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.


==Extent of urothelium==
=Normal urothelium=
===Urethra in males===
===Gross===
*Pre-prostatic urethra - transistional epithelium.
====Extent of urothelium====
*Prostatic urethra - transistional epithelium.
*[[Ureters]].
*Membranous urethra (from apex of prostate to bulb of penis (bulb of the corpus spongiosusm)) - pseudostrat. columnar epithelium.
*Renal pelvis.
*Spony urethra - pseudostratified columnar epi. (proximal) & strat. squamous (distal).
*[[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).


==Normal histology==
===Microscopic===
*Prominent nucleoli (???).
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]].


*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.


===IHC===
*Rare superficial [[CK20]] staining.
====Image====
<gallery>
Image: Benign urothelium - CK20 -- high mag.jpg | Benign urothelium - CK20 - high mag. (WC)
</gallery>
===Sign out===
<pre>
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=
==Where to start==
==Where to start==
July 1st PGY-2:
July 1st PGY-2:
Line 28: Line 60:
#Fibrovascular cores = papillae... may be cancer!
#Fibrovascular cores = papillae... may be cancer!


==Note about terminology==
==A checklist-like approach==
*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''.<ref name=pmid19160695>{{Cite journal  | last1 = Van der Kwast | first1 = TH. | last2 = Zlotta | first2 = AR. | last3 = Fleshner | first3 = N. | last4 = Jewett | first4 = M. | last5 = Lopez-Beltran | first5 = A. | last6 = Montironi | first6 = R. | title = Thirty-five years of noninvasive bladder carcinoma: a plea for the use of papillary intraurothelial neoplasia as new terminology. | journal = Anal Quant Cytol Histol | volume = 30 | issue = 6 | pages = 309-15 | month = Dec | year = 2008 | doi =  | PMID = 19160695 }}</ref>
**If the terminology in the urinary bladder were applied to the colon, we'd call all ''adenomas'', i.e. pre-malignant lesions, ''carcinomas''.
 
==Approach==
# Papillary structure - with fibrovascular cores?
# Papillary structure - with fibrovascular cores?
#* Nuclear pleomorphism?
#* Nuclear pleomorphism?
Line 46: Line 73:
#* 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''.


==Risk factors for UCC==
===Note about terminology===
Risk factors for UCC:
*The bladder is rather unique in that "carcinoma" is a label used for things that are non-invasive.
*Smoking.
**It has been suggested that many things that are called ''papillary urothelial carcinoma'', would be better described as ''papillary intraurothelial neoplasia''.<ref name=pmid19160695>{{Cite journal  | last1 = Van der Kwast | first1 = TH. | last2 = Zlotta | first2 = AR. | last3 = Fleshner | first3 = N. | last4 = Jewett | first4 = M. | last5 = Lopez-Beltran | first5 = A. | last6 = Montironi | first6 = R. | title = Thirty-five years of noninvasive bladder carcinoma: a plea for the use of papillary intraurothelial neoplasia as new terminology. | journal = Anal Quant Cytol Histol | volume = 30 | issue = 6 | pages = 309-15 | month = Dec | year = 2008 | doi =  | PMID = 19160695 }}</ref>
*Toxins.
**If the terminology in the urinary bladder were applied to the colon, we'd call all ''adenomas'', i.e. pre-malignant lesions, ''carcinomas''.
*Drugs, e.g. cyclophosphamide.
*Marijuana.<ref name=pmid16413342>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>


==Premalignant/Hyperplasic/Reactive changes==
=Overview in tables=
Several different benign/premalignant diagnoses can be made:
==General categorization==
*Reactive atypia.
Urothelial lesions can broadly be divided into:
*Flat urothelial hyperplasia.
#Flat lesions.
*Urothelial dysplasia.
#*Lack papillae.
 
#*Tend to be more aggressive.  
Cancer
#Papillary lesions.
*Urothelial carcinoma in situ.
#*Must have true papillae.
*Invasive UCC.
#*Very common.
#*More often benign/indolent.


