Urothelium

The urothelium lines the upper portion of the genitourinary tract... and a bit of the lower part.

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).

Normal histology

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

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

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.
   • 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!

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.
  • If the terminology in the urinary bladder were applied to the colon, we'd call all adenomas, i.e. pre-malignant lesions, carcinomas.

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, 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.

Risk factors for UCC

Risk factors for UCC:

• Smoking.
• Toxins.
• Drugs, e.g. cyclophosphamide.
• Marijuana.
• Chinese Herbs.

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.

Comparison urothelial changes - flat epithelium - benign/premalignant/cancerous:

	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.

Urothelial carcinoma in situ

Microscopic

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

• Nuclear pleomorphism.
  • Most important 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

• CK7+ CK20+.

UCC vs. Prostate

• UCC: p63+, PSA-, PSAP-, CK7+, CK20+.
• Prostate: p63-, PSA+, PSAP+, CK7-, CK20-.

UCC (papillary lesions)

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

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

Key characteristics:

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

High grade papillary UCC

Micro.

• "High grade nuclear features":
  • Nuclear pleomorphism - often 4-5x the size of stromal lymphocytes.
• Architectural complexity.
  • Fused papillary common.
  • Papillae branch.
• Mitoses common.

Low grade papillary UCC

Micro.

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

PUNLUMP

Micro.

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

Papilloma

Micro.

• Papillary fronds.
• Minimal branching or fusion.
• Cytological features of normal urothelium.
  • Normal urothelium approx. 2x the size of stromal lymphocytes.
• No mitoses.

Inverted papilloma

• Like papillomas... but grow downward.

Tabular comparison of papillary lesions

Urothelial cells in papillae - benign/premalignant/cancerous:

	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.	+/- 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.

Benign

Brunn nests:

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

Cystitis cystica:

• Brunn nests with urothelium.

cystitis glandularis:

• Brunn nests with cuboidal and columnar epithelium.

Invasive UCC

Staging:

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

Invasion vs. in situ

Useful features - present in invasion:

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

Renal cell carcinoma

Main article: Renal cell carcinoma

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

See also

• Prostate.
• Genitourinary pathology.