Bladder



Bladder






3.1 NORMAL UROTHELIUM VS. UROTHELIAL DYSPLASIA

Normal Urothelium

Urothelial Dysplasia


Age

Any age, but typically biopsied in adults

Typically adults


Location

Not pertinent

Anywhere with urothelial lining


Symptoms

Asymptomatic

Asymptomatic


Signs

None. Although biopsy typically done either during follow-up of prior urothelial neoplasia or for mapping at the time of biopsy of urothelial carcinoma to determine multifocality

None. Although biopsy typically done either during follow-up of prior urothelial neoplasia or for mapping at the time of biopsy of urothelial carcinoma to determine multifocality


Etiology

Not pertinent

Precursor in some cases to urothelial carcinoma in situ (CIS). Can also be seen adjacent to noninvasive low-grade papillary urothelial carcinoma


Histology


  1. Normal thickness consisting of 6-7 cell layers, yet no need to count (Figs.3.1.1, 3.1.2, 3.1.3)



  2. Cohesive cells



  3. Umbrella cells present



  4. Uniform cells without enlarged hyperchromatic nuclei



  5. Mitotic figures typically absent



  6. Polarity maintained


  1. Range from normal thickness to hyperplastic (Figs.3.1.4, 3.1.5, 3.1.6)



  2. Cohesive cells



  3. Umbrella cells present



  4. Scattered cells with scattered, slightly enlarged hyperchromatic nuclei (Figs.3.1.4, 3.1.5, 3.1.6)



  5. Mitotic figures typically absent but if few present still consistent with diagnosis (Fig. 3.1.5)



  6. Polarity in general maintained although slight loss may be present


Special studies

CK20 stains the umbrella cell layer only

CK20 stains full thickness of the urothelium, although exceptions occur


Treatment

Not applicable

Typically, dysplasia itself not treated. Patients followed more closely with shorter-interval cystoscopy and may undergo additional tissue sampling, urine cytology, and urine FISH studies to evaluate for CIS


Prognosis

Not applicable

Increased risk of CIS either concurrently or subsequently, although accurate data on the magnitude of risk are lacking, hampered by poor interobserver reproducibility of diagnosing dysplasia. Studies cite 5%-19% risk of progressing to urothelial carcinoma








Figure 3.1.1 Normal urothelium.






Figure 3.1.2 Urothelium with slight variation in nuclear size still consistent with normal.






Figure 3.1.3 Normal urothelium with slight variation in polarity but lacking nuclear atypia.






Figure 3.1.4 Dysplasia with scattered mildly enlarged hyperchromatic nuclei.






Figure 3.1.5 Dysplasia with scattered mildly enlarged hyperchromatic nuclei and mitotic figures (arrow).






Figure 3.1.6 Dysplasia with a thickened urothelium and diffuse mildly enlarged hyperchromatic nuclei.



3.2 UROTHELIAL DYSPLASIA VS. CARCINOMA IN SITU (CIS)

Urothelial Dysplasia

Carcinoma In Situ (CIS)


Age

Typically adults

Typically adults


Location

Anywhere with urothelial lining

Anywhere with urothelial lining


Symptoms

Asymptomatic

Asymptomatic or symptoms identical to that seen with urinary tract infections


Signs

None. Although biopsy typically done either during follow-up of prior urothelial neoplasia or for mapping at the time of biopsy of urothelial carcinoma to determine multifocality

None or hematuria, typically microscopic


Etiology

Precursor in some cases to urothelial CIS. Can also be seen adjacent to noninvasive low-grade papillary urothelial carcinoma

Most common is smoking, accounting for 60% and 30% of all urothelial carcinomas in males and females, respectively. Other risk factors include exposure to various chemicals, heredity, infection, prior radiation, and prior cyclophosphamide chemotherapy


Histology


  1. Range from normal thickness to hyperplastic



  2. Cohesive cells



  3. Umbrella cells present



  4. Scattered cells with scattered, slightly enlarged hyperchromatic nuclei (Figs.3.2.1, 3.2.2, 3.2.3, 3.2.4)



  5. Prominent nucleoli typically absent



  6. Relatively uniform nuclear size and shape without irregular nuclei



  7. Mitotic figures typically absent



  8. Typically abundant cytoplasm



  9. Polarity in general maintained although slight loss may be present


  1. Varies from a single cell layer to normal thickness to hyperplastic



  2. Often dyscohesive cells



  3. Umbrella cells typically absent, but in some cases present



  4. Markedly enlarged hyperchromatic nuclei (the largest nucleus 5× size of lamina propria lymphocyte nuclei) (Figs.3.2.5, 3.2.6, 3.2.7, 3.2.8)



  5. Some cases may show prominent nucleoli (Fig. 3.2.7)



  6. Variability of nuclear size and shape with scattered, irregular nuclei (Figs.3.2.5, 3.2.6, 3.2.7, 3.2.8)



  7. Mitotic figures, sometimes frequent, may be present



  8. Cytoplasm ranges from abundant to scant with marked variation of the nuclear-to-cytoplasmic (N:C) ratio



  9. Polarity lost resulting in cellular disorder


Special studies


  • CK20 stains abnormal cells, although exceptions occur



  • p53 typically negative



  • UroVysion FISH may demonstrate aneusomy for chromosomes 3,7,17 or loss of 9p, yet with less frequency than CIS


  • CK20 stains abnormal cells, although exceptions occur



  • p53 may be positive, yet only intense diffuse staining present specific



  • UroVysion FISH demonstrates aneusomy for chromosomes 3,7,17 or loss of 9p. Sensitivity and specificity are close to 100% for the diagnosis of CIS


Treatment

Typically, dysplasia itself not treated. The patient followed more closely with shorter-interval cystoscopy and may undergo additional tissue sampling, urine cytology to evaluate for CIS

Initial diagnosis of CIS typically treated with a course of intravesicular BCG. If CIS recurs following a complete course of BCG, some authorities recommend immediate cystectomy


Prognosis

Increased risk of CIS either concurrently or subsequently, although accurate data on the magnitude of risk are lacking, hampered by poor interobserver reproducibility of diagnosing dysplasia. Studies cite 5%-19% risk of progressing to urothelial neoplasia

Evolution from CIS to invasion highly variable with some cases having rapid progression and others a more protracted time course. Overall, invasive carcinoma develops in up to 50% of patients within 5 y. The initial tumor-free response with BCG is as high as 84%. Approximately 50% show a durable response for a median of 4 y








Figure 3.2.1 Dysplasia with scattered, mildly enlarged hyperchromatic nuclei (arrow).






Figure 3.2.2 Dysplasia with scattered, mildly enlarged hyperchromatic nuclei.







Figure 3.2.3 Dysplasia with scattered, mildly enlarged hyperchromatic nuclei (arrow).






Figure 3.2.4 Dysplasia with scattered, mildly enlarged hyperchromatic nuclei.






Figure 3.2.5 CIS with markedly enlarged hyperchromatic nuclei relative to stromal lymphocytes. Cells have abundant cytoplasm and a mitotic figure.






Figure 3.2.6 CIS with markedly enlarged hyperchromatic nuclei relative to the normal urothelium in von Brunn nest.






Figure 3.2.7 CIS with variably sized and shaped nuclei. Largest nuclei are markedly enlarged relative to stromal lymphocytes.






Figure 3.2.8 CIS with a thickened urothelium with diffusely enlarged and hyperchromatic nuclei.



