Discussion

The Paris System primarily focuses on detecting urothelial carcinoma in situ and high-grade urothelial carcinoma (HGUC), with the diagnosis of HGUC being the gold standard based on cytomorphologic criteria. However, upper urinary tract lesions, including both urothelial and non-urothelial types, pose significant classification challenges due to their rarity and diverse morphologies. Upper tract urothelial carcinomas typically arise in the renal pelvis or ureter and are most frequently evaluated using washing/barbotage specimens. The cytomorphologic criteria outlined by The Paris System for HGUC apply equally to both upper and lower urinary tract specimens. While The Paris System excels in identifying HGUC, it is essential for cytopathologists and cytotechnologists to also recognize non-urothelial malignancies that may appear in both upper and lower urinary tract specimens to ensure accurate diagnoses.

Secondary malignancies rarely involve the urinary tract, accounting for approximately 2% of surgically resected bladder tumors. These malignancies usually result from direct extension from adjacent organs (approximately 70%), with metastases from distant sites being less common (approximately 30%). Colorectal adenocarcinoma is the most common secondary malignancy in the bladder, typically involving the urinary tract through direct extension. Prostate adenocarcinoma is the second most common, and it can involve the urinary tract either by direct extension or through lymphatic spread.

Metastatic renal cell carcinoma (RCC) is exceedingly uncommon in urine cytology as they are typically detected prior to eroding into the urinary tract. Therefore, urine cytology plays no significant role in the diagnosis of RCC. However, when RCC extends into the renal pelvis or ureter, RCC cells can exfoliate into the urine and be identified in cytology specimens. Distinguishing HGUC from RCC in the upper urinary tract poses several challenges. Clinically, hematuria is the most common presenting symptom for both HGUC and RCC. Radiologically, HGUC with extension into the renal parenchyma and RCC with renal pelvis involvement cannot always be distinguished. In these cases, the cytologic diagnosis is critical. Diagnostic accuracy is tremendously important as the treatments for these entities differ significantly, impacting patient morbidity.

A selective immunohistochemistry panel is highly useful in accurately identifying RCC in the urine. By immunohistochemistry, RCC will be positive for PAX8 and negative for GATA3, whereas urothelial carcinoma is positive for GATA3 and negative for PAX8. CAIX shows diffuse membranous positivity in clear cell renal cell carcinoma. However, it can exhibit weak positivity in urothelial cells, so it should be interpreted in combination with PAX8 and GATA3. The defining molecular alteration in clear cell RCC is the inactivation of the von Hippel-Lindau (VHL) gene, which occurs in over 90% of cases. This inactivation typically results from the loss of the short arm of chromosome 3, followed by mutation or methylation of the remaining VHL gene. The loss of 3p can be identified through molecular cytogenetic studies or chromosomal microarray analysis.

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