Residency - Bladder Flashcards
The cellular thickness of the bladder epithelium depends upon. . .
. . . how distended the bladder is
As low as ~2 cells when distended,
As many as ~7 cells when nondistended.
Von Brunn nests
Invaginations of the surface urothelium into underlying lamina propria. Normal urothelium thickness & cytology. Round shape (not infiltrative), uniform size
You should be thinking urothelial carcinoma if instead there are many small nests of irregular size that are stacked on-top of one another.
Cystitis cystica
Note how the lining looks similar to Von Brunn nests. . . that’s because it is!
These are just cystically dilated Von Brunn nests
Cystitis glandularis - foveolar type
Similar to cystitis cystia, this is a Von Brunn nest that has undergone non-neoplastic change. It is a form of metaplasia found in the bladder. There is also a more intestinal/acinar type.
Cystitis glandularis - Intestinal/acinar type
Similar to cystitis cystia, this is a Von Brunn nest that has undergone non-neoplastic change. It is a form of metaplasia found in the bladder. There is also a foveolar type.
General things to know about urothelial tumors
More common in older males
Present as painless hematuria
90% in the bladder, 10% in upper urinary tract
May be multifocal
Cancers with the highest mutation rates
- Lung cancers
- Urothelial cancers
Pathways to urothelial carcinoma
-
The large chromosomal alteration pathway
* Large loss/gain of chromosomal material
* Tends to occur in higher-grade lesions -
Recurrent mutations
* TP53 deactivating, FGFR3 activating, TERT promoter activating
* Less common - PIK3CA, RB1, HRAS
Lynch syndrome-associated urothelial carcinoma
Tend to be in the upper urothelial tract
Especially MSH2 mutated Lynch syndrome
When approaching a suspected urothelial carcinoma, you first want to divide it into:
Flat or Papillary
Flat lesions may just appear as patchy erythema on cytoscopy. Tend to have high-grade nuclear features. Loss of polarity, increased cytoplasmic eosinophilia. Do NOT need to be full-thickness, and may exhibit Pagetoid spread.
Papillary lesions will appear . . . papillary. Their pathology can vary more widely, from non-malignant to high-grade.
When you see a flat urothelial lesion with dysplasia, you need to make the judgement call. . .
. . . is it CIS or is it just dysplasia?
There are no hard guidelines for this. It is a judgement call. Tremendous inter-observer variability.
Approach to papillary urothelial neoplasms
The main categories of papillary urothelial neoplasm
Urothelial papilloma
Note that while it is definitely papillary, the normal epithelial thickness is preserved.
10% will recur, but only 1% will progress to a carcinoma.
Treated with TURBT
Papillary urothelial neoplasm of low malignant potential (PUN-LMP)
Papillary lesion of slightly increased thickness with minimal atypia that is consistent throughout the lesion. Monotonous appearance with preserved cellular polarity.
Non-Invasive Papillary Urothelial Carcinoma - Low Grade
Relatively delicate papillae with extensive branching. Relatively orderly, but with some variation at high-power.
Mild to moderate nuclear pleomorphism. Any thickness, but often thicker than normal. Cellular polarity is maintained.
Grade based on highest-grade component (at least if >5%)
Recurrence rate ~30%; Treat with TURBT & surveillance
Non-Invasive Papillary Urothelial Carcinoma - High Grade
Disordered appearance with both architectural and cytologic
abnormalities. Loss of cell polarity and irregular spacing and nuclear overlap, often discohesive. Often fusion of papillae.
Nuclear pleomorphism, hyperchromasia, clumped chromatin. Sometimes prominent nucleoli.
Recurrence rate ~50%; Treat with TURBT & surveillance
Urothelial Proliferaiton of Uncertain Malignant Potential (U-PUMP)
Markedly thickened urothelium (> 10 cells).
No or minimal atypia, but increased cell density. Unlike papillary lesions, there are no true papillary fronds with fibrovascular
cores. Instead, there are just undulating mucosal folds.
This is a clonal neoplasm, and may be early pre-cursor to low grade papillary urothelial carcinoma (often at the “shoulder” of these lesions).
Followed clinically.
Oh my god, is that cancer?!
Nope, just an inverted urothelial papilloma.
Note how benign and bland the individual cells look. Typically 5-10 cells thick with a smooth stroma-epithelial interface and no stromal reaction.
