Case of the Month: Kidney

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2016, case 21, and is a cystic nephroma/mixed epithelial and stromal tumor.

Sections demonstrate a multilocular cystic lesion lined by epithelial cells, which range from flattened to attenuated cuboidal to hobnailed. The epithelial cells contain eosinophilic cytoplasm and round centrally placed nuclei with vesicular chromatin, occasionally conspicuous nucleoli, and without significant cytologic atypia. The cyst wall contains a spindle cell stromal component, which is moderately cellular and resembles ovarian-type stroma. Immunohistochemistry shows that the stromal component is positive for estrogen (ER) and progesterone (PR) receptors. These findings support a diagnosis of cystic nephroma/mixed epithelial stromal tumor (CN/MEST).

CN/MESTs are uncommon benign neoplasms of the kidney that occur predominantly in pre- and perimenopausal women and are usually found incidentally, although symptoms may occur including abdominal pain, hematuria, or urinary tract infections. These tumors are characterized by mixed epithelial and mesenchymal components. CN is entirely cystic, as in the current case, while MEST contains variable amounts of solid components. In both entities, the cystic spaces are lined by a single layer of flat, low cuboidal, or hobnail epithelium, while the septa and/or solid components contain a stroma, which is variably cellular and resembles ovarian-type stroma. The stromal component is positive for ER and PR receptors and less commonly for inhibin and calretinin by immunohistochemistry, while the epithelial component is positive for renal epithelial markers such as PAX8. The ER/PR-positivity along with the patient demographics (premenopausal women) suggests a probable role of hormonal stimulation in the pathogenesis of these tumors. While the epithelial component of CN/MEST has been regarded by many as “entrapped” renal tubular epithelium rather than a true neoplastic component, relatively recent studies have demonstrated clonality in both the epithelial and stromal components in at least some cases thus supporting the true biphasic nature of this neoplasm. CN/MESTs are benign neoplasms for which conservative surgical excision alone is adequate, although a few rare cases of local recurrence and malignant transformation have been reported.

While there has historically been some debate as to whether or not CN and MEST are distinct entities, most authors believe that the two lesions represent variations of the same entity. In addition to significant morphologic overlap, evidence from gene expression profiling studies suggests that the two are biologically related. The 2013 International Society of Urological Pathology Vancouver classification of renal neoplasia addresses this issue and quotes a 72% consensus agreement for the combined heading of CN/MEST. As an additional note on terminology, there is a similar pediatric entity termed “cystic nephroma,” which is favored to represent an entirely separate biologic entity that is associated with constitutional DICER1 mutations.

An important entity to exclude in the differential diagnosis of CN/MEST is multilocular cystic renal cell carcinoma (MCRCC). In MCRCC, clusters of clear cells, otherwise typical of clear cell renal cell carcinoma, are found within the walls and septa of cysts. Adequate sampling is advised in cystic renal neoplasms, largely to exclude this entity, as the diagnostic areas may be focal. In addition, the ovarian-type stroma characteristic of CN/MEST is not found in MCRCC, although in some cases of CN/MEST the stroma may appear hyalinized and/or fibrotic rather than truly ovarian-like. Furthermore, the ER/PR stromal positivity that is characteristic of CN/MEST is not entirely specific, as these markers may be positive in non-neoplastic renal lesions related to renal obstruction as well as angiomyolipoma with epithelial cysts, as discussed below.

Angiomyolipoma with epithelial cysts (AMLEC) is a recently described entity, with fewer than 20 cases reported in the literature. AMLEC is characterized by (1) epithelial cysts lined by cuboidal to hobnail cells, (2) cellular subepithelial müllerian-like stroma positive for ER/PR and melanocytic markers such as HMB45 and containing prominent admixed chronic inflammation, and (3) features of muscle-predominant angiomyolipoma with associated dysmorphic blood vessels exterior to the cellular subepithelial stroma. These latter two features are absent in the current case. In difficult cases, stains for desmin and HMB45 should resolve the differential.

Tubulocystic carcinoma (TCC) is an uncommon cystic renal neoplasm with a strong male predominance, in contrast to the strong female predominance observed in CN/MEST. Histologically, TCC may be distinguished from a predominantly cystic CN/MEST by the cyst lining cells, which have high-grade nuclei and abundant eosinophilic cytoplasm in the former. In addition, TCC often contains incomplete and free-floating septa. Lastly, ER/PR-positive stroma is not present in this tumor.

Cystic partially differentiated Wilms tumor (CPDWT) may resemble CN/MEST microscopically, at least in cases lacking the characteristic ovarian-type stroma. A careful search for blastema will confirm the diagnosis of CPDWT. In addition, the patient demographics are notably different; CPDWT is a tumor of childhood while CN/MEST is a disease of pre-and peri-menopausal women. While rare cases of Wilms tumor have been reported in adults, CN/MEST has not been reported in children.

1. Which of the following is true regarding cystic nephroma/mixed epithelial and stromal tumor (CN/MEST)?
   1. CN and MEST are favored to represent different biologic entities.
   2. CN/MEST occurs predominantly in men.
   3. CN/MEST contains an ovarian-type stroma which is positive for estrogen receptor and HMB45.
   4. CN/MEST is a benign neoplasm for which surgical excision is usually curative.
   5. Patients with CN/MEST usually have symptoms at presentation.
2. Which of the following immunohistochemical staining patterns is most characteristic of the stroma in cystic nephroma/mixed epithelial and stromal tumor?
   1. ER+, PR+, HMB45+
   2. ER+, PR+, HMB45-
   3. ER+, PR-, HMB45-
   4. ER-, PR+, HMB45-
   5. ER-, PR-, HMB45-
3. Which of the following is true regarding the differential diagnosis of cystic nephroma/mixed epithelial and stromal tumor?
   1. Minimal sampling of a cystic renal tumor is adequate to exclude renal cell carcinoma.
   2. Multilocular cystic renal cell carcinoma may be distinguished from CN/MEST by the presence of clear cells within the walls and septa of cyst in the former.
   3. Renal cell carcinoma never has a cystic component.
   4. Tubulocystic carcinoma is also characterized by an ovarian-type stroma.
   5. Tubulocystic carcinoma predominantly occurs in women, similar to CN/MEST.

1. Fine SW, Reuter VE, Epstein JI, Argani P. Angiomyolipoma with epithelial cysts (AMLEC): a distinct cystic variant of angiomyolipoma. Am J Surg Pathol. 2006;30(5):593-599.
2. Michal M, Hes O, Bisceglia M, et al. Mixed epithelial and stromal tumors of the kidney. A report of 22 cases. Virchows Arch. 2004;445(4):359-367.
3. Srigley, JR, Delahunt B, Eble JN, et al. The International Society of Urological Pathology (ISUP) Vancouver classification of renal neoplasia. Am J Surg Pathol. 2013;37(1):1469-1489.
4. Zhou M, Kort E, Hoekstra P, et al. Adult cystic nephroma and mixed epithelial and stromal tumor of the kidney are the same disease entity: molecular and histologic evidence. Am J Surg Pathol. 2009;33(1):72-80.

2016
Amy M. Coffey, MD
Surgical Pathology Committee
Surgical Pathology Fellow
Texas Children’s Hospital
Baylor College of Medicine
Houston, TX

1. CN/MEST is a benign neoplasm for which surgical excision is usually curative. (d)
2. ER+, PR+, HMB45- (b)
3. Multilocular cystic renal cell carcinoma may be distinguished from CN/MEST by the presence of clear cells within the walls and septa of cyst in the former. (d)