Microscopic Description:

In this case, both cystic epithelium and stromal elements are seen. There are various moderately thick-walled cysts with a hobnailed epithelium, meaning the nuclei are protruding into the center of the cyst. The stroma also appears ovarian-like, with a spindled and almost luteinized appearance, with large pink cells with clearer cytoplasm. Additionally, there is intermixed amorphous debris. Overall, there is no significant atypia of either the epithelial or stromal elements.

The IHC more definitively reveals the likely diagnosis, demonstrating positive staining for PR in the stromal component, with focal ER staining. CD10 is a marker for ovarian and endometrial stroma, which correlates with the ovarian-like stroma seen in this case. While not pictured, the epithelial component is the portion that would stain positive stain for CK7. Thus, the most likely diagnosis is a mixed epithelial and stromal tumor.

The other differentials can be ruled out through IHC and histologic morphology. Cystic nephromas can also have epithelial-lined cysts and can stain positive for ER/PR as depicted in this case, but a cystic nephroma is a predominately cystic tumor, often presenting with diffuse, thin-walled cysts with no solid components. The stroma of angiomyolipomas with epithelial cysts will stain positive for HMB45 and MelanA which are melanocytic markers, and are triphasic with fat, smooth muscle, and blood vessels which lack an inner elastic lamina. Synovial sarcomas are most commonly monophasic and arise from the renal tubules, although rare biphasic types are possible, and do not classically stain for PR/ER.

Discussion:

Currently, according to the WHO 2016 guidelines, both mixed epithelial and stromal tumors (MEST) and cystic nephromas are defined within a spectrum known as the MEST family, a single entity with varying amounts of cystic epithelial components and stromal components consisting of spindle-shaped cells.1,2 As mentioned, adult cystic nephromas have a more predominant cystic component whereas MEST has a more predominant stromal component and are more likely to show stromal luteinization and ovarian-like stromal features.1,3,4 This spectrum is thought to exist due to a similar mRNA expression profile between the two tumors.4 A study in 2007 proposed that both MEST and cystic nephromas had a similar origin, arising from misplaced mullerian remnants during embryogenesis, and suggested a unified term of “renal epithelial and stromal tumor” (REST). However, a more definitive classification requires further investigation of molecular markers to differentiate the two.

In general, MESTs are more common in perimenopausal women, especially those with a history of prolonged estrogen replacement therapy or men who have been treated with hormonal therapy, correlating with the stromal tendency to stain positive for ER/PR.4,5 MEST are 7x more likely to occur in female patients.4 Patients may present with general symptoms of a renal mass, including flank pain, hematuria, UTIs, or a palpable mass, but approximately ¼ of patients with a MEST are diagnosed incidentally on imaging. Most MESTs are benign, although rarely malignant transformation of either the epithelial or stromal component can occur. Described cases include transformation into a sarcoma, rhabdomyosarcoma, chondrosarcoma, and papillary renal cell carcinoma.5 Treatment classically involves a nephron sparing surgery through a partial nephrectomy whenever feasible, although rare local recurrence has been reported.

Notably, pediatric cystic nephromas are commonly associated with DICER1 mutations. Some have hypothesized that adult cystic nephromas on the MEST spectrum may be distinct from pediatric cystic nephromas which could be part of the Wilms tumor spectrum. However, it is still unclear if it arises as a developmental abnormality, as a neoplasm, or perhaps even as both.

References:

Domae K, Ichikawa Y, Kubooka M, et al. Mixed epithelial and stromal tumor of the kidney with long-term imaging follow-up. Radiol Case Rep. 2023;18(9):3212-3217. Published 2023 Jun 30. doi:10.1016/j.radcr.2023.06.044

Karşıyakalı N, Yücetaş U, Ateş HA et al. The Largest Cystic Nephroma Treated by Laparoscopic Nephron-sparing Surgery: A Case Report and Review of the Literature. J Urol Surg. 2019;6(2):148-151. doi:10.4274/jus.galenos.2018.2190

Turbiner J, Amin MB, Humphrey PA, et al. Cystic nephroma and mixed epithelial and stromal tumor of kidney: a detailed clinicopathologic analysis of 34 cases and proposal for renal epithelial and stromal tumor (REST) as a unifying term. Am J Surg Pathol. 2007;31(4):489-500. doi:10.1097/PAS.0b013e31802bdd56

Choy B. Kidney tumor: Renal cell tumors – benign/indolent: Mixed epithelial and stromal cell tumor. Pathology Outlines. 2024. Available from: https://www.pathologyoutlines.com/topic/kidneytumormixedepithelial.html

Kalinowski P, Kalinowski T, Kucharz J, et al. Mixed epithelial and stromal tumor of the kidney: A case report. Oncol Lett. 2022;25(1):25. Published 2022 Nov 23. doi:10.3892/ol.2022.13611

Doros, L. A., Rossi, C. T., et al. DICER1 mutations in childhood cystic nephroma and its relationship to DICER1-renal sarcoma. Modern Pathology, 2014;27(9): 1267–1280. https://doi.org/10.1038/modpathol.2013.242

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