Transcript Selected Urothelial Lesions of Urinary Bladder and Their

Selected Urothelial Lesions of
Urinary Bladder and Their Common
Diagnostic Pitfalls
Cheng Wang, FRCPC, FCAP
Department of Pathology and Laboratory
Medicine
QEII health center and Dalhousie University
April, 2015
Disclosure
• Conflict of interest
– None
Objectives
• Be able to identify the histopathological
features and grasp the diagnostic criteria for
the selected urothelial lesions
• Be able to generate important differential
diagnoses based on their histomorphological
characteristics and develop practical approach
to further work-up
Urinary bladder cancer
• Seventh most common cancer worldwide
• In North American, over 90% of urothelial
origin
Bladder Cancer – Etiology
• Risk factors
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Age
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Gender
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Aniline dye
Aromatic amines
Medication:
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Cigarette smoking most important factor related to bladder cancer
more than 50% in men and more than 35% in women due to cigarette smoking
Occupational exposure: paint, rubber, leather industries (exposure to
organic chemicals)
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Approximately 3 times more common in men than women
Smoking
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Urothelial carcinoma is rare in young people
Analgesics such as phenacetin
Cyclophosphmide
Cholrnaphazine
Infections
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Schistosoma hematobium
Pathology of the
Urinary Tract Neoplasms
Superficial (Noninvasive) growth (70%)
-Papillary - exophytic
-Flat - intraepithelial (Carcinoma in-situ)
Invasive growth (30%)
-Starts as invasive carcinoma
-Progression from superficial to deep
Flat Urothelial Lesions ranging from
urothelial hyperplasia, reactive atypia,
dysplasia and urothelial CIS
Urothelial carcinoma in situ (CIS)
• High-grade urothelial carcinoma confined to the urothelium that is confined within
basement membrane of urothelium.
Epidemiology
• Similar distribution to invasive urothelial carcinomas
• Risk factors: tobacco smoke and exposure to industrial compounds such as aromatic
amines
• Common in the sixth to seventh decades, can be as young as 30 years
• Males gender
Presentation
• Generally identified in association with invasive urothelial carcinoma
• Hematuria, dysuria, or urgency
• Cystoscopically, urothelium oftenappears erythematous
Urothelial Carcinoma in Situ (CIS)
Three clinical forms:
Primary (de novo) CIS: Isolated CIS without prior or concurrent papillary neoplasm
(rare).
Secondary CIS: In patients with prior papillary neoplasm.
Concurrent CIS: Identified on bladder mucosa with concomitant papillary neoplasm or
invasive carcinoma.
Prognosis
• ~ 50% of patients develop invasive carcinoma within 5 years
Diagnostic Criteria for Urothelial CIS
(mainly a cytological diagnosis)
1. Enlarged, pleomorphic and hyperchromatic
nuclei
2. Coarse or condensed chromatin
3. Complete loss of polarity, marked crowding
4. Mitoses are common and can extend into the
upper cell layers
5. Any malignant cells are sufficient for CIS,
ranging from isolated cells (pagetoid) to fullthickness atypia
Urothelial CIS, just scattered atypical cells,
instead of full thickness involvement
Frozen section of ureter margins in
radical cystectomy specimen
• Ureteric mucosal margin evaluation
• Generally En face section including entire wall (urothelium,
muscularis, and adventitia)
• Frozen section artifact may cause “atypical” features, so
first identify normal urothelium (with longitudinal nuclear
grooves and normal polarity)and use it as an internal “built
in” control
• Be aware of urothelial Ca variants such as plasmacytoid
pattern within the adventitia, which resembles
inflammatory cells
• von Brunn nests are common and should be distinguished
from invasive Ca
Nuclear size enlargement threshold :
4x-6x of a mature lymphocyte nucleus
[998] Poropatich et. al. Nuclear Size Measurement for Distinguishing
Urothelial Carcinoma From Reactive Urothelium on Tissue Sections
Design: We measured the nuclear size (length and width) of individual urothelial
cells on digital images from H&E tissue sections, using standard imaging CellSens
software. At least 10 urothelial cells were measured in each image. Lymphocytes on
the corresponding sections were also measured as the standard. The specimens
studied include reactive urothelium (RU; n=5), low grade UC (n=12) and high grade
UC (n=7) including carcinoma in situ (CIS, n=4).
Results: The length (L) and width (W) of 289 cells are measured on bladder H&E
sections. The area was calculated by WxLx0.8 based on the oval shape of most
urothelial cells. Lymphocyte (LC) area and diameter were determined. These data
are in the table below:
Conclusion: High grade urothelial carcinoma including CIS had much greater
nuclear enlargement than reactive urothelium.
Pitfalls for Urothelial CIS
Case 1: Radiation cystitis
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Urothelium exhibits marked cytologic atypia characterized by nuclear
pleomorphism, smudgy chromatin and cytoplasmic vacuolations, but with normal or
maintained N/C ratio
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Background stroma also exhibits pronounced atypia
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Blood vessels are thickened and hyalinized
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Lamina propria with edema or fibrosis
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Pseudocarcinomatous epithelial hyperplasia may develop which can closely mimic
carcinoma.
