March 2022 – Genitourinary Pathology and Renal Pathology

Clear cell papillary renal cell carcinoma.

Clear cell papillary renal cell carcinoma (CCPRCC) is a subtype of renal cell carcinoma (RCC) included in 2016 WHO classification. The tumor was first described in kidneys with end-stage renal disease, however, the majority of cases reported subsequently have been sporadic. It is important to recognize this subtype as it follows an indolent course. 

Clear cell papillary renal cell carcinoma accounts for 1%–4% of all resected renal tumors. The mean age at presentation is 60 years (range: 18 to 88 years) and there is no sex predilection. They are usually diagnosed as low-stage tumors. They present as well-circumscribed nodules with a mean size <3.0 cm and are usually low grade (WHO/ISUP grade 1 or 2). Tumor necrosis, perineural invasion, and lymphovascular invasion have not been observed. A single metastatic case has been reported.^1,2 These tumors have much better prognosis than (conventional) papillary and clear cell renal cell carcinomas (RCCs). 

Tumors show a variable mixture of tubular (commonly predominant), papillary, acinar, cystic, cords, and solid growth patterns. Cuboidal or columnar cells with clear cytoplasm and nuclei uniformly arranged away from the basement membrane are the typical cytological features of these tumors. They may have overlapping features with conventional clear cell renal cell carcinoma, and immunohistochemical stains can help in this differential diagnosis.³

Clear cell papillary RCC are diffusely and strongly positive for cytokeratin 7 and show membranous CA-IX staining with absence of luminal staining (basolateral/ “cup-like” membranous localization). The hypothesized cell of origin is the distal nephron, as these tumors are frequently positive for GATA3 and high molecular weight cytokeratin. Specifically, GATA3 is considered a sensitive (76%) and specific (100%) marker for CCPRCC and can be used for accurate distinction from histologic mimics. The positive and negative predictive values are 100% and 74%, respectively. Coexpression of GATA3 and high molecular weight cytokeratin in most CCPRCC supports their origin from distal nephron.⁴ They are negative for AMACR, CD10, and RCC.⁵

Primary renal cell carcinomas with both papillary architecture and cells with clear cytoplasm can be diagnostically challenging, and the differential diagnosis includes clear cell RCC, papillary RCC, clear cell papillary RCC, and MiT family translocation RCC. Accurate diagnosis has prognostic implications and immunohistochemical stains can help establish the diagnosis.⁵

These tumors are mutationally silent and genomically stable. No specific molecular alterations have been identified other than accumulation of sugar alcohol sorbitol on metabolomic profiling, and this contrasts with clear cell renal cell carcinoma that have loss of function VHL alterations (mutation/deletions/epigenetic silencing).⁶

These are indolent tumors with a benign course and favorable prognosis. They usually present as low stage and low-grade tumors. In a follow-up study of 362 cases, no tumor recurrence, metastasis, or disease-related deaths were reported. Only a single case of metastatic behavior has been reported in the current English language literature.^1,2

References

1. Gupta S, Inwards CY, Van Dyke DL, Jimenez RE, Cheville JC. Defining clear cell papillary renal cell carcinoma in routine clinical practice. Histopathology. 2020;76(7):1093-1095. doi:10.1111/his.14071
2. Gupta S, Pitel BA, Knight SM, Halling KC, Jimenez RE, Cheville JC. Re: Stanley Weng, Renzo G. DiNatale, Andrew Silagy, et al. The Clinicopathologic and Molecular Landscape of Clear Cell Papillary Renal Cell Carcinoma: Implications in Diagnosis and Management. Eur Urol 2021;79:468–77. Eur Urol. 2021;80(2):e62-e63. doi:10.1016/j.eururo.2021.05.011
3. Weng S, DiNatale RG, Silagy A, et al. The Clinicopathologic and Molecular Landscape of Clear Cell Papillary Renal Cell Carcinoma: Implications in Diagnosis and Management. Eur Urol. 2021;79(4):468-477. doi:10.1016/j.eururo.2020.09.027
4. Mantilla JG, Antic T, Tretiakova M. GATA3 as a valuable marker to distinguish clear cell papillary renal cell carcinomas from morphologic mimics. Hum Pathol. 2017;66:152-158. doi:10.1016/j.humpath.2017.06.016
5. Williamson SR. Clear cell papillary renal cell carcinoma: an update after 15 years. Pathology (Phila). 2021;53(1):109-119. doi:10.1016/j.pathol.2020.10.002