3.3 NORMAL UROTHELIUM ON FROZEN SECTIONS OF THE URETER VS. CARCINOMA IN SITU (CIS) ON FROZEN SECTIONS OF THE URETER

Normal Urothelium on Frozen Sections of the Ureter

Carcinoma In Situ (CIS) on Frozen Sections of the Ureter


Age

Adults

Typically adults


Location

Distal ureter

Distal ureter


Symptoms

None

Asymptomatic in this setting


Signs

None

None in this setting


Etiology

Frozen sections of the ureter margin typically done at the time of cystectomy for urothelial carcinoma

Frozen sections of the ureter margin typically done at the time of cystectomy for urothelial carcinoma


Histology


  1. Using the 10× lens, nuclei should appear very small and do not stand out as abnormal. Appears almost the same size as lymphocyte nuclei (Figs.3.3.1, 3.3.2, 3.3.3, 3.3.4)



  2. Normal thickness consisting of six to seven cell layers, yet no need to count



  3. Cohesive cells, yet difficult to evaluate with a frozen-section artifact



  4. Umbrella cells present, yet hard to appreciate on frozen section



  5. Mitotic figures typically absent



  6. At most minimal variability of nuclear size and shape, yet variability can be exaggerated at high magnification on frozen section


  1. Using the 10× lens, some nuclei appear large and abnormal (Figs.3.3.5, 3.3.6, 3.3.7, 3.3.8)



  2. May vary from just a single cell layer to normal thickness to hyperplastic



  3. Often dyscohesive cells ranging from cells just starting to detach from each other, to clusters of cells lifting off the basement membrane, to more widely dispersed individual cells



  4. Umbrella cells typically absent, but in some cases present



  5. Mitotic figures may be present



  6. Some variability of nuclear size and shapes among abnormal cells with scattered irregular nuclei


Special studies

Not pertinent

Not pertinent


Treatment

No need to take an additional section of the ureter

Urologist will take an additional section of the ureter closer to the kidney and submit for another frozen section. If there is persistent CIS close to the kidney, most urologists will not perform a nephrectomy to obtain negative margins. The contralateral renal pelvis and ureter are also at increased risk of developing urothelial carcinoma, and renal preservation is critical given the morbidity and mortality of renal dialysis in the situation of bilateral nephrectomies


Prognosis

Still at risk of developing multifocal urothelial neoplasia in the ipsilateral renal pelvis and remaining ureter, as well as rest of the urothelial tract

If CIS is left at a margin and there is recurrence of urothelial carcinoma, it is typically not at the site of the resection but elsewhere in the urothelial tract








Figure 3.3.1 Benign ureteral margin at frozen section. All images in this chapter are taken at the same magnification of 10× lens.






Figure 3.3.2 Benign ureteral margin at frozen section.






Figure 3.3.3 Benign ureteral margin at frozen section with hyperplastic appearance possibly due to tangential sectioning.






Figure 3.3.4 Benign ureteral margin at frozen section with an air-drying artifact giving rise to an appearance of slightly enlarged nuclei.






Figure 3.3.5 CIS with overtly enlarged and hyperchromatic nuclei.






Figure 3.3.6 CIS with overtly enlarged and hyperchromatic nuclei.







Figure 3.3.7 CIS with overtly enlarged and hyperchromatic nuclei.






Figure 3.3.8 More difficult case where it is borderline CIS, but there is still sufficient nuclear enlargement compared to the more normal urothelium (arrow) to ask the urologist to resect more ureter in an attempt to obtain a normal urothelium.



3.4 CARCINOMA IN SITU (CIS), CLINGING TYPE VS. DENUDED UROTHELIUM

Carcinoma In Situ (CIS), Clinging Type

Denuded Urothelium


Age

Typically adults

Any age, but typically biopsied in adults


Location

Anywhere with urothelial lining

Anywhere with urothelial lining


Symptoms

May be asymptomatic or can have symptoms identical to that associated with urinary tract infections

Asymptomatic


Signs

May be none or can be associated with hematuria, typically microscopic

None. Although biopsy typically done either during follow-up of prior urothelial neoplasia or for mapping at the time of biopsy of urothelial carcinoma to determine multifocality


Etiology

See Section 3.5

May result from instrumentation or shedding of CIS cells


Histology


  1. Areas of the specimen lack the urothelium



  2. Single cells either resting on the basement membrane or dyscohesive (Figs.3.4.1, 3.4.2, 3.4.3, 3.4.4, 3.4.5)



  3. Markedly enlarged hyperchromatic nuclei visibly abnormal using the 10× lens with the largest nucleus 5× size of lamina propria lymphocyte nuclei (Figs.3.4.1, 3.4.2, 3.4.3, 3.4.4, 3.4.5)



  4. Some variability of nuclear size and shapes among abnormal cells with scattered irregular nuclei



  5. Mitotic figures, sometimes frequent, may be present


  1. Areas of the specimen lack the urothelium



  2. May have areas of a preserved cohesive normal urothelium or single cells resting on the basement membrane



  3. Preserved urothelium appears like small dots using 10× lens with the largest nucleus 2-3× size of lamina propria lymphocyte nuclei (Fig. 3.4.6)



  4. Uniform cells without enlarged hyperchromatic nuclei



  5. Mitotic figures typically absent unless accompanied by inflammation and reactive changes


Special studies


  • CK20 stains abnormal cells, although exceptions occur



  • p53 may be positive, yet only intense diffuse staining present, specific for CIS



  • UroVysion FISH demonstrates aneusomy for chromosomes 3, 7, 17 or loss of 9p


  • CK20 negative in cells, as the only positive cells are umbrella cells, which are absent in areas of denudation



  • p53 negative yet false positive occurs with weak to moderate nuclear staining



  • UroVysion FISH demonstrates lack of aneusomy for chromosomes 3,7,17 or loss of 9p. Sensitivity and specificity are close to 100% for the diagnosis of CIS


Treatment

Same treatment as usual CIS (see Section 3.2)

Denudation is an abnormal finding especially if biopsy taken without the use of cautery. Urinary cytology and close follow-up recommended due to the associated finding of denudation with concurrent or subsequent CIS


Prognosis

Same prognosis as usual CIS (see Section 3.2)

In the setting of denuded biopsies, CIS develops within 24 mo in 45% of patients where specimens obtained by cold cup biopsy compared to none obtained by hot wire loop biopsy. CIS develops within 24 mo in 75% of patients if in addition to cold cup biopsy there is a history of CIS vs. 29% if cold cup biopsy and no history of CIS








Figure 3.4.1 CIS with lifting of the urothelium from the basement membrane.






Figure 3.4.2 CIS with loosely cohesive cells with markedly enlarged hyperchromatic nuclei.






Figure 3.4.3 CIS with loosely cohesive cells with markedly enlarged hyperchromatic nuclei. The largest nucleus (left) is four to five times the size of lymphocytes.






Figure 3.4.4 CIS with loosely cohesive cells with markedly enlarged hyperchromatic nuclei.






Figure 3.4.5 CIS with loosely cohesive cells with markedly enlarged hyperchromatic nuclei and mitotic figures (arrow).






Figure 3.4.6 Benign urothelium with denudation. The remaining urothelium consists of cells with relatively small uniform nuclei.



3.5 CARCINOMA IN SITU (CIS) VS. REACTIVE UROTHELIUM

Carcinoma In Situ (CIS)

Reactive Urothelium


Age

Typically adults

Any age, but typically biopsied in adults


Location

Anywhere with urothelial lining

Anywhere with urothelial lining


Symptoms

May be asymptomatic or can have symptoms identical to that associated with urinary tract infections

Asymptomatic or may be associated symptoms relating to specific etiology


Signs

May be none or can be associated with hematuria, typically microscopic

Associated signs relating to any condition that irritates the bladder.


