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The Paris System for Reporting Urinary Cytology
- 1. THE PARIS SYSTEM FOR REPORTING URINARY CYTOLOGY Rawa Muhsin
- 2. History ◦ Bethesda system for cervical cytology since 1988 ◦ Paris system for urinary cytology conceived in Paris during the IACC in 2013 ◦ Led by Rosenthal and Wojcik
- 4. What matters in urine cytology? ◦ Is there high-grade urothelial carcinoma or not? ◦ Only HGUC can invade muscle ◦ Progression of LGUC to HGUC is uncertain, with more recent studies reporting a lower rate (1-5%) ◦ RAS mutations mutually exclusive with FGFR3 mutation, so may be totally separate pathways
- 6. Categories in the Paris system ◦ Negative for high-grade urothelial carcinoma ◦ Positive for high-grade urothelial carcinoma ◦ Not quite enough ◦ Atypical urothelial cells (AUC) and suspicious for high-grade urothelial carcinoma (SHGUC) ◦ Difference is quantitative
- 7. Adequacy ◦ If there are atypical cells, adequacy does not matter ◦ If there are no atypical cells ◦ Lack of obscuring features ◦ Appropriate benign urothelial cellularity (20 cells per 10 hpf) ◦ Adequate volume (30 mL) ◦ Don’t discard the first drops of the urine stream; they are rich in cells ◦ Anything below these cut-offs is “less-than-optimal” for evaluation
- 8. Negative for High-Grade Urothelial Carcinoma ◦ >70% of all urine cytologies ◦ All entities that pose no significant risk to the patient for developing HGUC based upon available studies ◦ Benign urothelial, glandular, and squamous cells ◦ Stone-related changes ◦ Viral cytopathic effect ◦ Post-therapy effect
- 9. Urothelial cells ◦ Adequacy criteria (20 cells per 10 hpf) ◦ Umbrella cells ◦ May appear atypical, but do not justify a diagnosis of atypia ◦ May contain abnormal amounts of DNA and confound DNA ploidy studies
- 12. Squamous cells ◦ Urethra, vagina, and bladder trigone
- 14. Glandular cells ◦ Uterine cervix and corpus ◦ Alert in post-menopausal women ◦ Bladder dome and trigone ◦ Cystitis cystica/glandularis ◦ Endometriosis and Mullerian rests ◦ Renal tubular epithelial cells ◦ Usually degenerated and resemble histiocytes
- 19. Stone-related changes ◦ Clinical history and imaging ◦ Urothelial tissue fragments ◦ Crystalline material
- 25. Viral cytopathic effect ◦ Polyoma virus ◦ Nuclear enlargement ◦ Chromatin homogenization with spider web dissolution ◦ Very smooth nuclear outline; if irregular look for malignancy
- 28. Post-therapy effect ◦ Radiation ◦ Cytomegaly with preserved N/C ratio, cytoplasmic vacuoles, polychromasia ◦ BCG immunotherapy ◦ Granulomas ◦ Chemotherapy ◦ Nuclear enlargement, multinucleation, hyperchromasia of superficial cells ◦ Bladder diversion ◦ Large red intracytoplasmic inclusions
- 34. Low-grade urothelial neoplasia ◦ Used for the histologic entities of urothelial papilloma, PUNLMP, and low-grade urothelial carcinoma ◦ 3D cellular papillary clusters (with nuclear overlapping) with fibrovascular cores including capillaries ◦ Risk of progression to high-grade urothelial carcinoma is low (if it happens at all)
- 37. Who is this?