Case 2: Polyoma Virus Infection
• Characterized by large, homogeneous basophilic nuclear
inclusions (“decoy cells”)
• Enlarged cell with round nucleus, smooth border, ground
glass with marginated chromatin
• Maybe some overlap with high grade cells
• Some reports on the co-existence of Decoy cells and high
grade UC/CIS in urine cytology
• Some reports indicate the Polyoma virus is likely causing
bladder Ca in kidney transplant patient. Careful follow-up of
immunocompromised patient is recommended.
• SV40 immunostain to confirm Polyoma virus infection
Urothelial Carcinoma in Situ can involve Von
Brunn’s Nests or cystitis cystica, which need to be
differentiated from Endometriosis
Case 4: Radical Prostatectomy, 70M what
is the intraductal lesion with high grade
nuclear atypia and necrosis?
Case 5: Core needle biopsy of Prostate, 60 M, shows
intraductal component with high grade nuclear atypia
and comedonecrosis
Urothelial CIS involving prostatic ducts Vs.
Intraductal adenocaricnoma of prostate (IDCP)
• Intraductal Urothelial CIS
• IDCP criteria
o Marked nucleomegaly (46x size of a normal
lymphocyte nucleus)
– solid intraductal growth
o Coarse, condensed
nuclear chromatin
– loose
cribriform/micropapillary
with nuclear size >6x
normal
o Mitoses including atypical
forms
o Loss of polarity and
crowding
– dense cribriform
– Comedonecrosis
– dilated ducts >2x normal
Guidelines for IHC in differentiating UC
Vs. High grade Pca
UC versus Pca
• First line markers:
– PSA and GATA3
• Second line markers:
– HMWK, p63, PAP,
P501S and NKX3.1
Case 6: Urothelial Papilloma
• Clinical Issues
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Very uncommon urothelial lesion (~ 1% of papillary urothelial neoplasms)
Typically occur in younger adults and are seen in children
Gross or microscopic hematuria
Recurrence is rare (0-8%)
Posterior or lateral walls of bladder, close to ureteral orifices
Urethra is another common site of occurrence
• Microscopic Pathology
– Exophytic papillary neoplasm lined by urothelium in normal thickness
– No significant cytologic atypia, mitosis rare to absent.
– Slender, minimally branching papillary architecture
• Main Differential Diagnosis:
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Nephrogenic adenoma/hyperplasia
Polypoid/papillary cystitis
Fibroepithelial polyp of the urathra
Prostatic type polyp of the urathra
Ductal adenocarcioma of prostate
Case 7: Bladder papillary lesion:
nephrogenic adenoma/hyperplasia
Case 7: Nephrogenic adenoma/Hyperplasia
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Etiology/Pathogenesis
– Many are secondary to urothelial injury
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Clinical Issues
– Usually incidental microscopic findings
– May have irritative symptoms from underlying inflammatory process
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Macroscopic Features
– May appear as papillary-polypoid mass or irregular flat velvety lesion
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Microscopic Pathology
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Papillary cores lined by single cuboidal epithelial layer
Tubular pattern with "hobnail" arrangement of epithelial cells
Rare cases have myxoid stroma and cording or spindling of cells (fibromyxoid pattern)
Rare cases have diffuse sheet-like growth
Thick basement membrane/hyalinized sheath may underlie epithelium
Degenerative-type atypia may be present
Ancillary Tests
– Express cytokeratins and pax-8
– May express PSA, PAP, and AMACR
Case 8: Polypoid/papillary Cystitis
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Terminology
– Papillary cystitis is nonneoplastic inflammatory lesion of urinary bladder, Characterized by
edema of lamina propria and exophytic polypoid or papillary projections
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Etiology/Pathogenesis
– Many cases are related to indwelling catheter or vesical fistula
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Clinical Issues
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May affect any age group
Hematuria
Irritative bladder symptoms from underlying cause
No excision required
Microscopic Pathology
– Characterized by variable exophytic projections of urothelium secondary to lamina propria
edema
– Papillae lack complex branching typical of papillary urothelial neoplasia
– Stromal cores are comprised of edema and fibrosis, not typical fibrovascular cores of papillary
urothelial neoplasia
– Stromal cores are characteristically broader at base and taper to point distally
– Reactive urothelial atypia may be prominent
Case 9: Male patient, papillary
Lesion from prostatic urethra
PSA positive in the papillary lesion, Differential diagnosis?
