the paris system - moffitt cancer center · •attempt to standardize terminology for urinary...
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The Paris System for Reporting Urinary Cytology
J. Dhillon Assistant member
Anatomic Pathology, Cytopathology Moffitt Cancer Center
Assistant Professor Department of Oncologic Sciences and Pathology
University of South Florida
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No Disclosures
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Classifications
Papilloma Grade I Grade II Grade III
Papilloma PUNLMP Low Grade High Grade
WHO/ISUP 2004
~ 10-20% ~ 50-60% ~ 80-90%
URINE CYTOLOGY SENSITIVITY
High false negatives
WHO 1973
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The Paris System
• What is the main goal of urinary cytology?
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The Paris System
• What is the main goal of urinary cytology? – Detection of urothelial carcinoma that is clinically
significant – high-grade urothelial carcinoma (HGUC)
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The Paris System
• Attempt to standardize terminology for urinary cytology
• Despite two well established pathways in urothelial carcinoma, cytologic terminology remains disparate and complex
• The idea for developing The Paris System for Reporting Urinary Cytopathology was conceived during IAC Congress held in Paris in 2013
• Drs. Rosenthal and Wojcik have led the Paris System Working Group
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The Paris System Subgroups prior to The Paris System • Negative for malignant cells • Atypical urothelial cells • Suspicious • High Grade Urothelial
Carcinoma • Low Grade Urothelial
Carcinoma • Other malignancies, both
primary and secondary
Subgroups Defined by the Paris System • Negative for High Grade
Urothelial Carcinoma • Atypical urothelial cells • Suspicious for HGUC • High Grade Urothelial
Carcinoma • Low Grade Urothelial
Neoplasm • Other malignancies, both
primary and secondary
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The Paris System Adequacy of Urine Specimens
• 1. Non-urothelial features obscuring urothelial morphology – Numerous acute inflammatory cells, Rbcs, lubricant obscuring
urothelial cell morphology • 2. Inadequate volume with inappropriate benign urothelial
cellularity – <30 ml
• 3. Instrumented urine specimen with inappropriate benign urothelial cellularity – Bladder washes – 10-20 well-preserved and well-visualized urothelial
cells/10 hpfs – Satisfactory but limited by low cellularity – <10 well-preserved and well-visualized urothelial cells/10 hpfs –
unsatisfactory/nondiagnostic
• Presence of any atypical, suspicious, or malignant findings – Adequate
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Subgroups Defined by The Paris System
• Adequacy • Negative for High Grade Urothelial Carcinoma (HGUC) • Atypical urothelial cells • Suspicious • High Grade Urothelial Carcinoma • Low Grade Urothelial neoplasm • Other malignancies, both primary and secondary • Ancillary Studies • Clinical management • Preparatory techniques relative to Urinary Tract samples
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Negative for HGUC • Benign/reactive urothelial cells, squamous and glandular cells • True tissue fragments and clusters without morphologic changes
in the absence of instrumentation and after instrumentation • Alterations caused by urinary bladder and renal calculi • Viral cytopathic effect, especially polyoma (BK) virus • Post-treatment effect of bladder instillations, especially BCG • Post-treatment effect for non-bladder disease, e.g., pelvic
irradiation for other malignancies; systemic chemotherapy that may effect the urothelium, e.g., cyclophosphamide
• Enteric epithelium following a surgical urinary diversion post-cystectomy
• Unexpected normal cells, e.g., sperm, seminal vesicle cells, cells from the female genital tract
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Reactive Urothelial Cells
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Glandular Cells
• Sources: endometrium, prostate, kidneys, urachal remnants, metaplasia
Rosenthal, Wojcik, Kurtycz. The Paris System for Reporting Urinary Cytology, Springer , Page 19
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Viral Cytopathic Effects
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Bladder Diversion Urine
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Benign Urothelial Tissue Fragments
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Immunotherapy - BCG
Rosenthal, Wojcik, Kurtycz. The Paris System for Reporting Urinary Cytology, Springer , Page 31
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Basal Urothelial Cells
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What are we calling Atypia?
• There are rare cells, reminiscent to that of high grade UC
• Lots of clusters, worrisome for low grade UC • Other (degenerated cells, cells/groups that
don’t fit in either group above) • Clusters of small basal urothelial cells • Polyoma virus, therapy related changes, atypia
secondary to calculi
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Atypia as defined by Paris System
• There are rare cells, reminiscent to that of high grade UC
• Lots of clusters, worrisome for low grade UC • Other (degenerated cells, cells/groups that
don’t fit in either group above) • Clusters of small basal urothelial cells • Polyoma virus, therapy related changes, atypia
secondary to calculi
Negative for High Grade Urothelial Carcinoma
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Criteria for Atypical Urothelial Cells
• Cells where cytologic changes fall short of a diagnosis of suspicious for HGUC or HGUC
• MAJOR CRITERION (required)
– Non-superficial and (non-degenerated) urothelial cells with an high N/C ratio >0.5
• MINOR CRITERIA (1 required)
– Nuclear hyperchromasia – Irregular nuclear membranes – Irregular, coarse, clumped chromatin
Diagnosis of AUC is appropriate in cases where there is suspicion for HGUC there is also extensive degeneration.