Etiology

Numerous environmental risk factors. Most common is history of smoking, accounting for 60% and 30% of all urothelial carcinomas in males and females, respectively. Other risk factors include exposure to various chemicals (especially aromatic amines), heredity, infection, prior radiation, and prior chemotherapy with cyclophosphamide

Some of the more common situations resulting in a reactive urothelium include urinary calculi, colovesical fistula, infection, and instrumentation


Histology


  1. The urothelium may be thin, hyperplastic, or of normal thickness



  2. Most cases have cells with markedly enlarged nuclei. Visibly abnormal using 10× lens with the largest nucleus 5× size of lamina propria lymphocyte nuclei



  3. Nuclei typically very hyperchromatic although occasionally with prominent nucleoli (Figs.3.5.1, 3.5.2, 3.5.3)



  4. Nuclei are often irregular (Figs.3.5.1, 3.5.2, 3.5.3)



  5. Mitotic figures, sometimes frequent, may be present



  6. Most cases lack inflammation within the urothelium, although exceptions occur (Figs.3.5.1, 3.5.2, 3.5.3)


  1. The urothelium may be thin, hyperplastic, or of normal thickness



  2. Enlarged nuclei, may be as large as CIS



  3. Nuclei vesicular with central prominent nucleoli (Figs.3.5.4, 3.5.5, 3.5.6, 3.5.7)



  4. Nuclei uniform in size and shape



  5. Mitotic figures may be numerous (Fig. 3.5.5)



  6. Degree of reactive changes proportional to the extent of intramucosal inflammation. Both acute and chronic inflammation within the urothelium can result in reactive changes. Even a few inflammatory cells in the urothelium can lead to reactive changes. There are always some lymphocytes in the lamina propria, which by themselves are not enough to give rise to reactive atypia


Special studies


  • CK20 stains abnormal cells, although exceptions occur



  • p53 may be positive, yet only intense diffuse staining present is specific for CIS



  • CD44 supposed to label the basal cell layer or absent



  • Ki-67 is increased but not specific for CIS



  • UroVysion FISH demonstrates aneusomy for chromosomes 3,7,17 or loss of 9p. Sensitivity and specificity are close to 100% for the diagnosis of CIS


  • CK20 labels only umbrella cells, although not 100% sensitive or specific (Fig. 3.5.8)



  • p53 negative, yet false positive occurs with weak to moderate nuclear staining (Fig. 3.5.9)



  • CD44 supposed to label full thickness, although not as widely used as CK20



  • Ki-67 may be increased in the reactive urothelium to the same extent as CIS (Fig. 3.5.10)



  • UroVysion FISH demonstrates lack of aneusomy for chromosomes 3,7,17 or loss of 9p


Treatment

See Section 3.2

Tailored to the specific etiology


Prognosis

See Section 3.2

Treatment of the underlying cause resolves reactive changes








Figure 3.5.1 CIS with inflammation. Cells show marked nuclear pleomorphism.






Figure 3.5.2 CIS with inflammation. Cells show marked nuclear pleomorphism.






Figure 3.5.3 CIS with prominent nucleoli. In contrast to reactive changes, there is no inflammation in the urothelium, and nuclei are variable in size and shape.






Figure 3.5.4 Reactive changes with numerous intramucosal lymphocytes and vesicular nuclei with visible nucleoli.







Figure 3.5.5 Reactive changes with numerous intramucosal neutrophils and vesicular nuclei with prominent nucleoli and mitotic figures (arrows).






Figure 3.5.6 Reactive changes with numerous intramucosal neutrophils and vesicular nuclei with prominent nucleoli. Nuclei are uniformly enlarged and lack variation in shape.






Figure 3.5.7 Reactive changes with numerous intramucosal neutrophils and eosinophils. Nuclei are vesicular with prominent nucleoli and are uniformly enlarged without pleomorphism.






Figure 3.5.8 CK20 typically stains umbrella cells only in the normal and reactive urothelium (left) with diffuse CK20 immunoreactivity in dysplasia and CIS (right).






Figure 3.5.9 Diffuse strong p53 staining in CIS (left) compared to weak and moderate patchy p53 labeling (right) that is not diagnostic for CIS.






Figure 3.5.10 Reactive urothelium (right) with a marked increase in Ki-67 labeling (left).



3.6 CARCINOMA IN SITU (CIS) VS. RADIATION/CHEMOTHERAPY UROTHELIAL ATYPIA

Carcinoma In Situ (CIS)

Radiation/Chemotherapy Urothelial Atypia


Age

Typically adults

Any age, but typically biopsied in adults


Location

Anywhere with urothelial lining

Anywhere with urothelial lining


Symptoms

May be asymptomatic or can have symptoms identical to that associated with urinary tract infections

Asymptomatic or may be associated irritative symptoms


Etiology

Prior irradiation or cyclophosphamide can predispose to development of CIS, typically years after therapy

Intravesical chemotherapy with mitomycin typically only affects morphology of umbrella cells. Cyclophosphamide and radiation can cause changes mimicking CIS. Changes in the urothelium lining the lumen should not persist beyond 1 year after cessation of radiation/chemotherapy. Radiation/chemotherapy atypia within von Brunn nests, the urothelium can persist for years


Histology


  1. The urothelium may be thin, hyperplastic, or of normal thickness



  2. Most cases have cells with markedly enlarged hyperchromatic nuclei visibly abnormal using 10× lens with the largest nucleus 5× size of lamina propria lymphocyte nuclei



  3. Multinucleated and vacuolated nuclei absent (Fig. 3.6.1)



  4. Mitotic figures, sometimes frequent, may be present (Fig. 3.6.1)



  5. Cytoplasm may be scant or abundant, but not spindled or excessive



  6. In some cases, CIS is not distinguishable from radiation/chemotherapy atypia. In the setting of prior radiation/chemotherapy, only unequivocal CIS should be diagnosed.


  1. The urothelium may be thin, hyperplastic, or of normal thickness



  2. Enlarged nuclei, as large seen in CIS, are vesicular with central prominent nucleoli



  3. Nuclei are bizarre with multinucleation and vacuolization (Figs.3.6.2, 3.6.3, 3.6.4, 3.6.5, 3.6.6)



  4. Mitotic figures are absent



  5. Cytoplasm typically abundant and often spindled with strap-like cells (Figs. 3.6.2, 3.6.3, and 3.6.6)



  6. In some cases with urothelial atypia and a short (<1 y) interval between end of radiation/chemotherapy, the histologic distinction between CIS is not clear and close follow-up and repeat biopsy with a longer follow-up are recommended


Special studies


  • CK20 stains abnormal cells, although exceptions occur



  • p53 may be positive, yet only intense diffuse staining is more specific for CIS


  • Data not definitive on CK20 in radiation/chemotherapy atypia



  • p53 negative, yet false positive occurs with weak to moderate nuclear staining


Treatment

See Section 3.2

No treatment needed unless other side effects from the prior therapy such as hemorrhagic cystitis


Prognosis

See Section 3.2

Prior irradiation or systemic cyclophosphamide therapy associated with an increased risk of CIS years after treatment








Figure 3.6.1 CIS with markedly enlarged hyperchromatic nuclei and mitotic figures and modest amount of cytoplasm.






Figure 3.6.2 Radiation atypia with enlarged nuclei with a degenerative appearance with nuclear vesicles. Cells also have abundant spindled cytoplasm.






Figure 3.6.3 Radiation atypia with degenerative nuclear atypia and abundant cytoplasm.






