Editor: Mahmut Akgul (

2022-22/June 6

Contributors: Daniel Geisler, Gabriela M. Quiroga-Garza

The patient is a female in her 60s who presents with an incidentally detected kidney mass. Computed tomography shows an enhancing exophytic, solid right kidney mass of the lower pole. The patient elects to undergo a laparoscopic partial nephrectomy of the massThe specimen measures 3.0 x 2.0 x 1.2 cm and consists of a well-defined, partially cauterized,enucleated, and encapsulated lesion. The cut surface shows a well-defined, glistening, tan-red-brown, and rubbery to spongy mass with no obvious necrosis(Figure 1).The lesion abuts both the parenchymal margin and capsular surface, without discrete involvement of either.



Papillary renal neoplasm with reverse polarity

The lesion is well-circumscribed with varying papillary and tubulopapillary architecture (Figure 2A-B). The papillae are lined by a single layer of small to medium-sized cells with eosinophilic cytoplasm. The nuclei are generally uniform and ovoid with inconspicuous nucleoli arranged away from the basal aspect of the cell (Figure 2C-D). The scant stroma is composed of hyalinized to loose fibroconnective tissue with focal edematous areas. Tumor necrosis, mitotic figures, lymphovascular invasion, and perirenal invasion are not identified.

Immunohistochemical stains performed on the tumor show CK7 (Figure 3A), GATA3 (Figure 3B), and EMA (Figure 3C) positivity. The tumor cells are negative for vimentin (Figure 3D), renal cell carcinoma antigen, CD10, carbonic anhydrase IX, and CD117. Parvalbumin demonstrates patchy, weak positivity. Ki-67 shows a low proliferation index with less than 1% of tumor cells positive.

Papillary renal cell carcinoma, the second most common renal cell carcinoma, encompasses a spectrum of tumors with different clinical, morphologic, histologic, and molecular features. Due to the poor interobserver reproducibility and overlapping histologic features, the prior division into type 1 and 2 subtypes is no longer recommended.(1–5) New tumor variants have been recently emerging within the papillary renal cell carcinoma spectrum with specific histomorphology, immunoprofile, and clinical behavior.(5) Papillary renal neoplasm with reverse polarity (PRNRP) is one such newly proposed entity that was originally recognized in 2008 and described as a favorable papillary renal cell carcinoma characterized by oncocytic cells with nonoverlapping, peripheralized low-grade nuclei.(6) Al-Obaidy et al (7) further characterized these tumors, showing consistent KRAS mutations, and proposed the name PRNRP. Typical clinicopathologic features include a mean age of presentation of 63 years old (range, 36-82 years old), a slight male predominance (56:44 M:F ratio), and an average tumor size of 2.1 cm (range, 0.8 to 8.5 cm).(8) PRNRP accounts for 4% of papillary renal cell carcinomas.(7) Characteristic histomorphologic findings include a well-circumscribed, solid to partially cystic tumor with predominant thin papillary to tubulopapillary growth patterns. Papillae cores are variably hyalinized to cystically dilated with floating macrophages. The epithelial lining is formed by cuboidal cells with finely granular, eosinophilic cytoplasm. The nuclei are characteristically apically located, away from the basement membrane, and show lower Fuhrman and WHO/International Society of Urological Pathology (ISUP) nuclear grades of 1-2. Necrosis, mitotic figures, psammoma bodies, and tight clusters of foamy macrophages are absent.(6–11)

The immunohistochemical profile of PRNRP shows CKAE1/AE3, CK7, GATA3, EMA, and L1CAM positivity. CD117 and vimentin are consistently negative. Alpha-mehtylacyl-CoA-racemase (AMACR) and CD10 shows variable staining.(5–12) Unique KRAS missense mutationshave been identified in 85% of cases tested, with the most common KRAS mutation being p.G112V in 54% of cases.(7,8,11,12) FISH analysis has shown trisomy 7, trisomy 17, and chromosome Y deletion in 33%, 33%, and 14% of PRNRP cases, which is more classically associated with other papillary renal cell carcinomas.(7) Most cases present with low pathologic stage (pT1a, 97%), and patient follow-up has shown no recurrence, metastasis, or tumor-related death during the follow up period.(7,8,11) The differential diagnosis includes kidney neoplasms with eosinophilic cytoplasm and papillary growth patterns. High grade eosinophilic kidney neoplasms with papillary growth could include fumarate hydratase-deficient renal cell carcinoma, MiT/TFE family translocation renal cell carcinomas, acquired cystic disease-associated renal cell carcinoma, and other renal papillary carcinoma variants. These tumors, however, will showhigh grade histologic features, including high WHO/ISUP nuclear grade. Tumors in the low grade spectrum that can mimic PRNRP include oncocytoma and chromophobe carcinoma, however, these tumors will not typically show a papillary growth pattern and will bepositive for CD117. Other low-grade papillary renal cell carcinomas or morphologic variants of clear cell renal cell carcinoma may also be included in the differential, and ancillary immunohistochemical or molecular testing to show classic PRNRP CK7 and GATA3 positivity or KRAS mutations may be helpful in these scenarios.

