Urothelium

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The urothelium lines the upper portion of the genitourinary tract... 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.
  • 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:

  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]

Flat lesions

Premalignant/Hyperplasic/Reactive changes

Several different benign/premalignant diagnoses can be made:

  • Reactive atypia.
  • Flat urothelial hyperplasia.
  • Urothelial dysplasia.

Cancer:

  • Urothelial carcinoma in situ.
  • Invasive UCC.

Urothelial carcinoma in situ

Microscopic

  • Nuclear changes key feature.
    • Enlargement of nuclei (often 4-5x the size of stromal lymphocytes) -- diagnostic.[9]
      • 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

  • Abbreviated UCC.

General

  • These lesions lack papillae and are typical flat.

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.

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:

Papillary urothelial cell carcinoma

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.[9]
  • No mitoses.

Inverted 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,[11] 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.[12]

Images:

Papillary urothelial neoplasm of low malignant potential

  • Abbreviated PUNLMP.

Microscopic

Features:[5]

  • Rare fused papillae.
  • Infrequent mitoses.
  • Nuclei larger than papilloma - but monotonous.[13]

Low grade papillary urothelial carcinoma

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

Microscopic

Features:[5]

  • Fused papillae.
  • Papillae branch.
  • Larger nuclei than PUNLMPs.

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.[9]
  • Architectural complexity.
    • Fused papillary common.
    • Papillae branch.
  • Mitoses common.

Benign urothelial lesions

Brunn nests:[14]

  • Benign inbudding nests of urothelium.
    • Should lead to consideration of "inverted papilloma".

Cystitis cystica:[14]

  • Brunn nests with urothelium.

cystitis glandularis:[14]

  • Brunn nests with cuboidal and columnar epithelium.

Invasive UCC

Staging:

  • T1 - lamina propria.
    • Several subdivisions of T1 exist:[15]
      • T1a - superficial or in muscularis mucosae.
      • T1b - beyond muscularis mucosae - into submucosa.
  • T2 - muscularis propria.

Invasion vs. in situ

Useful features - present in invasion:[16]

  • Thin-walled vessels.
  • Stromal reaction (hypercellularity).
  • Retraction artefact around the tumour cell nests.

Subtypes

There are numerous subtypes:[17]

  • Squamous differentiation.
  • Clear cell.
  • Plasmacytoid.
    • Abundant gray cytoplasm, eccentric nucleus.
  • Micropapillary.
    • Small nests (< ~10 cells/nest).
  • Many others...

Renal cell carcinoma

Main article: Renal cell carcinoma

Clinically, it may not be possible to differentiate renal pelvis UCC and RCC.

Nephrogenic metaplasia

  • AKA mesonephric adenoma,[18] AKA nephrogenic adenoma.

General

Features:[19]

  • Benign.
  • Classic location is the urinary bladder.
    • Also reported in ureter and prostatic urethra.
  • May mimic adenocarcinoma

Microscopic

Features:[19]

  • 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:

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. ↑ PMID 16413342.
  8. ↑ URL: http://content.nejm.org/cgi/content/full/343/17/1268. Accessed on: 27 May 2010.
  9. ↑ 9.0 9.1 9.2 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.
  10. ↑ 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.
  11. ↑ THvdK. 21 June 2010.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 14.0 14.1 14.2 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.
  15. ↑ Sternberg, H4P 4th Ed., P.2048-9.
  16. ↑ Sternberg, H4P, P.2047.
  17. ↑ URL: http://www.nature.com/modpathol/journal/v22/n2s/full/modpathol200926a.html. Accessed on: 19 August 2011.
  18. ↑ 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.
  19. ↑ 19.0 19.1 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.
  20. ↑ 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.
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