. Nuclear - size/pleomorphism.
  2. Papillae branching.
  3. Papillae fusion.

Urothelial papilloma

Main article: Urothelial papilloma

Inverted urothelial papilloma

Main article: Inverted urothelial papilloma

Papillary urothelial neoplasm of low malignant potential

  • Abbreviated PUNLMP.
    • This is pronounced pun-lump.
Main article: Papillary urothelial neoplasm of low malignant potential

Low-grade papillary urothelial carcinoma

  • Abbreviated LGPUC.[13]
  • AKA low-grade papillary urothelial cell carcinoma.
Main article: Low-grade papillary urothelial carcinoma

High-grade papillary urothelial carcinoma

  • Abbreviated HGPUC.
  • AKA high-grade papillary urothelial cell carcinoma, abbreviated HGPUCC.
Main article: High-grade papillary urothelial carcinoma

Papillary urothelial hyperplasia

  • AKA papillary hyperplasia.
  • AKA reactive papillary hyperplasia.
Main article: Papillary urothelial hyperplasia

Benign urothelial lesions

Cystitis

Note:

  • So called "giant cell cystitis" is dealt with separately; it is a benign non-pathologic change that may or may not be associated with inflammation.[14]

The big table of cystitis

Type Key feature DDx Reference
Florid proliferative cystitis expanded lamina propria with von Brunn's nests, cystitis cystica et glandularis von Brunn's nests, cystitis cystica et glandularis, low-grade urothelial carcinoma [15]
Polypoid cystitis wide base, height > base papillary cystitis, bullous cystitis [16]
Bullous cystitis wide base, height < base papillary cystitis, polypoid cystitis [16]
Papillary cystitis narrow base, height > base polypoid cystitis, bullous cystitis [16]
Interstitial cystitis +/-ulceration (uncommon) - requires clinical correlation urothelial CIS [17]
Follicular cystitis lymphoid follicles non-Hodgkin lymphoma [18]
Infectious cystitis dependent cause (bacterial, viral, fungal) [19]
Granulomatous cystitis granulomas tuberculosis, schistosomiasis, fungal infection, post-BCG [19]
Radiation cystitis edema, vascular congestion, +/- erosions -- acute; fibrosis in LP and detrusor -- chronic [20]

Interstitial cystitis

Main article: Interstitial cystitis

Follicular cystitis

Microscopic

Features:[18]

  • Lymphoid follicles in the lamina propria.

DDx:

Sign out

URINARY BLADDER, BIOPSY:
- UROTHELIAL MUCOSA WITH CHRONIC INFLAMMATION AND BENIGN LYMPHOID NODULES WITH GERMINAL CENTRE FORMATION.
- MUSCULARIS PROPRIA PRESENT.
- NEGATIVE FOR UROTHELIAL CARCINOMA IN SITU AND NEGATIVE FOR MALIGNANCY.

Polypoid cystitis

General

  • Uncommon.
  • Wide age range.
  • Benign.

Microscopic

Features:[16]

  • Polypoid urothelium-covered projections with:
    1. Broad bases.
    2. Height > base.
    3. Extensive edema.

DDx:

  • Papillary cystitis - not a broad base.
  • Bullous cystitis.

Image:

von Brunn nests

General

  • Benign.

Microscopic

Features:[21]

  • Nests of (benign) urothelium budding into the lamina propria.

Note:

  • Nests should not extend into the muscularis propria.

DDx:

IHC

Features:[22]

  • p53 -ve.
  • MIB-1 <3%.

Cystitis cystica

Main article: Cystitis cystica

Cystitis glandularis

Main article: Cystitis glandularis

Malakoplakia

Main article: Malakoplakia

Nephrogenic adenoma

  • AKA mesonephric adenoma.
  • AKA nephrogenic metaplasia.
Main article: Nephrogenic adenoma