DDx 1: Prostatic type Polyp
• Etiology/Pathogenesis
– Multiple theories proposed
• Clinical Issues
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Broad range: 19-89 years
Trigone is most common site in bladder
Most common in prostatic urethra
Hematuria, hematospermia
Polypoid mass with variable exophytic fronds
• Microscopic Pathology
– Polypoid or papillary/filiform exophytic process
– Stroma contains benign prostatic-type secretory glandular epithelium and
admixed urothelium
– Excrescences lined by cytologically benign prostatic secretory cells &/or
urothelium
– Long, finger-like projections are rarely seen
Higher power of the current urethral
papillary lesion showing columnar cells
with enlarged nuclei, prominent
nucleoli and amphophilic cytoplasm
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Case 9 Final Dx: Ductal prostatic adenocarcinoma
8/10 (4,4)
Terminology
– Adenocarcinoma of prostatic epithelial cell origin with large glandular and papillary architecture
lined by tall columnar cells, often with pseudostratified growth
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Clinical Issues
– Pure ductal adenocarcinoma accounts for 0.4-0.8% of all prostate cancers
– Mixed ductal and acinar adenocarcinoma reported in 5-6.3% of prostate cancers
– Most studies suggest a more aggressive clinical behavior than acinar adenocarcinoma
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Macroscopic Features
– Centrally located tumors can have exophytic friable fronds protruding in urethral lumen
– Peripheral tumors are more often posteriorly situated as firm, gray-white parenchymal mass
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Microscopic Pathology
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Main architectural patterns: Papillary, cribriform, individual glands, solid
Tall columnar cells in single or pseudostratified growth pattern
Cytoplasm usually amphophilic and nucleus oblongated with variably prominent nucleolus
Can grow intraluminally into preexisting ducts retaining "native" basal cell layer
Positive for AMACR in 77% of cases
Majority has no detectable basal cells by p63 or HMCK(34βE12)
ISUP 2005 consensus recommends grading as Gleason pattern 4; if necrosis is present, pattern 5
High Grade Papillary Urothelial Carcinoma
(can be a spectrum)
Higher than low grade and, yet,
lower than high grade? Grade 2.5?
• High grade but low end of the spectrum
• What are the features might be helpful to
determine if high grade or not?
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2.
3.
4.
Nuclear atypia (enlargement and coarse chromatin)
Mitosis and apoptotic bodies
Papillary fusion/necrosis
Invasive components (but low grade papillary
urothelial carcinoma can rarely be invasive)
High-grade papillary urothelial
carcinoma with lamina propria invasion
• Features favor stromal invasion
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Histologic grade: usually high nuclear grade
Irregularly shaped nests
Single cell infiltration
Paradoxical differentiation
Stromal inflammatory response
Desmoplasia or fibrotic stroma
Retraction artifact
Myxoid stroma
Lymphovascular invasion versus
retraction artifact
• Vascular invasion may be present, which must
be distinguished from retraction artifact, by
– the presence of endothelial cell lining
– associated red blood cells
– muscle wall
Invasion versus Inverted/endophytic growth
• Inverted urothelial lesion is beneath the surface urothelium
and shows a smooth, non-destructive outlines.
Variants of Urothelial Ca
• Be aware of the bland cytology of nested and
microcystic variants, which can be challenges
to diagnose in a small sample.
Clear Cell Variant of Invasive
Urothelial Carcinoma
DDx: Metastatic clear cell RCC, Spreading of Clear cell adenocarcinoma of
Mullerian origin and Metastatic prostate AdenoCa
Case 10: Suptum ctyology from a 61F, history of DVT
for two months, now severe SOB. Imaging shows
liver, bone, chest hilar lesions and a bladder mass
• Sputum cytology showing 3D-clusters of
atypical cells with enlarged nuclei and
cytoplasmic vacuoles
Autopsy Findings
• Patient passed away three days after
presenting to hospital. The bladder tumor is
invasive urothelial carcinoma containing both
micropapillary and plasmacytoid variants
• Distant metastasis in Bone, heart, liver, lymph
nodes and brain were identified
Lung Metastatic Micropapillary Variant
of Invasive Urothelial Carcinoma, the
morphology of which resembles to the
atypical cells seen in sputum cytology
Urothelial Carcinoma Micropapillary Variant
• More frequent in elderly men (M:F 5:1, mean age: 66)
and present with hematuria
• Often co-exists with the conventional urothelial
carcinoma. Pure micropapillary variant is rare (about
1% of all urothelial carcinoma).
• Most cases of the micropapillary variant are high stage
cancer at diagnosis with frequent lymph node
metastasis
• Need to report MP variant (using specific morphology
criteria) in the invasive component
• Be aware of retraction artifact can be mistaken as MP
variant
MP variant tends to metastasize to lymph nodes
Important to recognize the cytological features of potential
micropapillary variant in Urine Cytology specimens, especially
those not accompanied by tissue bx
Small cell carinoma of urinary bladder
• Sheets and occasionally nests of cells with scant cytoplasm and high
n/c ratio
• Chromatin is finely stippled, and nucleoli are inconspicuous
• Geographic areas of necrosis, high mitotic rate, and areas of crush
artifact are also frequent
• Other subtypes of primary bladder carcinoma may be admixed
– Urothelial carcinoma in situ, invasive urothelial carcinoma, squamous
cell carcinoma, adenocarcinoma, or sarcomatoid carcinoma
• Highly aggressive clinical behavior
• Even focal small cell component should be reported
Reference
• Ming Zhou, Genitourinary Pathology, Expert
Consult series
• Amin et al. Diagnostic Pathology: Genitourinary
• Cheng et al., Bladder Pathology
• Cibas and Ductaman: Cytology Diagnostic
Principles and Clinical Correlates