Urothelium

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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

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:

  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
    • Consider cystitis cystica, cystitis glandularis, cystitis cystica et glandularis, Brunn's nest, inverted papilloma.
  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]

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

  • 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:

  • 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.
  • 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.
  • T2 - muscularis propria.

Subtypes

There are numerous subtypes:[13]

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:

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:

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]

  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

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:

Images:

Papillary urothelial neoplasm of low malignant potential

  • Abbreviated PUNLMP.

General

Treatment:

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:

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BLADDER LESION ("TUMOUR"), TRANSURETHRAL RESECTION OF BLADDER TUMOUR (TURBT):
- LOW-GRADE PAPILLARY UROTHELIAL CARCINOMA.
- NEGATIVE FOR LAMINA PROPRIA INVASION.
- NO MUSCULARIS PROPRIA IDENTIFIED.

BLADDER LESION ("TUMOUR"), TRANSURETHRAL RESECTION OF BLADDER TUMOUR (TURBT):
- LOW-GRADE PAPILLARY UROTHELIAL CARCINOMA.
- NEGATIVE FOR LAMINA PROPRIA INVASION.
- MUSCULARIS PROPRIA PRESENT.

High grade papillary urothelial carcinoma

  • AKA high grade urothelial cell carcinoma.
    • Abbreviated high grade UCC.

General

  • Aggressive.

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:

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URINARY BLADDER ("TUMOUR"), TRANSURETHRAL RESECTION URINARY BLADDER TUMOUR (TURBT): 
- INVASIVE HIGH-GRADE PAPILLARY UROTHELIAL CARCINOMA AT LEAST INTO MUSCULARIS PROPRIA. 
- LYMPHOVASCULAR INVASION PRESENT.

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

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

  • AKA mesonephric adenoma,[27] AKA nephrogenic metaplasia.

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:

Images:

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

  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 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.
  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. ↑ 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.
  11. ↑ Sternberg, SE. Histology for Pathologists. P.2047.
  12. ↑ 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.
  13. ↑ URL: http://www.nature.com/modpathol/journal/v22/n2s/full/modpathol200926a.html. Accessed on: 19 August 2011.
  14. ↑ 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.
  15. ↑ 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/.
  16. ↑ 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.
  17. ↑ Online 'Mendelian Inheritance in Man' (OMIM) 600160
  18. ↑ THvdK. 21 June 2010.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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. ↑ 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. ↑ 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. ↑ 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.
  27. ↑ 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. ↑ 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
  29. ↑ 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.
  30. ↑ 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.
  31. ↑ Alexiev, BA.; Levea, CM. (Mar 2012). "Nephrogenic Adenoma of the Urinary Tract: A Review.". Int J Surg Pathol. doi:10.1177/1066896912439095. PMID 22415059.
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