Urothelium
The urothelium lines the upper portion of the genitourinary tract, i.e. ureters, urinary bladder), and a bit of the lower part.
Normal histology
- Maturation (cuboidal at base - squamoid at surface).
- Surface cells called 'umbrella cells' (umbrella cells CK20+).
- Urothelium should be 4-5 cell layers thick.
- +/-Prominent nucleoli.
- Should NOT have papillary architecture -- if it does it is likely cancer!
- If it is 'papillary' -- it must have fibrovascular cores.
Extent of urothelium
- Ureters.
- Renal pelvis.
- Urinary bladder.
- Part of the urethra.
Urethra in males
- Pre-prostatic urethra - transistional epithelium.
- Prostatic urethra - transistional epithelium.
- Membranous urethra (from apex of prostate to bulb of penis (bulb of the corpus spongiosusm)) - pseudostrat. columnar epithelium.
- Spony urethra - pseudostratified columnar epi. (proximal) & strat. squamous (distal).
Approach
Where to start
July 1st PGY-2:
- 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.
- Nucleoli are common in urothelium.
- Round structures should make you think of papillae and prompt looking for fibrovascular cores.
- Fibrovascular cores = papillae... may be cancer!
A checklist-like approach
- 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
- Nuclear pleomorphism?
- Flat lesions?
- Nuclear pleomorphism?
- Maturation to surface?
- No --> Dx: sectioning artefact vs. flat UCC.
- Yes --> likely benign.
- Normal thickness?
- Normal is 4-5 cell layers.
- Nests of glandular cells
- Consider cystitis cystica, cystitis glandularis, cystitis cystica et glandularis, Brunn's nest, inverted papilloma.
- 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:
- Flat lesions.
- Lack papillae.
- Tend to be more aggressive.
- Papillary lesions.
- Must have true papillae.
- Very common.
- More often benign/indolent.
Flat urothelial lesions
Comparison urothelial changes - flat epithelium - benign/premalignant/cancerous:[3]
| Normal | Reactive atypia | Flat urothelial hyperplasia | Urothelial dysplasia | UCC in situ | Invasive UCC | |
| Nuclear enlargement (X stromal lymphocyte) |
none (2x) | moderate, prominent (3x) | none (2x) | moderate (3x) | signif. (4-5x) | signif. (4-5X) |
| Nucleoli | small | prominent | small | small, some multiple | +/-large | +/-large |
| size var., shape | none, round | none, round | none, round | mod. variation, some irregularity | marked, irregular | marked, irregular |
| Polarity | matures to surface | as normal | as normal | lost | lost | lost |
| Mitoses | none/minimal | some, none atypical | as normal | rare, none atypical | common, atypical | common, atypical |
| Thickness | 4-5 cells | as normal | increased | as normal | thin, thick or norm. | thin, thick or norm. |
| Inflammation | none | severe, acute or chronic | usu. none | usu. none | +/- | +/- |
| Other | - | - | - | - | - | stromal invasion |
The bold entry is considered the key feature.
Papillary urothelial lesions
Urothelial cells in papillae - benign/premalignant/cancerous:[4][5]
| Papilloma | PUNLMP | low grade PUCC | high grade PUCC | |
| papillae features | fat papillae, thick FV core |
slender FV core | slender FV core, thick epithelium |
mixed population |
| papillae branching | rare | uncommon | frequent | common |
| papillae fusion | none | rare | some | common |
| nuclear size | normal (2x lymphocyte) | enlarged - uniform | enlarged with variation | 4-5x lymphocyte, marked pleomorphism |
| mitoses | very rare basal | rare basal only | infreq., usually basal | common, everywhere |
| DDx | PUNLMP, low gr. PUCC | papilloma, low gr. | PUNLMP, high gr. | low gr., invasive UCC |
| IHC | p53-, CK20+ umbrella cells | CK20+ umbrella | -/+ p53, CK20+ umbrella | diffuse CK20+, p53+ in 50% |
| Other | cytologically normal | low cellular density (@ low power) vs. low gr.[6] | +/- small nucleoli | nucleoli prominent |
| Key feature | normal cells, fat papillae |
uniformly enlarged cell pop., slender papillae |
nuc. pleomorphism, thick epithelium |
marked nuclear pleomorphism |
Notes:
- FV core = fibrovascular core.
- PUCC = papillary urothelial carcinoma.
Risk factors for urothelial carcinoma
Others:
- Lynch syndrome.
- Should be considered in ureteral cancers.[9]
Flat urothelial lesions
Overview
Several different benign & pre-malignant diagnoses can be made:
- Reactive atypia.
- Flat urothelial hyperplasia.
- Urothelial dysplasia.
- Urothelial carcinoma in situ.
- Invasive urothelial carcinoma.
Urothelial carcinoma in situ
General
- Lack papillae.