See also

References

  1. ↑ JS. 9 June 2010.
  2. ↑ Van der Kwast, TH.; Zlotta, AR.; Fleshner, N.; Jewett, M.; Lopez-Beltran, A.; Montironi, R. (Dec 2008). "Thirty-five years of noninvasive bladder carcinoma: a plea for the use of papillary intraurothelial neoplasia as new terminology.". Anal Quant Cytol Histol 30 (6): 309-15. PMID 19160695.
  3. ↑ Zhou, Ming; Magi-Galluzzi, Cristina (2006). Genitourinary Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 155-163. ISBN 978-0443066771.
  4. ↑ Zhou, Ming; Magi-Galluzzi, Cristina (2006). Genitourinary Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 166-175. ISBN 978-0443066771.
  5. ↑ 5.0 5.1 Humphrey, Peter A; Dehner, Louis P; Pfeifer, John D (2008). The Washington Manual of Surgical Pathology (1st ed.). Lippincott Williams & Wilkins. pp. 310. ISBN 978-0781765275.
  6. ↑ GAG. 26 February 2009.
  7. ↑ Chacko, JA.; Heiner, JG.; Siu, W.; Macy, M.; Terris, MK. (Jan 2006). "Association between marijuana use and transitional cell carcinoma.". Urology 67 (1): 100-4. doi:10.1016/j.urology.2005.07.005. PMID 16413342.
  8. ↑ URL: http://content.nejm.org/cgi/content/full/343/17/1268. Accessed on: 27 May 2010.
  9. ↑ Crockett, DG.; Wagner, DG.; Holmäng, S.; Johansson, SL.; Lynch, HT. (May 2011). "Upper urinary tract carcinoma in Lynch syndrome cases.". J Urol 185 (5): 1627-30. doi:10.1016/j.juro.2010.12.102. PMID 21419447.
  10. ↑ Hodges, KB.; Lopez-Beltran, A.; Davidson, DD.; Montironi, R.; Cheng, L. (Feb 2010). "Urothelial dysplasia and other flat lesions of the urinary bladder: clinicopathologic and molecular features.". Hum Pathol 41 (2): 155-62. doi:10.1016/j.humpath.2009.07.002. PMID 19762067.
  11. ↑ 11.0 11.1 Amin, Mahul B. (2010). Diagnostic Pathology: Genitourinary (1st ed.). Amirsys. pp. 2-57. ISBN 978-1931884280.
  12. ↑ URL: http://pathology.jhu.edu/bladder/definitions.cfm. Accessed on: 8 January 2014.
  13. ↑ Watts, KE.; Montironi, R.; Mazzucchelli, R.; van der Kwast, T.; Osunkoya, AO.; Stephenson, AJ.; Hansel, DE. (Aug 2012). "Clinicopathologic characteristics of 23 cases of invasive low-grade papillary urothelial carcinoma.". Urology 80 (2): 361-6. doi:10.1016/j.urology.2012.04.010. PMID 22857755.
  14. ↑ Amin, Mahul B. (2010). Diagnostic Pathology: Genitourinary (1st ed.). Amirsys. pp. 2:6. ISBN 978-1931884280.
  15. ↑ Zhou, Ming; Magi-Galluzzi, Cristina (2006). Genitourinary Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 113. ISBN 978-0443066771.
  16. ↑ 16.0 16.1 16.2 16.3 Zhou, Ming; Magi-Galluzzi, Cristina (2006). Genitourinary Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 120. ISBN 978-0443066771.
  17. ↑ Zhou, Ming; Magi-Galluzzi, Cristina (2006). Genitourinary Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 124. ISBN 978-0443066771.
  18. ↑ 18.0 18.1 Zhou, Ming; Magi-Galluzzi, Cristina (2006). Genitourinary Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 122. ISBN 978-0443066771.
  19. ↑ 19.0 19.1 Zhou, Ming; Magi-Galluzzi, Cristina (2006). Genitourinary Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 127. ISBN 978-0443066771.
  20. ↑ Zhou, Ming; Magi-Galluzzi, Cristina (2006). Genitourinary Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 138. ISBN 978-0443066771.
  21. ↑ Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. pp. 1028. ISBN 0-7216-0187-1.
  22. ↑ 22.0 22.1 Volmar, KE.; Chan, TY.; De Marzo, AM.; Epstein, JI. (Sep 2003). "Florid von Brunn nests mimicking urothelial carcinoma: a morphologic and immunohistochemical comparison to the nested variant of urothelial carcinoma.". Am J Surg Pathol 27 (9): 1243-52. PMID 12960809.
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