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Atypical Urothelial Cells
N/C – 0.5 HYPERCHROMSIA Note – mild degenerative features preclude adequate assessment of the chromatin
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Concurrent Bladder Biopsy
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Atypical Urothelial Cells
N/C >0.5 NO HYPERCHROMASIA IRREGULAR MEMBRANES
Rosenthal, Wojcik, Kurtycz. The Paris System for Reporting Urinary Cytology
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Urine Specimens MCC DATA
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Low Grade Urothelial Neoplasms
• Urothelial papilloma • Papillary urothelial neoplasm of low malignant
potential (PUNLMP) • Low-grade papillary urothelial carcinoma (LGPUC) • Flat low-grade intraurothelial neoplasia (dysplasia)
Note – cytologic distinction between low-grade lesions and normal urothelium is extremely difficult
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Cytologic criteria of LGUN
• Definitive Feature – Presence of three-dimensional cellular papillary
clusters with fibrovascular cores including capillaries • Features suggestive of
– Three-dimensional cellular clusters without fibrovascular cores
– Increased numbers of monotonous single (non-umbrella) cells
Note – Cases suggestive of LGUC are categorized as NHGUC
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Monotonous single cells, grooves Absence of umbrella cells Increased N/C ratio Category?
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Concurrent Biopsy
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Suspicious for HGUC
• MAJOR CRITERIA (required) – N/C ratio – 0.5-0.7 – Hyperchromasia – moderate to severe
• MINOR CRITERIA (1 required) – Irregular clumpy chromatin – Marked irregular nuclear membranes
Note – The cells have to be non-superficial and non-degenerating Cut off range 5-10 cells in urine Upper tract – 10 cells
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Suspicious for HGUC
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Criteria for High-Grade Urothelial Carcinoma (HGUC)
• Cellularity: 5-10 abnormal cells • N/C ratio: 0.7 or greater
– Some may show N/C 0.5-0.7
• Nucleus: Moderate to severe hyperchromasia • Nuclear membrane: Markedly irregular • Chromatin: Coarse/clumped
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HGUC
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Diagnosis?
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Diagnosis?
N/C - >0.7 Hyperchromatic – no Not – HGUC or Suspicious for HGUC
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Diagnosis?
N/C - >0.7 Hyperchromatic – no Not – HGUC or Suspicious for HGUC
N/C - >0.5 Hyperchromatic – no Coarse chromatin clumping – no Nuclear membrane irregularity - ?
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Diagnosis?
• Negative for HGUC or AUC • History of intravesical therapy – Yes • Reason of “Atypia” is known – excludes it’s
inclusion in the “Atypical” category • Dx – Negative for HGUC • UroVysion FISH and subsequent biopsy were
negative
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Other Malignancies and Non-Urothelial Lesions
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Other Malignancies and Non-Urothelial Lesions
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Other Malignancies and Non-Urothelial Lesions
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Other Malignancies and Non-Urothelial Lesions
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Other Malignancies and Non-Urothelial Lesions
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UroVysion FISH • UroVysion is a commercially available multitarget,
multicolor FISH probe set that was developed in a collaborative effort between Mayo Clinic and Vysis, Inc.
• It contains four single stranded DNA probes – Three probes are chromosome enumeration probes targeting
pericentromeric regions of chromosomes 3, 7, and 17. – The 4th probe is a locus-specific identifier probe targeting 9p21
locus on gene p16. – All probes are directly labeled with fluorescent dyes
• It has been approved by FDA as an aid for initial diagnosis of bladder cancer in patient’s with hematuria and/or subsequent monitoring for tumor recurrence in patient’s previously diagnosed with bladder cancer.
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UroVysion FISH
• The pooled sensitivity and specificity of FISH are reported to be 72% and 83% respectively compared with 42% and 96% respectively for cytology
• The most rewarding application – Atypical urothelial cells – U-FISH was positive in 89% of AUC cases (Skacel et al) – “Anticipatory positives” – FISH is positive, AUC but
cystoscopy negative – Currently not generally recommended – not going to
change the surveillance strategies, cost effective
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Positive UroVysion Test
• Chromosomal abnormalities tested for by Urovysion FISH
• Distinguishes cancer cells from benign cells • This test is not specific for urothelial
carcinoma; may be seen in non-urothelial carcinomas as well
• Cytopathologists and urologists should correlate Urovysion FISH results with cytomorphology and clinical information.
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UroVysion FISH in non-urothelial carcinomas
• Adenocarcinoma, squamous cell carcinoma and small cell carcinoma of the bladder
• Colonic adenocarcinoma • Prostatic adenocarcinoma • Cervical adenocarcinoma • Renal cell carcinomas • Benign cells –
– Reactive umbrella cells (tetraploid) – Post radiation
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UroVysion FISH
• Papanicolaou Society of Cytopathology recommends UroVysion FISH testing in combination with routine cytology for the evaluation of PB strictures
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Ancillary Tests • Liquid-based Tests – Approved by FDA
BTA (Bladder Tumor Associated Antigen) Test • Measures human complement factor H and related proteins • Elevated in bladder cancer • Hematuria – false positive
NMP22 Test • Immunoassay that detects nuclear mitotic apparatus protein • Levels correspond to cell turnover in bladder • Not a tumor specifc protein • False positive – intrumentation, inflammatory, reparative processes • Specificity of urine cytology is better