Figure 3.6.4 Radiation atypia with a multinucleated hyperchromatic nucleus.






Figure 3.6.5 Radiation atypia with a multinucleated nucleus.






Figure 3.6.6 Radiation atypia with degenerative nuclear atypia and abundant cytoplasm.



3.7 POLYPOID CYSTITIS VS. PAPILLARY UROTHELIAL NEOPLASM

Polypoid Cystitis

Papillary Urothelial Neoplasm


Age

Any age, but typically biopsied in adults

Any age, but typically biopsied in adults


Location

Anywhere with urothelial lining

Anywhere with urothelial lining


Symptoms

Asymptomatic or may be associated symptoms relating to specific etiology

Typically gross or microscopic hematuria


Signs

Associated signs relating to any condition that irritates the bladder. At cystoscopy, the lesion is often clearly reactive to the urologist

At cystoscopy, the urologist can usually recognize that a lesion is a papillary urothelial neoplasm as opposed to polypoid cystitis


Etiology

Most often cited is indwelling catheter but others include urinary calculi, colovesical fistula, infection, instrumentation, and prior irradiation

Numerous environmental risk factors. Most common is history of smoking, accounting for 60% and 30% of all urothelial carcinomas in males and females, respectively. Other risk factors include exposure to various chemicals, heredity, infection, prior radiation, and prior chemotherapy with cyclophosphamide


Histology


  1. Simple folds of urothelium in continuity with the underlying bladder (Figs. 3.7.1, 3.7.2, 3.7.3). Rare fronds may appear to be free floating or branching



  2. Stroma within fronds appears pale as a result of edema with scattered inflammatory cells (Figs.3.7.1, 3.7.2, 3.7.3).



  3. Stroma within fronds may in later stages appear more dense pink as a result of fibrosis with scattered lymphocytes (Figs.3.7.4, 3.7.5, 3.7.6, 3.7.7)



  4. Stalks typically lack prominent numerous small capillaries



  5. In majority of cases, some of the fronds will have broad base although others in the same case may be narrow



  6. Reactive urothelium may be seen, including mitotic figures (see Section 3.5) (Fig. 3.7.8)



  7. In about one-third of cases may be focal or diffuse thickening of the urothelium. Most normal thickness (Figs. 3.7.1, 3.7.2, and 3.7.4, 3.7.5, 3.7.6, 3.7.7 and 3.7.8)



  8. At low magnification, >90% of the lesion has features of polypoid cystitis, yet there may be isolated fronds that out of context could be interpreted as a low-grade papillary urothelial neoplasm (Figs. 3.7.2, 3.7.6, and 3.7.8)


  1. As a result of complex branching papillary fronds, most of the papillary structures in a given plane of section appear to be free floating detached from the underlying bladder surrounded on the slide by white space (Fig. 3.7.9)



  2. Stalks may occasionally appear clear at low power, usually due to dilated lymphatics but occasionally due to stromal edema. Inflammatory cells within stalks are typically absent or minimal (Fig. 3.7.10).



  3. Stalks have loose connective tissue with delicate light eosinophilic appearance



  4. Stalks often have numerous small capillaries (Fig. 3.7.9)



  5. Base of fronds typically narrow



  6. Urothelial atypia consists of enlarged variably sized hyperchromatic nuclei



  7. With the exception of papilloma, the urothelium thickened (Fig. 3.7.9)



  8. At low magnification, the entire lesion looks like a papillary urothelial neoplasm


Special studies

Not helpful in this differential

Not helpful in this differential


Treatment

Tailored to the specific etiology

Tailored to the tumor’s grade, size, multifocality and whether the lesion is a recurrence or primary lesion (see Sections 3.9, 3.10, 3.11)


Prognosis

Treatment of the underlying cause resolves the reactive changes

See Sections 3.9, 3.10, 3.11








Figure 3.7.1 Polypoid cystitis with simple folds of pale, edematous urothelium.






Figure 3.7.2 Polypoid cystitis with mostly simple folds with wide base but occasional smaller edematous papillary structures (arrows) that could be misdiagnosed as a papillary urothelial neoplasm.






Figure 3.7.3 Polypoid cystitis with simple folds of pale edematous urothelium containing inflammatory cells.






Figure 3.7.4 Polypoid cystitis with simple folds and densely fibrotic and inflamed stroma.







Figure 3.7.5 Polypoid cystitis with occasional branching folds and densely fibrotic and inflamed stroma.






Figure 3.7.6 Typical polypoid cystitis (top) with simple broad based folds replaced by densely eosinophilic fibrotic stroma. Focal small fronds with fibrous cores (arrow) were misdiagnosed as papillary urothelial carcinoma.






Figure 3.7.7 Unusual case of polypoid cystitis with long simple folds containing abundant inflammation and fibrous tissue.






Figure 3.7.8 Polypoid cystitis with areas showing simple broad based folds with intense inflammation. Focal small fronds (arrow) were misdiagnosed as papillary urothelial carcinoma. Inset shows an inflamed reactive urothelium.






Figure 3.7.9 Low-grade papillary urothelial carcinoma with edematous yet not inflamed stalks containing numerous prominent capillaries. Focally, the urothelium is markedly thickened.






Figure 3.7.10 Low-grade papillary urothelial carcinoma with dilated lymphatic in stalk. Lesion has multiple “free-floating” fronds indicative of a complex branching papillary lesion.



3.8 PAPILLARY UROTHELIAL HYPERPLASIA VS. UROTHELIAL PAPILLOMA

Papillary Urothelial Hyperplasia

Urothelial Papilloma


Age

Mean age mid-late 50s with wide range

Mean age mid-late 50s with wide range. Can rarely be seen in children


Location

Anywhere with urothelial lining

Anywhere with urothelial lining


Symptoms

Most commonly asymptomatic detected at cystoscopy for follow-up of prior urothelial neoplasms. Next most commonly presents with hematuria

Typically gross or microscopic hematuria


Signs

At cystoscopy, the lesion is subtle and in order of decreasing frequency thought to be a papillary neoplasm, papillary irregularity, or irregular mucosa

At cystoscopy, delicate papillary lesion, typically solitary and relatively small


Etiology

A subset of papillary urothelial hyperplasia demonstrates loss of chromosomal arm 9q, which is among the earliest event in bladder cancer progression, demonstrating that some cases of papillary hyperplasia are precancerous lesions of the bladder

Thought to be the same as urothelial carcinoma


Histology


  1. Simple folds of the urothelium in continuity with the underlying bladder (Figs.3.8.1, 3.8.2, 3.8.3, 3.8.4)



  2. May see subtle slight branching of folds at the tips of papillary folds



  3. In most cases, there is thickening of the urothelium



  4. Cytology is normal. In some cases, there is the architecture of papillary urothelial hyperplasia yet with marked cytologic atypia, which is termed CIS with early papillary formation



  5. Umbrella cells inconspicuous



  6. Base of the papillae may show collection of dilated capillaries


  1. As a result of complex branching papillary fronds, most of the papillary structures in a given plane of section appear to be free floating detached from the underlying bladder surrounded on the slide by white space (Figs. 3.8.5 and 3.8.6)



  2. In a minority of cases, can see secondary branching of smaller fronds from larger ones



  3. The urothelium is normal thickness



  4. Cytology is normal



  5. Umbrella cells vary from inconspicuous to apocrine to having prominent degenerative atypia



  6. Within the papillae are often a collection of small congested capillaries


Special studies

Not helpful in this differential

Not helpful in this differential


Treatment

Typically, not treated but patients closely followed. In cases of CIS with early papillary formation, treated as CIS

Typically, resected by TUR and not treated with adjuvant therapy


Prognosis

60% have a history of prior urothelial neoplasms, 80% of which are low grade. The 5-y actuarial risk of subsequently developing an urothelial neoplasm in the setting of papillary urothelial hyperplasia is 28% and 50% for those without and with a history of prior papillary urothelial neoplasms. In two-thirds of cases, the subsequent neoplasm is low grade (papilloma, PUNLMP, low-grade carcinoma). All together two-thirds of patients with papillary urothelial hyperplasia have a history of prior, concurrent, or subsequent urothelial neoplasms

In most cases once resected, the lesion does not recur. In about 10% of cases, the lesion recurs as papilloma and in 10% as low-grade papillary carcinoma or PUNLMP. Only rare cases in patients with immunosuppression progress to high-grade papillary or invasive carcinoma








Figure 3.8.1 Papillary urothelial hyperplasia with thickened folds of the urothelium.