Microscopic
Features:
- Nuclear changes key feature.
- Enlargement of nuclei (often 4-5x the size of stromal lymphocytes) -- diagnostic.[10]
- Normal urothelium approx. 2x the size of stromal lymphocytes.
- Nuclear pleomorphism - marked variation in size of nuclei.
- Enlargement of nuclei (often 4-5x the size of stromal lymphocytes) -- diagnostic.[10]
- Disordered arrangement/crowding of cells.
- In normal urothelium the cell line-up on the basement membrane.
- Umbrella cells often absent.
- Mitoses present.
- +/-Enlarged nucleoli.
Urothelial cell carcinoma
- See urine cytology for the cytopathology.
- Abbreviated UCC.
- AKA urothelial carcinoma.
General
- 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
Features:
- Nuclear pleomorphism - key feature.
- Compare nuclei to one another.
- Increased N/C ratio.
- Lack of maturation to surface (important).
- Cells become dyscohesive.
- Mostly useless in my experience.
Invasion vs. in situ: Useful features - present in invasion:[11]
- Thin-walled vessels.
- Stromal reaction (hypercellularity).
- Retraction artefact around the tumour cell nests.
Note:
- The presence/absence of muscle should be commented on in biopsy specimens.
- Adipose tissue may be seen in the lamina propria; tumour adjacent to adipose tissue on a biopsy does not imply invasion deep to the muscularis propria.[12]
Staging
- T1 - lamina propria.
- Several subdivisions of T1 exist:
- T1a - superficial or in muscularis mucosae.
- T1b - beyond muscularis mucosae - into submucosa.
- Several subdivisions of T1 exist:
- T2 - muscularis propria.
Subtypes
There are numerous subtypes:[13]
- Squamous differentiation.
- Clear cell.
- Plasmacytoid.
- Micropapillary.
- Small nests (< ~10 cells/nest).
- Sarcomatoid.
- Many others...
Benign patterns - mnemonic Much GIN:
- Microcystic.
- Small tubular/glandular.
- Inverted.
- Nested.
Plasmacytoid urothelial cell carcinoma
Features:
- Abundant gray cytoplasm, eccentric nucleus.
Images:
Nested urothelial cell carcinoma
- AKA nested variant urothelial cell carcinoma.
Features:[14]
- High density of well-circumscribed nests.
- Mild-to-moderate nuclear atypia.
- +/-Foci of unequivocal conventional urothelial carcinoma.
- Focally solid or gland fusion.
- Moderate-to-severe nuclear atypia +/- abundant mitoses.
- +/-Extension into the muscularis propria.
DDx:
Images:
- Nested variant of urothelial carcinoma - intermed. mag. (WC).
- Nested variant of urothelial carcinoma - high mag. (WC).
- Nested variant of urothelial carcinoma - very high mag. (WC).
- Several images of NUCC (nih.gov).[15]
IHC
Features:
- CK7 +ve CK20 +ve.
- CK20 may be negative.
UCC vs. Prostate:
- UCC: p63+, PSA-, PSAP-, CK7+, CK20+.
- Prostate: p63-, PSA+, PSAP+, CK7-, CK20-.
UCC vs. RCC:
- UCC: p63+.[16]
Molecular
Not used for diagnosis.
Changes:
- 9p deletion -- site of CDKN2A[17] (AKA p16).
- 17p deletion -- site of PT53 (AKA p53).
Papillary urothelial lesions
Papillary urothelial lesions are grouped into one of five categories (listed from good to bad prognosis):[5]
- Urothelial papilloma.
- Inverted papilloma.
- Papillary urothelial neoplasm of low malignant potential (PUNLMP).
- PUNLMP is pronouced "pun-lump".
- Low grade papillary urothelial carcinoma.
- High grade papillary urothelial carcinoma.
Key characteristics:
- Nuclear - size/pleomorphism.
- Papillae branching.
- Papillae fusion.
Urothelial papilloma
General
- 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:[5]
- Papillary fronds.
- Minimal branching or fusion.
- Cytological features of normal urothelium.
- Normal urothelium approx. 2x the size of stromal lymphocytes.[10]
- No mitoses.
- Thickness < 7 cells.[citation needed]
DDx:
Inverted urothelial papilloma
General
- May be confused with papillary urothelial carcinoma with an inverted growth pattern.
Microscopic
Features:
- Like papillomas... but grow downward.[5]
- According to THvdK,[18] 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.[19]
- Nests have peripheral palisading of nuclei - important.
DDx:
- Low grade papillary urothelial carcinoma with an inverted growth pattern.
Images:
Papillary urothelial neoplasm of low malignant potential
- Abbreviated PUNLMP.