===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
|-
| '''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'''
| -
|-
|-
|Nuclear enlargement<br>(X stromal lymphocyte) ||none (2x) ||moderate, prominent (3x) ||none (2x) ||moderate (3x) ||'''signif. (4-5x)'''|| signif. (4-5X)
| '''Flat urothelial hyperplasia'''
| none (2x)
| small
| none, round
| as normal
| as normal
| '''increased'''
| usu. none
| -
|-
|-
|Nucleoli ||small ||prominent ||small ||small, some multiple ||+/-large ||+/-large
| '''[[Urothelial dysplasia]]'''
| moderate (3x)
| small, some multiple
| mod. variation, some irregularity
| '''lost'''
| rare, none atypical
| as normal
| usu. none
| -
|-
|-
|size var., shape ||none, round ||none, round ||none, round ||mod. variation, some irregularity ||marked, irregular ||marked, irregular
| '''[[Urothelial carcinoma in situ]]'''
| '''signif. (4-5x)'''
| +/-large
| marked, irregular
| lost
| common, atypical
| thin, thick or norm.
| +/-
| -
|-
|-
|Polarity ||matures to surface ||as normal ||as normal ||'''lost''' ||lost ||lost
| '''[[Urothelial carcinoma|Invasive UCC]]'''
| signif. (4-5X)
| +/-large
| marked, irregular
| lost
| common, atypical
| thin, thick or norm.
| +/-
| '''stromal invasion'''
|-
|-
|Mitoses ||none/minimal ||some, none atypical ||as normal ||rare, none atypical ||common, atypical ||common, atypical
|}
The '''bold''' entry is considered the key feature.
 
===Papillary urothelial lesions===
Urothelial cells in papillae - benign/premalignant/cancerous:<ref>{{Ref GUP|166-175}}</ref><ref name=Ref_WMSP310>{{Ref WMSP|310}}</ref>
{| class="wikitable sortable"
! 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
|-
|-
|Thickness ||4-5 cells ||as normal ||'''increased''' ||as normal ||thin, thick or norm. ||thin, thick or norm.
| [[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
|-
|-
|Inflammation ||none ||'''severe, acute or chronic''' ||usu. none ||usu. none ||+/- ||+/-
| [[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
|-
|-
|Other ||- ||- ||- ||- ||- ||'''stromal invasion'''
| [[High grade papillary urothelial carcinoma|High grade PUCC]]
| mixed population
| common
| common
| '''4-5x lymphocyte,'''<br>'''marked pleomorphism'''
| common, everywhere
| low gr., invasive UCC
| '''diffuse CK20+''', p53+ in 50%
| nucleoli prominent
| marked nuclear pleomorphism
|-
|-
|}
|}
The '''bold''' entry is considered the key feature.
Notes:
*FV core = fibrovascular core.
*PUCC = papillary urothelial carcinoma.
 
=Risk factors for urothelial carcinoma=
*[[Smoking]].
*Toxins.
*Drugs, e.g. cyclophosphamide.
*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>
 
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=
==Overview==
Several different benign & pre-malignant diagnoses can be made.
 
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.
*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===
*May be confused with [[urothelial carcinoma in situ]].<ref name=Ref_Amin2-57>{{Ref Amin|2-57}}</ref>
*Uncommon.
*Considered to be [[normal urothelium]].


==Urothelial carcinoma in situ==
===Microscopic===
===Microscopic===
*Nuclear changes (key feature).
Features:<ref name=Ref_Amin2-57>{{Ref Amin|2-57}}</ref>
**Enlargement of nuclei (often 4-5x the size of stromal lymphocytes) -- diagnostic.<ref name=Ref_GUP161>{{Ref GUP|161}}</ref>
*Umbrella cells have:
***Normal urothelium approx. 2x the size of stromal lymphocytes.
**Mild nuclear enlargement ~3-4x lymphocyte.
**Nuclear pleomorphism - marked variation in size of nuclei.
**Round/regular nuclear membranes.
*Disordered arrangement/crowding of cells.
**+/-Multi-nucleation.
**In normal urothelium the cell line-up on the basement membrane.
**Focally clear cytoplasm with cobwebs.
*Umbrella cells often absent.
***Clear cytoplasm with eosinophilic reticulations.
*Mitoses present.
*+/-Inflammation.
*+/-Enlarged nucleoli.
*No mitotic activity.
 