Figure 3.8.2 Papillary urothelial hyperplasia with thickened folds of the urothelium.






Figure 3.8.3 Papillary lesion that is borderline between papillary urothelial hyperplasia and early papilloma.






Figure 3.8.4 Papillary urothelial hyperplasia (right and inset) with adjacent papilloma (left).






Figure 3.8.5 Early papilloma with branching and beginning of “detached” papillary fronds.






Figure 3.8.6 Papilloma with “free-floating” fronds.



3.9 UROTHELIAL PAPILLOMA VS. PAPILLARY UROTHELIAL NEOPLASM OF LOW MALIGNANT POTENTIAL (PUNLMP)

Urothelial Papilloma

Papillary Urothelial Neoplasm of Low Malignant Potential


Age

Mean age mid-late 50s with wide range. Can rarely be seen in children

Mean age mid-60s with wide range. Can rarely be seen in children


Location

Anywhere with urothelial lining

Anywhere with urothelial lining


Symptoms

Typically gross or microscopic hematuria

Typically gross or microscopic hematuria


Signs

At cystoscopy, delicate papillary lesion, typically solitary and relatively small

At cystoscopy, papillary lesion, typically solitary with wide range in size


Etiology

Thought to be the same as urothelial carcinoma

Thought to be the same as urothelial carcinoma


Histology


  1. Typically small lesion that fits on one slide



  2. Discrete, nonfused papillae



  3. Inverted growth pattern not common



  4. The urothelium is normal thickness (Figs. 3.9.1 and 3.9.2)



  5. Cytology is normal with some cells having nuclear grooves



  6. Umbrella cells vary from inconspicuous to apocrine to prominent degenerative atypia



  7. Mitotic figures absent.


  1. Ranges in size but can be large requiring multiple slides to totally submit



  2. Usually discrete, nonfused papillae but some may be fused



  3. Often with a prominent inverted growth pattern



  4. The urothelium is overtly thick, even at low magnification (Figs. 3.9.3 and 3.9.4)



  5. Cytology is normal or at most slightly enlarged nuclei with some cells having nuclear grooves (Fig. 3.9.5)



  6. Umbrella cells inconspicuous.



  7. Mitotic figures virtually absent or at most rarely seen toward the basement membrane.


Special studies

Not helpful in this differential.

Not helpful in this differential.


Treatment

Typically, resected by TUR and not treated with adjuvant therapy. Urologists recommend routine cystoscopies for life, although if after many years there is no recurrence, patients typically stop coming back for follow-up

Typically, resected by TUR and not treated with adjuvant therapy. Followed for life with routine cystoscopy


Prognosis

In most cases once resected, the lesion does not recur. In about 10% of cases, the lesion recurs as papilloma and in 10% as low-grade papillary carcinoma or PUNLMP. Only rare cases in the literature in patients with immunosuppression progress to high-grade papillary or invasive carcinoma

About 30% risk of recurrence over 15 years, typically as PUNLMP but occasionally as low-grade carcinoma. Only rare cases recur as higher-grade cancer with invasion. No deaths due to bladder cancer








Figure 3.9.1 Papilloma with the urothelium of normal thickness and cytology.






Figure 3.9.2 Papilloma.






Figure 3.9.3 PUNLMP with the overtly thickened urothelium.






Figure 3.9.4 Same case as Figure 3.9.3 with benign cytology.



3.10 PAPILLARY UROTHELIAL NEOPLASM OF LOW MALIGNANT POTENTIAL (PUNLMP) VS. LOW-GRADE PAPILLARY UROTHELIAL CARCINOMA

Papillary Urothelial Neoplasm of Low Malignant Potential (PUNLMP)

Low-Grade Papillary Urothelial Carcinoma


Age

Mean age mid-60s with wide range. Can rarely be seen in children

Mean age mid-60s with wide range. Can rarely be seen in children


Location

Anywhere with urothelial lining

Anywhere with urothelial lining


Symptoms

Typically gross or microscopic hematuria

Typically gross or microscopic hematuria


Signs

At cystoscopy, papillary lesion. May be solitary or multifocal

At cystoscopy, papillary lesion, typically solitary or multifocal


Etiology

Thought to be the same as urothelial carcinoma

Numerous environmental risk factors. Most common is history of smoking, accounting for 60% and 30% of all urothelial carcinomas in males and females, respectively. Other risk factors include exposure to various chemicals, heredity, infection, prior radiation, and prior chemotherapy with cyclophosphamide


Histology


  1. Ranges in size. Can be large requiring multiple slides to totally submit



  2. Usually discrete, nonfused papillae but some may be fused



  3. Often with a prominent inverted growth pattern



  4. The urothelium is overtly thick, even at low magnification (Figs.3.10.1, 3.10.2, 3.10.3, 3.10.4)



  5. Polarity strictly maintained



  6. Cytology is normal or at most slightly enlarged nuclei some with nuclear grooves (Figs.3.10.1, 3.10.2, 3.10.3, 3.10.4)



  7. Every microscopic field is monotonous with uniformly sized and shaped nuclei having light chromatin



  8. Nucleoli indistinct



  9. Mitotic figures virtually absent or at most rarely seen toward the basement membrane


  1. Ranges in size but can be large requiring multiple slides to totally submit



  2. Usually discrete, nonfused papillae but some may be fused



  3. Often with a prominent inverted growth pattern



  4. The urothelium is typically overtly thickened



  5. Polarity maintained although may not appear quite as regular as in PUNLMP



  6. Cytology is mostly normal with scattered slightly enlarged hyperchromatic nuclei that stand out even at lower magnification. Nuclear grooves not as common



  7. Scattered larger hyperchromatic nuclei with minimal variation in shape. Lacks the uniformity of PUNLMP (Figs.3.10.5, 3.10.6, 3.10.7, 3.10.8)



  8. Nucleoli range from indistinct to small but visible



  9. Mitotic figures range from uncommon to scattered seen at all layers of the urothelium


Special studies

Not helpful in this differential

Not helpful in this differential


Treatment

Typically, resected by TUR and not treated with adjuvant therapy. Followed for life with routine cystoscopy

Typically, resected by TUR with immediate instillation of intravesical chemotherapy recommended even for lesions with low risk of recurrence. Intravesical BCG not used for initial therapy, yet potentially used in patients with recurrent low-grade papillary urothelial carcinoma. Followed for life with routine cystoscopy


Prognosis

At 5 and 15 y, 10% and 30% risk of recurrence, respectively, typically as PUNLMP but occasionally as low-grade carcinoma. Only rare cases recur as higher-grade cancer with invasion. No deaths due to bladder cancer

At 5 and 15 y, 30% and 40% risk of recurrence, respectively, typically as low-grade carcinoma but occasionally as higher-grade carcinoma. Higher rate of recurrence vs. PUNLMP. 10% of cases recur as higher-grade cancer with invasion, higher rate than in PUNLMP. 1%-2% of patients eventually die due to bladder cancer








Figure 3.10.1 PUNLMP with uniform cytology, lacking scattered cells with nuclear hyperchromasia.