There may also be some cystic lesions, like cystitis cystica associated with Von Brunn nests.
Inverted Papillary Urothelial Carcinoma
To differentiate from simple inverted papillomas, these are >10 cells thick, have a more nodular and expansile growth pattern, and display more cytologic atypia and more mitoses.
Variants of invasive urothelial carcinoma
Squamous (either keratinizing or intercellular bridging - makes up 50% of IUCs)
Glandular (makes up 20% of IUCs, often with enteric immunophenotype)
Trophoblastic (giant cells resembling trophoblasts that may also secrete hCG!)
Plasmacytoid (also CD138+!)
Micropapillary
Nested
Lymphoepithelial-like
Sarcomatoid (sometimes with heterologous differentiation, like osteosarcoma)
The big decision to make once you have an invasive bladder carcinoma
Is there muscularis propria invasion?
If so, this buys the patient stage T2, a cystectomy, and chemotherapy.
If < T2, then the patient gets conservative treatment with TURBT
Primary urothelial squamous cell carcinoma
So this is kind of a confusing topic.
A pure SCC of the bladder has no urothelial components whatsoever.
Generally, SCC of the bladder is pretty rare in the US, but is more common where Schistosomiasis is endemic (Africa, Middle East). More generally, chronic bladder inflammation is the major risk factor.
Neuroendocrine tumors of the bladder
Small cell neuroendocrine carcinoma —same as pulmonary (and other organ) small cell carcinoma. Frequently associated with traditional urothelial carcinoma (that then de/transdifferentiates). Can express TTF1. Aggressive.
Large cell neuroendocrine carcinoma—Very rare. Aggressive.
Well-differentiated neuroendocrine tumors—resemble those of the GI tract. Often have prominent pseudoglandular pattern (resembling cystitis cystica/glandularis). Often mucosal and excellent prognosis
Nephrogenic adenoma
These are often on the differential and you need to be able to tease them out. They are benign reactions to urothelial injury.
May present in a tubular, papillary, or fibromyxoid architecture.
Cells are often hobnailed and on a thickened basement membrane, with no significant nuclear atypia.
IHC: PAX8+
Villous adenoma
Histologically identical to colonic adenomas, with papillary architecture.
May also progress to an adenocarcinoma, which can be hard to distinguish from a GI metastasis. β-Catenin strong nuclear reactivity in most colon cancers, but not in bladder adenocarcinomas. Other markers (e.g., CDX2) can be positive in both.
Urachal carcinoma
Arise from urachal remnants. Often adenocarcinomas.
Frequently intestinal-type and/or mucinous appearing
Four criteria:
1) Location in bladder dome or anterior wall (midline)
2) Epicenter in bladder wall (not mucosal)
3) Absence of widespread cystitis cystica near tumor
4) Absence of other known primaries
Clear cell carcinoma of the bladder
Derived from pre-existing Müllerian precursors (Accordingly more common in women, can also get endometrioid carcinomas). Most common in urethra, bladder neck, and trigone.
Characteristic morphology:
Abundant clear to eosinophilic cytoplasm. Severe cytologic atypia. Hyperchromatic nuclei. Varied architecture: Tubules, papillary, diffuse, etc..
IHC:
Positive CAM5.2, CK7, PAX8, HNF1β, AMCAR
Negative PSA, PSAP, p63, HMWCK, ER, PR, GATA3
Poor prognosis
Paraganglioma
Presents with symptoms of catecholamine secretion.
It is submucosal, since it is derived from paraganglion cells of the bladder. “Zellballen” pattern (aka balls of cells) with nests separated with a rich vascular network of sustentacular cells. Cells have amphophilic to acidophilic cytoplasm.
IHC:
Synaptophysin/Chromogranin positive in tumor
cells; S100/Sox10 positive in sustentacular cells.
CK negative. GATA3 positive.
Molecular: Germline SDH mutations present in some cases, associated with familial GIST.
Often benign behavior if low stage, but can metastasize. Mostly a problem due to its endocrine effects.
Polypoid cystitis
Benign reaction to an inflammatory insult, such as an indwelling catheter
Submucosal edema, fibrosis, and inflammation → broad bulbous projections covered with reactive urothelium
No epithelial branching, epithelial thickening, atypia or delicate cores, like in papillary neoplasms