DDx:<ref>URL: [http://pathology.jhu.edu/bladder/definitions.cfm http://pathology.jhu.edu/bladder/definitions.cfm]. Accessed on: 8 January 2014.</ref>
*[[Urothelial carcinoma in situ]].
*[[Urothelial dysplasia]].
 
====Images====
<gallery>
Image: Benign urothelium with large superficial cells -- intermed mag.jpg | Benign large superf. cells - intermed. mag. (WC)
Image: Benign urothelium with large superficial cells -- high mag.jpg | Benign large superf. cells - high mag. (WC)
Image: Benign urothelium with large superficial cells -- very high mag.jpg | Benign large superf. cells - very high mag. (WC) 
</gallery>
 
===IHC===
*Ki-67 low.
*p53 -ve.
 
===Sign out===
<pre>
URINARY BLADDER, TRANSURETHRAL BIOPSY:
- UROTHELIAL MUCOSA WITH MILD CHRONIC INFLAMMATION.
- NO EVIDENCE OF MALIGNANCY.
 
COMMENT:
Levels were cut and show large benign umbrella cells.
</pre>


==Urothelial cell carcinoma UCC (flat)==
====Micro====
*Nuclear pleomorphism.
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.
**Most important feature.
**Compare nuclei to one another.
*Increased N/C ratio.
*Lack of maturation to surface (important).


*Cells become dyscohesive.
==Urothelial dysplasia==
**Mostly useless in my experience.
*[[AKA]] ''low-grade (urothelial) dysplasia''.
{{Main|Urothelial dysplasia}}


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


UCC vs. Prostate
==Urothelial cell carcinoma==
*UCC: p63+, PSA-, PSAP-, CK7+, CK20+.
:See ''[[Urine_cytopathology#Urothelial_cell_carcinoma|urine cytology]]'' for the [[cytopathology]].
*Prostate: p63-, PSA+, PSAP+, CK7-, CK20-.
*Abbreviated ''UCC''.
*[[AKA]] ''urothelial carcinoma''.
{{Main|Urothelial carcinoma}}


==UCC (papillary lesions)==
=Papillary urothelial lesions=
Papillary urothelial lesions are grouped into one of five categories (listed from bad to good prognosis):<ref name=Ref_WMSP310>{{Ref WMSP|310}}</ref>
Papillary urothelial lesions are grouped into one of five categories (listed from good to bad prognosis):<ref name=Ref_WMSP310>{{Ref WMSP|310}}</ref>
*High grade papillary.
#[[Urothelial papilloma]].
*Low grade papillary.
#[[Inverted urothelial papilloma|Inverted papilloma]].
*Papillary urothelial neoplasm of low malignant potential (PUNLMP).
#[[Papillary urothelial neoplasm of low malignant potential]] (PUNLMP).
**''PUNLMP'' is pronouced "pun-lump".
#*''PUNLMP'' is pronouced "pun-lump".
*Inverted papilloma.
#[[Low grade papillary urothelial carcinoma]].
*Urothelial papilloma.
#[[High grade papillary urothelial carcinoma]].


Key characteristics:
Key characteristics:
Line 140: Line 333:
#Papillae fusion.
#Papillae fusion.


===High grade papillary UCC===
==Urothelial papilloma==
Micro.<ref name=Ref_WMSP310>{{Ref WMSP|310}}</ref>
{{Main|Urothelial papilloma}}
*"High grade nuclear features":
 
**Nuclear pleomorphism - often 4-5x the size of stromal lymphocytes.<ref name=Ref_GUP161>{{Ref GUP|161}}</ref>
==Inverted urothelial papilloma==
*Architectural complexity.
*[[AKA]] ''[[inverted papilloma]]''.
**Fused papillary common.
{{Main|Inverted urothelial papilloma}}
**Papillae branch.
*Mitoses common.


===Low grade papillary UCC===
==Papillary urothelial neoplasm of low malignant potential==
Micro.<ref name=Ref_WMSP310>{{Ref WMSP|310}}</ref>
*Abbreviated ''PUNLMP''.
*Fused papillae.
**This is pronounced ''pun-lump''.
*Papillae branch.
{{Main|Papillary urothelial neoplasm of low malignant potential}}
*Larger nuclei than PUNLMPs.


