cow-2022-33

a) KRAS mutation

b) Loss of chromosome Y

c) Trisomy 7

d) Trisomy 17

e) PTEN deletion

Papillary renal neoplasm with reverse polarity; KRAS mutation

The section shows a well-circumscribed, largely cystic lesion with a pseudocapsule. Adjacent kidney shows secondary atrophic changes due to compression. The more solid areas of the lesion show mostly papillary structures with true fibrovascular cores. The lining epithelial cells are mostly uniform, and bland-appearing. The cells have large eosinophilic cytoplasm and apically arranged nuclei. Other areas with oncocytic cells and hobnail cells are also noted. The cells are positive for GATA3, CK7, and Racemase; and negative for Vimentin. A heterozygous mutation in KRAS gene codon 12 (G12V, c.35>T) was detected by PCR.

Papillary renal cell carcinoma with reverse polarity is an emerging entity that has been referred to in the literature as “oncocytic low-grade papillary RCC” and “type 4 papillary RCC”. It has distinct morphology, IHC profile, and recurrent molecular alterations. They are usually small and cystic lesions with no reported progression in the literature to date. The classic morphology is defined as oncocytic cells arranged in a tubulopapillary architecture with low-grade nuclei (WHO/ISUP Grade 1-2) that are apically located in the cytoplasm. These tumors are uniformly positive for GATA3 and CK7 with variable expression for vimentin and Racemase. Most cases harbor KRAS mutations (80-90%).

GATA3 expression and KRAS mutations suggest this may be a unique tumor. However, the presence of papillary architecture and the molecular alterations that are seen in papillary RCC such as trisomy 7 and 17, and loss of chromosome Y suggest that this is a subtype of papillary RCC. GATA3 expression has been shown in a variety of renal neoplasms such as clear cell papillary RCC, oncocytoma, and chromophobe RCC. It is a transcription factor that plays important role in the nephron development. Its expression is high in the distal and collecting ducts and low in the proximal tubules. This profile is in line with GATA 3 expression in benign and malignant renal lesions. For example, in glomerulocystic renal disease that originates from Bowman’s capsule and proximal tubules, the cyst lining is negative for GATA3. On the other hand, in polycystic kidney disease that originates from the distal tubules, the cyst lining is positive for GATA3. Similarly, clear cell RCC and papillary RCC that originate from proximal tubules are negative for GATA3. Oncocytoma and chromophobe RCC that originate from the junction of loop of Henle are positive for GATA3 in 50% of tumors. Clear cell papillary renal tumor is considered to originate from the distal tubules and is positive for GATA3. Therefore, it is reasonable to suggest that papillary renal tumor with reverse polarity may originate from the distal portion of nephron. However, ultrastructural and molecular analyses are needed to further support this proposal.

Differential diagnosis includes other papillary tumors of the renal parenchyma. There are multiple new variants included in the spectrum of papillary RCC with specific morphology, immunoprofile, and predicted clinical behavior. Papillary RCC with reverse polarity is a distinct entity with its classic morphology and unique GATA3 expression and KRAS mutations.

• 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. 2021 Jul;34(7):1392-1424.

• Al-Obaidy KI, Eble JN, Cheng L, Williamson SR, Sakr WA, Gupta N, Idrees MT, Grignon DJ. Papillary Renal Neoplasm With Reverse Polarity: A Morphologic, Immunohistochemical, and Molecular Study. Am J Surg Pathol. 2019 Aug;43(8):1099-1111.

• 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 Apr;33(4):690-699.

• Deebajah M, et al. GATA3 Is a Useful Immunohistochemical Marker to Differentiate Variants of Renal Tubular Lesions from Different Segments of Renal Tubules, American Journal of Clinical Pathology, Volume 156, Issue Supplement_1, October 2021, Pages S152–S153

• Van Esch H, Bilous RW. GATA3 and kidney development: why case reports are still important. Nephrol Dial Transplant. 2001 Nov;16(11):2130-2.

• Cairns P. Renal cell carcinoma. Cancer Biomark. 2010;9(1-6):461-73. • Lindgren D, Sjölund J, Axelson H. Tracing Renal Cell Carcinomas back to the Nephron. Trends Cancer. 2018 Jul;4(7):472-484.

Levent Trabzonlu, Maria M. Picken
Department of Pathology and Laboratory Medicine, Loyola University Medical Center
Maywood, IL

Kidney

Papillary renal neoplasm with reverse polarity, kidney, papillary RCC