- 39. END OF PART 1
- 40. High-grade urothelial carcinoma ◦ Urine cytology has high sensitivity (up to 85%) and specificity (up to 88%) for HGUC ◦ Lower sensitivity for LGUC (up to 43.6%) ◦ Positive urine cytology is significantly associated with ◦ Subsequent recurrence of upper urinary tract urothelial carcinoma ◦ Tumor progression in Ta urothelial carcinoma (20% vs 2% at 5 years)
- 41. High-grade urothelial carcinoma ◦ Cannot distinguish invasive HGUC from noninvasive HGUC or CIS ◦ Background in latter is clean ◦ Features ◦ High N/C ratio >0.7 (use lymphocytes as control) ◦ Hyperchromasia (use normal cells as control) and coarse chromatin ◦ Irregular nuclear membrane ◦ Necrosis ◦ At least 5—10 abnormal cells should be present ◦ Prominent nucleoli can also be present in reactive urothelial cells
- 48. High-grade urothelial carcinoma ◦ HGUC can show differentiation towards ◦ Squamous ◦ Keratinization and intercellular bridges ◦ Glandular ◦ Glandular formation, cytoplasmic vacuolization ◦ Diagnosis of SqCC and adenoCA requires extensive sampling of the excision sample
- 52. High-grade urothelial carcinoma ◦ Rate of malignancy: 1.0-6.3% ◦ Risk of malignancy: >90% ◦ Anticipatory phenomenon ◦ Positive urine cytology with an initial period of clinically undetectable disease followed by discovery of occult urothelial carcinoma ◦ Longer follow-up required to avoid mislabeling as false positive
- 53. Suspicious for HGUC ◦ Difference is quantitative only ◦ Identical nuclear features ◦ Few (<5-10) cells ◦ Exclude superficial and degenerated cells from consideration ◦ In voided specimens and history of HGUC use lower (5 cells) cut-off, in instrumented samples use higher (10 cells) cut-off
- 57. Atypical urothelial cells ◦ Difference is qualitative ◦ Partial nuclear features of HGUC ◦ Degenerative features including incomplete cytoplasm, incomplete nuclear membranes, poor chromatin detail ◦ Exclude known causes of atypia such as infections, reactive changes, seminal vesicle cells (these belong in negative for HGUC)
- 62. Level of certainty Negative for HGUC Atypical urothelial cells Suspicious for HGUC HGUC
- 64. Risk of malignancy ◦ Negative for HGUC: 15.5% ◦ Atypical urothelial cells: 8.3-37.5% ◦ Suspicious for HGUC: 80-95% ◦ HGUC: 78-100%
- 65. END OF PART 2
Notes de l'éditeur
- Urothelial carcinoma has two pathways: hyperplasia and dysplasia pathways Both have high recurrence rates, but progression to muscle-invasive disease only occurs in dysplasia pathway Progression from low-grade to high-grade urothelial carcinoma is questionable
- Instrumented urine specimens include any specimen that was obtained by any instrument or whenever force was applied to dislodge individual cells from the lining urothelium. These include catheterized urines, bladder washings, brushings, and upper urinary tract urine specimens obtained by urinary catheterization.
- cytoplasm of large superfi cial cells is very frothy and abundant resulting in a low N/C ratio. Nuclei have pale fi nely granular chromatin. Nucleoli can be prominent, but don’t refl ect any abnormality. Multinucleation is common, especially in instrumented samples
- “umbrella” cells possess a thickened cytoplasmic edge that doesn’t go all around the cell (asymmetric unit membrane)
- Benign squamous cells. Two benign squamous cells line up below an umbrella cell with three nuclei. The presence of squamous cells in voided urine may come from external genitalia, including the vagina. In a catheterized patient, their origin is usually in an area of metaplasia in the lining of the bladder between the ureteral orifi ces and the urethra, the trigone
- Benign glandular cells—endometriosis, Mullerianosis. ( a ) Glandular cells in a urinary tract specimen may be native to the urinary collecting system, or external to it. The larger cells are urothelial or squamous. The cluster of small dark cells originated in an endometriosis of the ureter. The patient was presenting with hematuria and pain coincident with the patient’s menstrual periods
- Glandular cells from a focus of Mullerianosis are not distinguishable from other glandular cells in the urinary bladder. This very rare lesion is related to endometriosis, both considered a metaplasia. Their origin must be biopsy proven correlating the morphology with the location deep in the bladder wall
- Cystitis cystica/glandularis. ( a ) Glandular cells from the lining of the bladder can originate from a focus native to the urothelium, metaplasia from an infl ammatory focus (cystitis cystica/glandularis), or from a glandular neoplasm either primary or secondary. Unless the cytomorphology suggests a neoplasm, all such TTFs or cell groups are considered benign
- RTEC—glandular. This large TTF of RTEC is unusual in size, and represents a tubular cast. The renal tubular cells vary from small with scant cytoplasm to larger and vacuolated. The patient was in renal failure
- These cells have round nuclei which are evenly spaced. Chromatin is fi nely granular and nucleoli are inconspicuous.