Figure 3.10.2 PUNLMP.






Figure 3.10.3 PUNLMP.






Figure 3.10.4 PUNLMP.







Figure 3.10.5 Low-grade papillary urothelial carcinoma with scattered hyperchromatic nuclei.






Figure 3.10.6 Low-grade papillary urothelial carcinoma with scattered hyperchromatic nuclei.






Figure 3.10.7 Low-grade papillary urothelial carcinoma with scattered hyperchromatic nuclei.






Figure 3.10.8 Low-grade papillary urothelial carcinoma with scattered hyperchromatic nuclei and mitotic figures (arrow).



3.11 LOW-GRADE PAPILLARY UROTHELIAL CARCINOMA VS. HIGH-GRADE PAPILLARY UROTHELIAL CARCINOMA

Low-Grade Papillary Urothelial Carcinoma

High-Grade Papillary Urothelial Carcinoma


Age

Mean age mid-60s with wide range. Can rarely be seen in children

Mean age mid-60s with wide range. Not as common as lower-grade papillary urothelial neoplasms under 20 y of age


Location

Anywhere with urothelial lining

Anywhere with urothelial lining


Symptoms

Typically gross or microscopic hematuria

Typically gross or microscopic hematuria


Signs

At cystoscopy, papillary lesion, solitary or multifocal

Same as low-grade papillary carcinoma, yet increased likelihood of sessile growth


Etiology

See Section 3.10

See Section 3.10


Histology


  1. Ranges in size, but can be large requiring multiple slides to totally submit



  2. Usually discrete, nonfused papillae but some may be fused



  3. Often with a prominent inverted growth pattern



  4. The urothelium is overtly thick, even at low magnification



  5. Polarity maintained with evenly space nuclei that are regularly distributed in an orderly almost row-like fashion (Figs.3.11.1, 3.11.2, 3.11.3)



  6. Cytology is mostly normal with scattered slightly enlarged hyperchromatic nuclei visible at lower magnification, comparable to nuclei of dysplasia (Figs.3.11.1, 3.11.2, 3.11.3)



  7. Nucleoli range from indistinct to small but visible



  8. Mitotic figures uncommon to scattered, seen in all layers of the urothelium.



  9. Cells typically cohesive



  10. Umbrella cells usually present



  11. Uncommon tumors where vast majority is low grade and <5% high grade. Controversial whether to call “high grade,” or “low grade with very focal high grade” adding a comment that the significance of this finding is unknown


  1. Ranges in size, but can be large requiring multiple slides to totally submit



  2. May have discrete, nonfused papillae but often fused



  3. Often with a prominent inverted growth pattern



  4. The urothelium is typically thickened



  5. Loss of polarity (irregular spacing of cells) or spindling of cells or irregular overlapping of nuclei (Fig. 3.11.4)



  6. Cytology is mostly abnormal with markedly enlarged hyperchromatic nuclei that stand out even at lower magnification, comparable to nuclei of CIS (Figs. 3.11.4 and 3.11.5)



  7. Nucleoli range from indistinct to small but visible. In some cases, diffuse very prominent nucleoli (Fig. 3.11.6)



  8. Mitotic figures frequent, seen in all layers of the urothelium (Figs. 3.11.4 and 3.11.6).



  9. Dyscohesive cells frequent (Fig. 3.11.7)



  10. Umbrella cells usually absent



  11. Uncommon cases with mixed low- and high-grade morphology. If high grade >5%, uniformly accepted should be called “high grade” (Fig. 3.11.8)


Special studies

Not helpful in this differential

Not helpful in this differential


Treatment

Typically, resected by TUR with immediate instillation of intravesical chemotherapy, even for lesions with low risk of recurrence. Intravesical BCG not used for initial therapy, yet potentially used with recurrent low-grade papillary urothelial carcinoma. Followed for life with routine cystoscopy

Typically, resected by TUR and then treated with intravesical BCG therapy. Followed for life with routine cystoscopy


Prognosis

At 5 y, 30% risk of recurrence, typically as low-grade carcinoma but occasionally as higher-grade carcinoma. 10% of cases recur as higher-grade cancer with invasion. 1%-2% of patients eventually die of disease

At 5 y, 30% risk of recurrence, typically as high-grade carcinoma. 30% of cases recur with invasion. 15% of patients eventually die of bladder cancer








Figure 3.11.1 Low-grade papillary urothelial carcinoma with uniform polarity and scattered minimally enlarged hyperchromatic nuclei.






Figure 3.11.2 Low-grade papillary urothelial carcinoma with uniform polarity and scattered minimally enlarged hyperchromatic nuclei.






Figure 3.11.3 Low-grade papillary urothelial carcinoma with uniform polarity and scattered minimally enlarged hyperchromatic nuclei.






Figure 3.11.4 High-grade papillary urothelial carcinoma with loss of polarity with nuclei not lining up in uniform spatial arrangement. Numerous mitotic figures noted.







Figure 3.11.5 High-grade papillary urothelial carcinoma with marked pleomorphism.






Figure 3.11.6 High-grade papillary urothelial carcinoma with diffuse prominent nucleoli and numerous mitotic figures.






Figure 3.11.7 High-grade papillary urothelial carcinoma with dyscohesive cells with hyperchromatic nuclei.






Figure 3.11.8 High-grade papillary carcinoma with areas showing more uniform cytology and preserved polarity (arrows) with rest of the tumor high grade.



3.12 INVERTED UROTHELIAL PAPILLOMA VS. NONINVASIVE UROTHELIAL CARCINOMA WITH INVERTED GROWTH PATTERN

Inverted Urothelial Papilloma

Noninvasive Urothelial Carcinoma with Inverted Growth Pattern


Age

Mean age mid-late 50s-60s with wide range

Mean age mid-60s with wide range


Location

Occurs at any location in the urothelial tract, yet most the common trigone or bladder neck

Anywhere with urothelial lining


Symptoms

Typically gross or microscopic hematuria, obstructive or irritative lower urinary tract symptoms

Typically gross or microscopic hematuria


Signs

At cystoscopy, polypoid with smooth surface. Over 95% unifocal. Usually <3 cm, but wide range in size

At cystoscopy, papillary lesion with delicate coral-like surface. Solitary or multifocal with wide range in size


Etiology

Unknown

See Section 3.10


Histology


  1. At low magnification, surface is smooth without exophytic papillary fronds, with exception of rare tangential sections resulting in a polypoid structure mimicking a frond (Figs.3.12.1, 3.12.2, 3.12.3, 3.12.4, 3.12.5, 3.12.6, 3.12.7)



  2. In some areas in continuity with surface but in most without, the lamina propria filled with anastomosing thin columns of the urothelium (Figs.3.12.1, 3.12.2, 3.12.3, 3.12.4, 3.12.5)