General
- Uncommon: prevalence ~ 0-3.5%.[20]
- PUNLMP vs. low grade papillary urothelial carcinoma has a poor inter-rater reliability.[21]
Treatment:
- Excision and on-going follow-up - like non-invasive low grade papillary urothelial carcinoma.[22]
Microscopic
Features:[5]
- Rare fused papillae.
- Infrequent mitoses.
- Nuclei larger than papilloma - but monotonous.[23]
DDx:
Images:
Low grade papillary urothelial carcinoma
- AKA low grade urothelial cell carcinoma.
- Abbreviated low grade UCC.
General
- Very common.
- Very good prognosis - if it is non-invasive.
Microscopic
Features:[5]
- Fused papillae.
- Papillae branch.
- Larger nuclei than PUNLMPs.
- +/-Invasion into the lamina propria.
Note:
- The presence/absence of muscle should be commented on in biopsy specimens.
- Adipose tissue may be seen in the lamina propria; tumour adjacent to adipose tissue on a biopsy does not imply invasion deep to the muscularis propria.[12]
DDx:
High grade papillary urothelial carcinoma
- AKA high grade urothelial cell carcinoma.
- Abbreviated high grade UCC.
Microscopic
Features:[5]
- "High grade nuclear features":
- Nuclear pleomorphism - often 4-5x the size of stromal lymphocytes.[10]
- Architectural complexity.
- Fused papillary common.
- Papillae branch.
- Mitoses common.
- +/-Invasion into the lamina propria.
Note:
- The presence/absence of muscle should be commented on in biopsy specimens.
- Adipose tissue may be seen in the lamina propria; tumour adjacent to adipose tissue on a biopsy does not imply invasion deep to the muscularis propria.[12]
DDx:
Benign urothelial lesions
von Brunn nests
General
- Benign.
Microscopic
Features:[24]
- Nests of (benign) urothelium budding into the lamina propria.
Note:
- Nests should not extend into the muscularis propria.
DDx:
IHC
Features:[25]
- p53 -ve.
- MIB-1 <3%.
Cystitis cystica
General
- Benign.
- Can be thought of as von Brunn nests with cystic change.[26]
- Called ureteritis cystica if it happens in a ureter.
Microscopic
Features:[24]
- Nests of urothelium within the lamina propria with cyst formation, i.e. lumens are present.
Note:
- Nests should not extend into the muscularis propria.
Cystitis glandularis
- Cystitis cystica et glandularis redirects to here.
General
- Benign.
- Can be thought of as cystitis cystica with mucin-secreting cells lining the cystic spaces.[26]
- When seen in conjunction with cystitis cystica it is called cystitis cystica et glandularis.
Microscopic
Features:[24]
- Nests of urothelium within the lamina propria with cyst formation, i.e. lumens are present.
- Cyst lining cells are cuboidal and/or columnar epithelium.
- Produce mucin.
- +/-Goblet cells, i.e. intestinal metaplasia.[26]
Note:
- Nests should not extend into the muscularis propria.
Malakoplakia
Main article: Malakoplakia
Nephrogenic adenoma
General
Features:[28]
- Benign.
- May mimic adenocarcinoma!
- Classic location is the urinary bladder.
- Also reported in ureter and prostatic urethra.
- It is thought to result from displacement of renal tubular cells, as this entity in renal transplant recipients is graft derived.[29]
Microscopic
Features:[28]
- Tubular structures - key feature.
- Hobnailed cells.
- +/-Thick eosinophilic basement membrane.
- Microcystic appearance.
- Usually associated with chronic inflammation.
Notes:
- May mimic vascular/lymphatic channels - can be sorted-out with IHC.
DDx:
- Urothelial carcinoma, microcystic and nested variants.
- Prostatic adenocarcinoma.
- Clear cell adenocarcinoma.
Images:
- www:
- WC:
IHC
Features:[31]
- CK7 +ve.
- PAX2 +ve.
- PAX8 +ve.
- AMACR +ve/-ve.
Others:[28]
- p53 -ve.
- CEA -ve.
- Ki-67 low (<5%).
See also
References
- ↑ JS. 9 June 2010.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 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.
- ↑ GAG. 26 February 2009.
- ↑ 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.
- ↑ URL: http://content.nejm.org/cgi/content/full/343/17/1268. Accessed on: 27 May 2010.
- ↑ 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.
- ↑ 10.0 10.1 10.2 Zhou, Ming; Magi-Galluzzi, Cristina (2006). Genitourinary Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 161. ISBN 978-0443066771.
- ↑ Sternberg, SE. Histology for Pathologists. P.2047.
- ↑ 12.0 12.1 12.2 Bochner, BH.; Nichols, PW.; Skinner, DG. (Mar 1995). "Overstaging of transitional cell carcinoma: clinical significance of lamina propria fat within the urinary bladder.". Urology 45 (3): 528-31. doi:10.1016/S0090-4295(99)80030-2. PMID 7879346.