===PUNLMP===
==Low-grade papillary urothelial carcinoma==
Microscopic:<ref name=Ref_WMSP310>{{Ref WMSP|310}}</ref>
*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>
*Rare fused papillae.
*[[AKA]] ''low-grade papillary urothelial cell carcinoma''.
*Infrequent mitoses.
{{Main|Low-grade papillary urothelial carcinoma}}
*Nuclei larger than papilloma - but monotonous.<ref name=Ref_GUP170>{{Ref GUP|170}}</ref>


===Papilloma===
==High-grade papillary urothelial carcinoma==
Micro.<ref name=Ref_WMSP310>{{Ref WMSP|310}}</ref>
*Abbreviated ''HGPUC''.
*Papillary fronds.
*[[AKA]] ''high-grade papillary urothelial cell carcinoma'', abbreviated ''HGPUCC''.
*Minimal branching or fusion.
{{Main|High-grade papillary urothelial carcinoma}}
*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 papilloma===
==Papillary urothelial hyperplasia==
*Like papillomas... but grow downward.<ref name=Ref_WMSP310>{{Ref WMSP|310}}</ref>
*[[AKA]] ''papillary hyperplasia''.
*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>
*[[AKA]] ''reactive papillary hyperplasia''.
{{Main|Papillary urothelial hyperplasia}}


Images:
=Benign urothelial lesions=
*[http://commons.wikimedia.org/wiki/File:Inverted_papilloma_high_mag.jpg Inverted papilloma - high mag. (WC)].
===Cystitis===
*[http://commons.wikimedia.org/wiki/File:Inverted_papilloma_intermed_mag.jpg Inverted papilloma - intermed. mag. (WC)].
*Inflammation of the [[urinary bladder]].
*Comes in many forms (see below).
*Typically a [[clinical diagnosis]] under the more general term [[urinary tract infection]].


===Tabular comparison of papillary lesions===
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>


Urothelial cells in papillae - benign/premalignant/cancerous:<ref>{{Ref GUP|166-175}}</ref><ref name=Ref_WMSP310>{{Ref WMSP|310}}</ref>
===The big table of cystitis===
{| class="wikitable"
{| class="wikitable sortable"  
| ||'''Papilloma''' ||'''PUNLMP''' ||'''low grade PUCC''' ||'''high grade PUCC'''
! Type
|-
! Key feature
|papillae features ||'''fat papillae''', <br>'''thick FV core''' ||'''slender FV core''' ||slender FV core, <br>'''thick epithelium''' ||mixed population
! DDx
|-
! Reference
|papillae branching ||rare ||uncommon ||frequent ||common
|-
|-
|papillae fusion ||none ||rare ||some ||common
|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>
|-
|-
|nuclear size ||normal (2x lymphocyte) ||'''enlarged - uniform''' ||'''enlarged with variation''' ||'''4-5x lymphocyte,'''<br>'''marked pleomorphism'''
|[[Polypoid cystitis]]
| wide base, height > base
| papillary cystitis, bullous cystitis
| <ref name=Ref_GUP120>{{Ref GUP|120}}</ref>
|-
|-
|mitoses ||very rare basal || rare basal only ||infreq., usually basal ||common, everywhere
|Bullous cystitis
| wide base, height < base
| papillary cystitis, polypoid cystitis
| <ref name=Ref_GUP120>{{Ref GUP|120}}</ref>
|-
|-
|DDx ||PUNLMP, low gr. PUCC ||papilloma, low gr. ||PUNLMP, high gr. ||low gr., invasive UCC
|Papillary cystitis
| narrow base, height > base
| polypoid cystitis, bullous cystitis
| <ref name=Ref_GUP120>{{Ref GUP|120}}</ref>
|-
|-
|IHC ||p53-, CK20+ umbrella cells ||CK20+ umbrella ||-/+ p53, CK20+ umbrella ||'''diffuse CK20+''', p53+ in 50%
|[[Interstitial cystitis]]
| +/-ulceration (uncommon) - requires clinical correlation
| urothelial CIS
| <ref name=Ref_GUP124>{{Ref GUP|124}}</ref>
|-
|-
|Other ||cytologically normal ||low cellular density (@ low power) vs. low gr.<ref>GAG. 26 February 2009.</ref> ||+/- small nucleoli ||nucleoli prominent
|Follicular cystitis
| lymphoid follicles
| non-Hodgkin [[lymphoma]]
| <ref name=Ref_GUP122>{{Ref GUP|122}}</ref>
|-
|-
|Key feature ||normal cells,<br>fat papillae ||uniformly enlarged cell pop., <br>slender papillae ||nuc. pleomorphism, <br> thick epithelium ||marked nuclear pleomorphism
|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>
|}
|}
Notes:
*FV core = fibrovascular core.
*PUCC = papillary urothelial carcinoma.