  3. Periphery of columns lined by cells with a palisading appearance (Fig. 3.12.8)



  4. Cells stream parallel to the basement membrane in center of nests (Fig. 3.12.8)



  5. No cytologic atypia with only rare cases showing bland multinucleated giant cells. Many cells with nuclear grooves



  6. Mitotic figures rare and when present only at the periphery of columns



  7. Cyst formation filled with eosinophilic secretions common (Fig. 3.12.3)



  8. Intervening stroma delicate with lack of inflammation


  1. Rare to have papillary urothelial neoplasm without any exophytic component, although uncommonly it occurs



  2. The lamina propria filled with large rounded nests of the urothelium (Figs. 3.12.9 and 3.12.10)



  3. Lack of palisading at periphery of nests



  4. No streaming of cells in center of nests



  5. Cytologic atypia depends on the grade. Inverted pattern of exophytic papilloma or PUNLMP may have no atypia (Figs. 3.12.9 and 3.12.11). Inverted pattern of low-grade carcinoma with scattered hyperchromatic enlarged nuclei (Figs. 3.12.10 and 3.12.12). Inverted pattern of high-grade carcinoma with marked cytologic atypia. Nuclear grooves seen in inverted pattern of exophytic papilloma and PUNLMP and less in low-grade and not in high-grade carcinoma



  6. Mitotic figures vary in frequency depending on the grade



  7. Cyst formation filled with eosinophilic secretions uncommon, although may see smaller gland-like lumina or true gland formation



  8. Intervening stroma may have inflammation


Special studies

Not helpful in this differential

Not helpful in this differential


Treatment

Resected by TUR. Controversial whether to recommend follow-up cystoscopy. If so, can be done less frequently than that for urothelial carcinoma and for only 3 y

Typically, resected by TUR with adjuvant therapy depending on the grade (see Sections 3.8, 3.9, 3.10, 3.11). Followed for life with routine cystoscopy


Prognosis

No risk of recurrence. No risk of progression to urothelial carcinoma. 1%-2% have prior history, synchronous, or subsequent urothelial carcinoma

Risk of recurrence, progression, and death varies according to grade (see Sections 3.8, 3.9, 3.10, 3.11)








Figure 3.12.1 Inverted papilloma with anastomosing columns of the urothelium beneath the smooth surface.






Figure 3.12.2 Inverted papilloma with anastomosing columns of the urothelium beneath the smooth surface.






Figure 3.12.3 Inverted papilloma with colloid-filled cysts.






Figure 3.12.4 Inverted papilloma with anastomosing columns of the urothelium beneath the slightly polypoid surface. Rare fronds (left) in the setting of typical inverted papilloma do not change the diagnosis.






Figure 3.12.5 Typical inverted papilloma.






Figure 3.12.6 Same case as Figure 3.12.5 with focal papillary fronds.







Figure 3.12.7 Higher magnification of Figure 3.12.6 with papillary fronds having the same spindled urothelium seen in the inverted portion of the tumor, still consistent with inverted papilloma.






Figure 3.12.8 Inverted papilloma with streaming of nuclei parallel to columns.






Figure 3.12.9 Inverted growth of PUNLMP with large rounded nests.






Figure 3.12.10 Inverted growth of low-grade papillary urothelial carcinoma with large rounded nests.






Figure 3.12.11 Same case as Figure 3.12.9 with bland cytology.






Figure 3.12.12 Same case as Figure 3.12.10 with scattered hyperchromatic nuclei and mitotic figures (arrow).



3.13 INVERTED UROTHELIAL PAPILLOMA VS. FLORID VON BRUN NEST PROLIFERATION

Inverted Urothelial Papilloma

Florid von Brunn Nest Proliferation


Age

Mean age mid-late 50s-60s with wide range

Wide age range


Location

Occurs at any location in the urothelial tract, yet most common the trigone or bladder neck

Occurs at any location in the urothelial tract with the ureter and renal pelvis as common sites


Symptoms

Typically gross or microscopic hematuria

Typically gross or microscopic hematuria


Signs

At cystoscopy, polypoid with smooth surface. Almost always solitary. Usually <3 cm, but wide range in size

At cystoscopy, can be tumor-like with polypoid mass with smooth surface. Almost always solitary. Usually <3 cm


Etiology

Unknown

Unknown


Histology


  1. At low magnification, surface is smooth without exophytic papillary fronds, with exception of rare tangential section resulting in a polypoid structure mimicking a frond



  2. In some areas in continuity with surface but in most without, the lamina propria filled with anastomosing thin columns of the urothelium (Figs.3.13.1, 3.13.2, 3.13.3)



  3. Periphery of columns lined by cells with a palisading appearance (Fig. 3.13.3)



  4. Cells stream parallel to the basement membrane in center of nests (Fig. 3.13.3)



  5. No cytologic atypia with only rare cases showing bland multinucleated giant cells. Many cells with nuclear grooves



  6. Mitotic figures rare and when present only at the periphery of columns



  7. Cyst formation filled with eosinophilic secretions common



  8. Intervening stroma delicate with lack of inflammation


  1. At low magnification, surface is smooth without exophytic papillary fronds



  2. The lamina propria filled with large rounded nests of the urothelium (Figs.3.13.4, 3.13.5, 3.13.6, 3.13.7, 3.13.8)



  3. Variable palisading at periphery of nests



  4. No streaming of cells in center of nests



  5. No cytologic atypia. May have nuclear grooves



  6. Mitotic figures rare and when present seen in the setting of inflammation



  7. Cyst formation filled with eosinophilic secretions common in the bladder and less in the ureter and renal pelvis (Figs.3.13.4, 3.13.5, 3.13.6)



  8. Intervening stroma may have inflammation that can cause reactive cytologic changes (see Section 3.5)


Special studies

Not helpful in this differential

Not helpful in this differential


Treatment

Resected by TUR. Controversial whether to recommend follow-up cystoscopy. If so, can be done less frequently than that for urothelial carcinoma and for only 3 y

Resected by TUR


Prognosis

No risk of recurrence. No risk of progression to urothelial carcinoma. 1%-2% have prior history, synchronous, or subsequent urothelial carcinoma

Not a neoplasm and no risk of recurrence or progression. Not related to inverted papilloma with exception of uncommon cases in the renal pelvis and ureter where there are multifocal lesions with some having morphology of inverted papilloma and other von Brunn nests. Typically, these uncommon cases are treated by nephroureterectomy based on the radiologic and ureteroscopic appearance. Given that major surgery has already been performed, these cases are best diagnosed as inverted papillomas with areas resembling von Brunn nests. The relationship of these overlap lesions with other urothelial neoplasms is unknown.








Figure 3.13.1 Inverted papilloma with smooth surface and underlying anastomosing thin columns of urothelium.






Figure 3.13.2 Inverted papilloma with anastomosing thin columns of urothelium with colloid cysts.






Figure 3.13.3 Inverted papilloma with streaming of nuclei parallel to columns and peripheral palisading of nuclei at epithelial-stromal interface.






Figure 3.13.4 Polypoid florid proliferation of von Brunn nests mimicking a tumor.







Figure 3.13.5 Same case as Figure 3.13.4 with rounded colloid-filled nests.






Figure 3.13.6 Rounded von Brunn nests with colloid.






Figure 3.13.7 Florid proliferation of von Brunn nests resulting in a tumor-like lesion.






Figure 3.13.8 Proliferation of rounded von Brunn nests.