- Cellular changes are mild when compared to those in the photos to follow. The absence of any fi brovascular stalk eliminates the diagnosis of a low grade LGUN
- Calcifi c concretions in voided urine may be recovered in patients with history of renal calculi
- A sheet of urothelium consists of relatively uniform cells with moderately hyperchromatic nuclei. Even though the nuclear chromatin is darker than normal, the presence of a bladder stone is reason enough for the changes. Because of the history and mild changes, this sample was placed in the “Negative” category
- Compare the cells in the center of the fi eld with those to the right, especially considering the nuclear chromatin and nuclear shapes. The central cells are hyperchromatic and the shapes vary. Infl ammation is seen in the background. Without the history of nephrolithiasis, these cells would indicate a diagnosis of “atypical urothelial cells” (AUC). If there were any consideration of a urothelial lesion in addition to lithiasis, a note is appropriate or a diagnosis of AUC
- In addition to the classic changes described in Fig. 3.12a , dissolution of the nuclear chromatin is also a characteristic of polyoma (BK) virus infection. The size and shape of the nucleus are the same as the classic features ( Voided, SP, high mag. ). ( c ) If the focal plane is changed, then a spider web of degenerated chromatin comes into view
- Multinucleation in usual superfi cial cells is common. In contrast, Langhans-type giant cells resulting from fused macrophages are multinucleated but have their smaller and slightly hyperchromatic nuclei clustered at one pole of the cytoplasm. Clinical history revealed recent BCG instillation following diagnosis of bladder cancer
- In addition to Langhans giant cells, granulomas can be found in urines following BCG immunotherapy. These granulomas are no different from any other body site, complete with monocytes, lymphocytes, and histiocytes in a tight mélange
- Enteric cells following a urinary diversion post-cystectomy. ( a ) One superfi cial urothelial cell is present to conveniently compare with the small round cells in the fi gure. All are of the same size and have small punctate nuclei. These are typical of degenerated enteric cells
- Following a cystectomy, a diversionary pouch is constructed, lined by cells from the portion of the intestine used. Remarkably, the cells don’t undergo metaplasia because of the toxic urine, but they do degenerate. They usually are single and closely resemble histiocytes. Sometimes they cluster, which can present a diagnostic dilemma. Careful focusing will reveal the small nuclei, dissimilar to HGUC
- progression may be much lower: 0 % for papillomas [ 30 ], 3.6 % for PUNLMP [ 31 ], and 5–25 % for LGPUC
- Positive for LGUN. ( a ) Three-dimensional cluster of cells with nuclear overlapping, forming papillae. There is a thin capillary vessel running through the center of the cluster
- Positive for LGUN. Three-dimensional papillary structures have central cores. Notice mild cytologic atypia and disorganization of cells forming papillae.
- Seminal vesicle cells Older patients, after DRE Smudgy chromatin (vs coarse chromatin in HGUC) Golden brown lipofuscin and mature spermatozoa
- cohesive group of malignant cells. The N/C ratio of 0.7 is noted in the majority of the tumor cells ( Bladder washing, TP, high mag. )
- Nuclear hyperchromasia is present in this cell from a patient with high-grade urothelial carcinoma (HGUC). Note the tumor necrosis clinging to the cells ( Bladder washing, TP, high mag. )
- coarse and clumped nuclear chromatin
- nuclear membrane irregularity with focal thickness of nuclear membranes. Nuclear shapes and sizes vary
- coarse chromatin and nuclear membrane irregularity
- ( a ) The sample is hypercellular showing numerous tumor cells that demonstrate pleomorphism and necro-sis in the background ( Voided urine, SP, low mag. ). ( b ) The sample was full of these abnormal cells with high N/C ratios and prominent nuclear profi les. The total sample was stained somewhat lightly, so observers are cautioned to use normal cells in the background as stain intensity controls. Also note the presence of lymphocytes in the sample that can be used as controls for nuclear size ( Washing, TP, medium mag. )
- A few cells exhibit classic features of high-grade urothelial carcinoma (HGUC) adjacent to cells of squamous differentiation
- High-grade urothelial carcinoma (HGUC) with cytoplasmic vacuolization reflects glandular differentiation. Nuclear membrane irregularity, hyperchromasia, and coarse chromatin typify HGUC.
- Scattered high-grade urothelial carcinoma (HGUC) tumor cells demonstrate focal glandular differentiation
- A cell cluster composed of six abnormal well-preserved intermediate urothelial cells showing increased N/C ratios, hyperchromasia, clumpy chromatin, and irregular nuclear membranes. Note that not all the cells have an N/C ratio that exceeds 0.7 but in the presence of similar nuclear characteristics, they should be considered part of the same lesion. A “positive for HGUC” diagnosis may be acceptable in this case, especially in the presence of a previous history of HGUC.
- Rare but abnormal well-preserved intermediate urothelial cells showing increased N/C ratios, hyperchromasia, and irregular nuclear membranes
- A few abnormal intermediate urothelial cells, one of which is well preserved (center) and features an increased N/C ratio, hyperchromasia, irregular clumpy chromatin, and severely irregular nuclear membrane. If more than five similar cells were found, the diagnosis of HGUC would be appropriate.
- Cell clusters of well-preserved intermediate urothelial cells some of which show an increased N/C ratio and hyperchromasia. The degree of hyperchromasia is mild in comparison to the normal intermediate cell nucleus ( upper right ). In addition, the cells do not show clumpy chromatin pattern or irregular nuclear membranes which preclude the assignment of a SHGUC diagnosis.
- Abnormal intermediate urothelial cells showing increased N/C ratio and irregular nuclear membranes in the absence of nuclear hyperchromasia preclude a diagnosis of SHGUC. The follow-up diagnosis was LGUC
- Atypical urothelial cells (AUC). Abnormal intermediate urothelial cells displaying increased N/C ratio and irregular nuclear membranes in the absence of nuclear hyperchromasia preclude a diagnosis of SHGUC
- One single and degenerated urothelial cell showing increased N/C ratio, hyperchromasia, and irregularly distributed clumpy chromatin. Note the presence of incomplete cytoplasm and discontinuous nuclear membranes. In the presence of cellular degeneration a SHGUC diagnosis should not be rendered