- ↑ URL: http://www.nature.com/modpathol/journal/v22/n2s/full/modpathol200926a.html. Accessed on: 19 August 2011.
- ↑ Talbert, ML.; Young, RH. (May 1989). "Carcinomas of the urinary bladder with deceptively benign-appearing foci. A report of three cases.". Am J Surg Pathol 13 (5): 374-81. PMID 2712189.
- ↑ Terada, T. (Oct 2011). "Nested variant of urothelial carcinoma of the urinary bladder.". Rare Tumors 3 (4): e42. doi:10.4081/rt.2011.e42. PMC 3282447. PMID 22355497. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3282447/.
- ↑ Langner, C.; Ratschek, M.; Tsybrovskyy, O.; Schips, L.; Zigeuner, R. (Aug 2003). "P63 immunoreactivity distinguishes upper urinary tract transitional-cell carcinoma and renal-cell carcinoma even in poorly differentiated tumors.". J Histochem Cytochem 51 (8): 1097-9. PMID 12871991.
- ↑ Online 'Mendelian Inheritance in Man' (OMIM) 600160
- ↑ THvdK. 21 June 2010.
- ↑ Albores-Saavedra J, Chable-Montero F, Hernández-Rodríguez OX, Montante-Montes de Oca D, Angeles-Angeles A (June 2009). "Inverted urothelial papilloma of the urinary bladder with focal papillary pattern: a previously undescribed feature". Ann Diagn Pathol 13 (3): 158–61. doi:10.1016/j.anndiagpath.2009.02.009. PMID 19433293.
- ↑ May M, Brookman-Amissah S, Roigas J, et al. (March 2009). "Prognostic Accuracy of Individual Uropathologists in Noninvasive Urinary Bladder Carcinoma: A Multicentre Study Comparing the 1973 and 2004 World Health Organisation Classifications". Eur. Urol. 57 (5): 850. doi:10.1016/j.eururo.2009.03.052. PMID 19346063.
- ↑ MacLennan GT, Kirkali Z, Cheng L (April 2007). "Histologic grading of noninvasive papillary urothelial neoplasms". Eur. Urol. 51 (4): 889–97; discussion 897–8. doi:10.1016/j.eururo.2006.10.037. PMID 17095142.
- ↑ Jones TD, Cheng L (June 2006). "Papillary urothelial neoplasm of low malignant potential: evolving terminology and concepts". J. Urol. 175 (6): 1995–2003. doi:10.1016/S0022-5347(06)00267-9. PMID 16697785.
- ↑ Zhou, Ming; Magi-Galluzzi, Cristina (2006). Genitourinary Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 170. ISBN 978-0443066771.
- ↑ 24.0 24.1 24.2 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.
- ↑ 25.0 25.1 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.
- ↑ 26.0 26.1 26.2 Humphrey, Peter A; Dehner, Louis P; Pfeifer, John D (2008). The Washington Manual of Surgical Pathology (1st ed.). Lippincott Williams & Wilkins. pp. 304. ISBN 978-0781765275.
- ↑ Singh, KJ. (Jan 2011). "Mesonephric adenoma in remnant ureteric stump: A rare entity.". Indian J Urol 27 (1): 140-1. doi:10.4103/0970-1591.78414. PMID 21716880.
- ↑ 28.0 28.1 28.2 Gokaslan, ST.; Krueger, JE.; Albores-Saavedra, J. (Jul 2002). "Symptomatic nephrogenic metaplasia of ureter: a morphologic and immunohistochemical study of four cases.". Mod Pathol 15 (7): 765-70. doi:10.1097/01.MP.0000019578.51568.24. PMID 12118115. http://www.nature.com/modpathol/journal/v15/n7/full/3880603a.html. Cite error: Invalid
<ref>tag; name "pmid12118115" defined multiple times with different content - ↑ Mazal, PR.; Schaufler, R.; Altenhuber-Müller, R.; Haitel, A.; Watschinger, B.; Kratzik, C.; Krupitza, G.; Regele, H. et al. (Aug 2002). "Derivation of nephrogenic adenomas from renal tubular cells in kidney-transplant recipients.". N Engl J Med 347 (9): 653-9. doi:10.1056/NEJMoa013413. PMID 12200552.
- ↑ Kunju, LP. (Oct 2010). "Nephrogenic adenoma: report of a case and review of morphologic mimics.". Arch Pathol Lab Med 134 (10): 1455-9. doi:10.1043/2010-0226-CR.1. PMID 20923300.
- ↑ Alexiev, BA.; Levea, CM. (Mar 2012). "Nephrogenic Adenoma of the Urinary Tract: A Review.". Int J Surg Pathol. doi:10.1177/1066896912439095. PMID 22415059.