==Benign==
==Interstitial cystitis==
Brunn nests:<ref name=Ref_PBoD1028>{{Ref PBoD|1028}}</ref>
{{Main|Interstitial cystitis}}
*Benign inbudding nests of urothelium.
 
**Should lead to consideration of "inverted papilloma".
==Follicular cystitis==
===Microscopic===
Features:<ref name=Ref_GUP122>{{Ref GUP|122}}</ref>
*Lymphoid follicles in the lamina propria.
 
DDx:
*Non-Hodgkin [[lymphoma]].
 
===Sign out===
<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===
*Uncommon.
*Wide age range.
*Benign.
 
===Microscopic===
Features:<ref name=Ref_GUP120>{{Ref GUP|120}}</ref>
*Polypoid urothelium-covered projections with:
*#Broad bases.
*#Height > base.
*#Extensive edema.
 
DDx:
*Papillary cystitis - not a broad base.
*Bullous cystitis.
 
Image:
*[http://www.webpathology.com/image.asp?case=51&n=3 Polypoid cystitis (webpathology.com)].
 
==von Brunn nests==
===General===
*Benign.
 
===Microscopic===
Features:<ref name=Ref_PBoD1028>{{Ref PBoD|1028}}</ref>
*Nests of (benign) urothelium budding into the lamina propria.


Cystitis cystica:<ref name=Ref_PBoD1028>{{Ref PBoD|1028}}</ref>
Note:
*Brunn nests with urothelium.
*Nests should '''not''' extend into the muscularis propria.


cystitis glandularis:<ref name=Ref_PBoD1028>{{Ref PBoD|1028}}</ref>
DDx:
*Brunn nests with cuboidal and columnar epithelium.
*[[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>
*[[Inverted urothelial papilloma|Inverted papilloma]].
*[[Cystitis cystica]] - have lumens, may be focal.


==Invasive UCC==
===IHC===
Staging:
Features:<ref name=pmid12960809/>
*T1 - lamina propria.
*p53 -ve.
**Several subdivisions of T1 exist:<ref>Sternberg, H4P 4th Ed., P.2048-9.</ref>
*MIB-1 <3%.
***T1a - superficial or in muscularis mucosae.
***T1b - beyond muscularis mucosae - into submucosa.
*T2 - muscularis propria.


===Invasion vs. in situ===
==Cystitis cystica==
Useful features - present in invasion:<ref>Sternberg, H4P, P.2047.</ref>
{{Main|Cystitis cystica}}
*Thin-walled vessels.
*Stromal reaction (hypercellularity).
*Retraction artefact around the tumour cell nests.


==Renal cell carcinoma==
==Cystitis glandularis==
{{main|Renal cell carcinoma}}
{{Main|Cystitis glandularis}}
Clinically, it may not be possible to differentiate renal pelvis UCC and RCC.


==Nephrogenic metaplasia==
==Malakoplakia==
*[[AKA]] ''nephrogenic adenoma''.
{{Main|Malakoplakia}}


Ref.: [http://www.nature.com/modpathol/journal/v15/n7/full/3880603a.html http://www.nature.com/modpathol/journal/v15/n7/full/3880603a.html].
==Nephrogenic adenoma==
*[[AKA]] ''mesonephric adenoma''.
*[[AKA]] ''nephrogenic metaplasia''.
{{Main|Nephrogenic adenoma}}


==See also==
=See also=
*[[Prostate]].
*[[Prostate]].
*[[Genitourinary pathology]].
*[[Genitourinary pathology]].
*[[Kidney tumours]].


==References==
=References=
{{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)

Sign out

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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