3.14 FLORID VON BRUNN NEST PROLIFERATION VS. NESTED UROTHELIAL CARCINOMA

Florid von Brunn Nest Proliferation

Nested Urothelial Carcinoma


Age

Wide age range

Mean age mid-60s with wide range. Uncommon in females


Location

Occurs at any location in the urothelial tract with the ureter and renal pelvis as common sites

Typically the bladder, with only rare cases in the renal pelvis or ureter


Symptoms

Typically gross or microscopic hematuria

Typically gross or microscopic hematuria


Signs

At cystoscopy, can be tumor-like with polypoid mass with smooth surface. Almost always solitary. Usually <3 cm, but wide range in size

At cystoscopy, nodular surface typically without an exophytic papillary component. Usually solitary. Wide range in size


Etiology


See Section 3.10


Histology


  1. At low magnification, surface is smooth without exophytic papillary fronds



  2. The lamina propria filled with large rounded nests of the urothelium in the bladder (Fig. 3.14.1). In the ureter and renal pelvis and uncommonly in the bladder, small rounded nests (Figs.3.14.2, 3.14.3, 3.14.4, 3.14.5)



  3. In resection specimens, can appreciate that the nests are linear or lobular without an infiltrative lower border (i.e., can mentally draw a straight line at the base of the lesion) (Figs.3.14.2, 3.14.3, 3.14.4)



  4. Nests evenly spaced



  5. Never invades the muscularis propria



  6. No cytologic atypia unless inflamed with reactive changes where mitotic figures may be seen (see Section 3.5)



  7. No stromal reaction



  8. Cyst formation filled with eosinophilic secretions common in the bladder and less in the ureter and renal pelvis (Fig. 3.14.1)



  9. Lack of tubular formation although can see gland-like lumina and cystitis glandularis toward centers of nests


  1. At low magnification, surface is typically smooth without exophytic papillary fronds (Figs. 3.14.6 and 3.14.7). Uncommon cases where surface shows CIS or papillary urothelial carcinoma



  2. The lamina propria filled with small crowded nests of the urothelium in the classic variant and large irregular nests in the large nested variant (Figs. 3.14.7 and 3.14.8)



  3. Has an irregular base with infiltrative nests extending to different depths (Figs. 3.14.6 and 3.14.9). Diagnosis should not be made on biopsy of the ureter or renal pelvis in the absence of the muscularis propria invasion, since cannot appreciate infiltrative border and overlapping morphologic features with von Brunn nests in these sites



  4. Nests often very crowded, back to back (Figs. 3.14.8 and 3.14.10)



  5. Often invades the muscularis propria (Figs. 3.14.6, 3.14.9, and 3.14.10)



  6. No cytologic atypia in areas, yet deeper nests may have prominent nucleoli and occasional mitotic figures (Figs.3.14.7, 3.14.8, 3.14.9, 3.14.10)



  7. Typically, no stromal reaction in usual variant but variable desmoplastic stroma with variable inflammatory response in large nested variant



  8. Can see small cyst formation



  9. Some cases have tubular differentiation. If predominant, called tubular variant of urothelial carcinoma (see Section 3.16)


Special studies

Most cases with low Ki-67 rate

Most cases with low Ki-67 rate, with only a few cases with rate >20%


Treatment

Resected by TUR

Radical surgery typically required as usually invades the muscularis propria


Prognosis

No risk of recurrence or progression

Aggressive behavior comparable to invasive high-grade urothelial carcinoma








Figure 3.14.1 Proliferation of von Brunn nests in the bladder consisting of large uniform nests with central cyst formation.






Figure 3.14.2 Proliferation of von Brunn nests in the bladder with small nests. The nests have a noninfiltrative base and cluster just beneath the surface.






Figure 3.14.3 Proliferation of von Brunn nests in the bladder with small nests. The nests have a noninfiltrative base and cluster just beneath the surface.






Figure 3.14.4 Proliferation of von Brunn nests in the bladder with small nests arranged in a lobular and linear array beneath the urothelium. Nests are circumferential around the ureter and are noninfiltrative.







Figure 3.14.5 Same case as Figure 3.14.4 at higher magnification.






Figure 3.14.6 Nested carcinoma with smooth surface and small- and medium-sized nests infiltrating the muscularis propria.






Figure 3.14.7 Nested carcinoma with smooth surface and small nests irregularly infiltrating lamina propria. Inset shows bland cytology.






Figure 3.14.8 Nested carcinoma with crowded small nests filling the lamina propria (left) having minimal cytologic atypia (right).






Figure 3.14.9 Nested carcinoma with irregular downward growth of small nests invading the muscularis propria. Inset shows no atypia.






Figure 3.14.10 Nested carcinoma with back-to-back small nests invading the muscularis propria. Cells resemble normal urothelial cells with some even having nuclear grooves (inset).



3.15 NESTED UROTHELIAL CARCINOMA, LARGE NEST VARIANT VS. NONINVASIVE CARCINOMA WITH INVERTED GROWTH PATTERN

Nested Urothelial Carcinoma, Large Nest Variant

Noninvasive Carcinoma with Inverted Growth Pattern


Age

Mean age mid-60s with wide range

Mean age mid-60s with wide range


Location

Most commonly the bladder

Occurs at any location in the urothelial tract


Symptoms

Typically gross or microscopic hematuria

Typically gross or microscopic hematuria


Signs

At cystoscopy, an exophytic papillary component is present in the majority of cases corresponding to a low-grade papillary carcinoma component. Usually solitary. Wide range in size

At cystoscopy, papillary lesion with delicate coral-like surface. Solitary or multifocal with wide range in size. Rare cases with purely inverted growth pattern without an exophytic component


Etiology

See Section 3.10

See Section 3.10


Histology


  1. At low magnification, surface has a papillary component in over 80% of cases, the vast majority low-grade papillary urothelial carcinoma



  2. The lamina propria filled with large, irregularly shaped nests (Figs.3.15.1, 3.15.2, 3.15.3)



  3. Has an irregular base with infiltrative nests extending to different depths



  4. Nests can be crowded but typically irregularly spaced apart



  5. Often invades the muscularis propria (Figs.3.15.1, 3.15.2, 3.15.3)



  6. No cytologic atypia in areas, yet deeper nests may have prominent nucleoli (Figs.3.15.4, 3.15.5, 3.15.6)



  7. Mitotic figures average 1 to 2 per HPF



  8. Variable desmoplastic stroma with variable inflammatory response (Figs. 3.15.3 and 3.15.4)



  9. Necrosis in one-third of cases


  1. Vast majority of papillary urothelial neoplasms have some exophytic component, although uncommonly entire lesion is inverted



  2. The lamina propria filled with large, rounded nests of the urothelium (Figs. 3.15.7 and 3.15.8)



  3. Nests lack an infiltrative border at the base of the lesion



  4. Nests crowded with more uniform spacing (Figs. 3.15.7 and 3.15.8)



  5. Does not involve the muscularis propria



  6. Cytologic atypia depends on the grade. Inverted pattern of exophytic papilloma or PUNLMP may have no atypia. Inverted pattern of low-grade carcinoma with scattered hyperchromatic enlarged nuclei. Inverted pattern of high-grade carcinoma with marked cytologic atypia



  7. Mitotic figures vary in frequency depending on the grade



  8. Lacks desmoplastic stroma



  9. Lacks necrosis


Special studies

Most cases would be expected to have low Ki-67 rate, yet no studies on this issue

Ki-67 varies depending on the grade of the tumor


Treatment

Radical surgery typically required as usually invades the muscularis propria

Typically, resected by TUR with adjuvant therapy depending on the grade (see Sections 3.8, 3.9, 3.10, 3.11). Followed for life with routine cystoscopy


Prognosis

Limited number of cases with follow-up, yet capable of metastatic behavior and death

Risk of recurrence, progression, and death varies according to grade (see Sections 3.8, 3.9, 3.10, 3.11)

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Jul 9, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Bladder

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