1. Delahunt B, Eble JN, McCredie MR, Bethwaite PB, Stewart JH, Bilous AM. Morphologic typing ofpapillary renal cell carcinoma: comparison of growth kinetics and patient survival in 66 cases. Hum Pathol. 2001;32(6):590-595. doi:10.1053/hupa.2001.24984

2. Saleeb RM, Plant P, Tawedrous E, et al. Integrated Phenotypic/Genotypic Analysis of Papillary Renal Cell Carcinoma Subtypes: Identification of Prognostic Markers, Cancer-related Pathways, and Implications for Therapy. Eur Urol Focus. 2018;4(5):740-748. doi:10.1016/j.euf.2016.09.002

3. Saleeb RM, Brimo F, Farag M, et al. Toward Biological Subtyping of Papillary Renal Cell Carcinoma With Clinical Implications Through Histologic, Immunohistochemical, and Molecular Analysis. Am J Surg Pathol. 2017;41(12):1618-1629. doi:10.1097/PAS.0000000000000962

4. Chevarie-Davis M, Riazalhosseini Y, Arseneault M, et al. The morphologic and immunohistochemical spectrum of papillary renal cell carcinoma: study including 132 cases with pure type 1 and type 2 morphology as wellas tumors with overlapping features. Am J Surg Pathol. 2014;38(7):887-894. doi:10.1097/PAS.0000000000000247

5. Trpkov K, Hes O, Williamson SR, et al. New developments in existing WHO entities and evolving molecular concepts: The Genitourinary Pathology Society (GUPS) update on renal neoplasia. Mod Pathol Off J U S Can Acad Pathol Inc. 2021;34(7):1392-1424. doi:10.1038/s41379-021-00779-w

6. Kunju LP, Wojno K, Wolf JS, Cheng L, Shah RB. Papillary renal cell carcinoma with oncocytic cells and nonoverlappinglow grade nuclei: expanding the morphologic spectrum with emphasis on clinicopathologic, immunohistochemical and molecular features. Hum Pathol. 2008;39(1):96-101. doi:10.1016/j.humpath.2007.05.016

7. Al-Obaidy KI, Eble JN, Cheng L, et al. Papillary Renal Neoplasm With Reverse Polarity: A Morphologic, Immunohistochemical, and Molecular Study. Am J Surg Pathol. 2019;43(8):1099-1111. doi:10.1097/PAS.0000000000001288

8. Wei S, Kutikov A, Patchefsky AS, et al. Papillary Renal Neoplasm With Reverse Polarity Is Often Cystic: Report of 7 Cases and Review of 93 Cases in the Literature. Am J Surg Pathol. Published online August 5, 2021. doi:10.1097/PAS.0000000000001773

9. Kiyozawa D, Kohashi K, Takamatsu D, et al. Morphological, immunohistochemical, and genomic analyses of papillary renal neoplasm with reverse polarity. Hum Pathol. 2021;112:48-58. doi:10.1016/j.humpath.2021.03.009

10. Zhou L, Xu J, Wang S, et al. Papillary Renal Neoplasm With Reverse Polarity: A Clinicopathologic Study of 7 Cases. Int J Surg Pathol. 2020;28(7):728-734. doi:10.1177/1066896920918289

11. Kim SS, Cho YM, Kim GH, et al. Recurrent KRAS mutations identified in papillary renal neoplasm with reverse polarity—a comparative study with papillary renal cell carcinoma. Mod Pathol. 2020;33(4):690-699. doi:10.1038/s41379-019-0420-8

12. Chang HY, Hang JF, Wu CY, et al. Clinicopathological and molecular characterisation of papillary renal neoplasm with reverse polarity and its renal papillary adenoma analogue. Histopathology. 2021;78(7):1019-1031.doi:10.1111/his.14320

Daniel Geisler, Gabriela M. Quiroga-Garza
University of Pittsburgh Medical Center
Pittsburgh, PA


Kidney, neoplasm, papillary renal neoplasm with reverse polarity