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After reading the summary, try answering the three related multiple-choice questions below.
A 48-year-old woman presented with flank pain. Imaging studies revealed a multicystic lesion of the right kidney suspicious for renal cell carcinoma. A nephrectomy was performed. The resected 754 g kidney contained a 12.5 x 12.0 x 9.0 cm multiloculated cystic mass with focal white solid nodules, grossly abutting the renal pelvis but apparently confined to the kidney.
Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2009, case 13, and is mixed epithelial and stromal tumor.
Criteria for Diagnosis and Comments:
The distributed sections show multiple cysts lined by attenuated to cuboidal epithelium with bland nuclei. Occasionally hobnail cells are noted. The cysts are separated by stroma, which is variably collagenous and ovarian-like with interspersed thick walled blood vessels. The combined clinical, morphologic, and immunohistochemical findings are most compatible with a mixed epithelial and stromal tumor of the kidney (MEST).
MEST is a benign neoplasm previously described as adult mesoblastic nephroma and cystic hamartoma of the renal pelvis. This lesion occurs almost exclusively in perimenopausal women, many of whom have a history of prolonged estrogen use. Most are discovered incidentally in imaging studies performed for another complaint; however, some patients do present with symptoms, most commonly hematuria, flank pain, or urinary tract infections. MEST is typically solitary, centered on the renal pelvis, well circumscribed, and confined to the kidney. The macroscopic appearance is distinctive, with multiple cysts, small and large, separated by tan, fleshy to yellow-white solid stromal nodules. Microscopically, the cysts in MEST are lined by cuboidal, flattened or, more commonly, hobnail epithelium with amphophilic, and rarely clear, cytoplasm. Occasionally the epithelium may be columnar, ciliated, or urothelial-like. Rarely, reactive epithelial atypia is observed; however, significant pleomorphism and mitotic activity are lacking. The spindle cell stromal component may be paucicellular and collagenous or cellular with a fascicular pattern. When well sampled, virtually all lesions will contain ovarian-like stroma. The more cellular lesions may appear leiomyomatous. Some lesions will show alternating zones of high and low cellularity with eosinophilic collagen bundles, as seen in solitary fibrous tumor. Thick-walled blood vessels, myxoid change, fat cells, and stromal edema may all be observed; blastema, immature mesenchymal tissue, mitotic activity and necrosis are absent. A significant minority of MEST exhibit condensation of the stroma around branching epithelial structures, closely resembling phyllodes tumor of the breast.
The immunohistochemical profile of these neoplasms is distinctive. The stromal cells are variably immunoreactive for smooth muscle actin, desmin, estrogen receptor, progesterone receptor, and CD10. The latter three markers are most commonly observed in the ovarian-like stroma, which may also exhibit immunoreactivity for calretinin and inhibin, reflecting luteinization of the stromal cells. Recently, a PEComatous variant has been described in which HMB-45 positivity is present in a subset of the smooth muscle actin positive myoid stromal cells. The epithelial component uniformly expresses keratin and vimentin with a subset showing immunoreactivity for CD10 in a brush border pattern; the morphologically Mullerian type epithelium may be positive for estrogen and progesterone receptors.
It is postulated that MEST arises from periductal fetal mesenchyme or through the abnormal migration of ovarian stroma during embryogenesis. This tissue has the potential to proliferate in a state of hormonal imbalance (menopause, unopposed estrogen use) and induce the development of a closely apposed epithelial component. Some authors have further suggested that there is a link between MEST and similar mucinous cystic neoplasms with ovarian-like stroma in the liver and pancreas. These histogenetic hypotheses are supported by the clinical presentation of this neoplasm and the presence of estrogen and progesterone receptor expression in stromal cells.
The clinical behavior of MEST is virtually always benign although recurrences have been described and there have been rare reports documenting malignant transformation of the stromal component. The principal differential diagnosis of MEST is with other cystic neoplasms of the kidney: cystic nephroma (CN), cystic partially differentiated nephroblastoma (CPDN) and multilocular cystic renal cell carcinoma (MCRCC). Although cystic nephroma does not exhibit the architectural complexity of cysts and glands, or the complex branching, columnar, clear and urothelial-like epithelium that may be seen in MEST, CN shows significant clinical and morphologic overlap with MEST; recently it has been suggested that CN and MEST represent two ends of a histologic spectrum and should be combined into a single entity – renal epithelial stromal tumor (REST). This proposal is supported by molecular data showing that the mRNA profile of these two tumors is similar and distinct from other renal neoplasms. However, in the current WHO classification the two neoplasms remain separate entities with CN defined by a predominance of cysts and, by arbitrary definition, stromal septa that are no greater than 5 mm in thickness.
CPDN is a distinctive variant of nephroblastoma, which like all nephroblastomas, is a lesion of children, most less than 2 years old. Adult CPDN has been described; however, these lesions are generally thought to be MEST. In contrast to CPDN, blastema, undifferentiated mesenchyme, and nephroblastic epithelium have not been described in MEST. MCRCC shows cysts lined by epithelium with clear cytoplasm and thin fibrous septa; in cases with attenuated or absent epithelium, these tumors may mimic MEST. In contrast to MEST, however, on careful sampling, nodules of cytologically atypical clear cells are found within the fibrous septa. Metanephric adenofibroma, a rare biphasic tumor of children and young adults, is easily distinguished from MEST by clinical features, by the paucity of cysts, and by the presence of a characteristic metanephric-adenoma like epithelial component. Angiomyolipoma and solitary fibrous tumor would enter the differential diagnosis only in very rare cases of non-cystic MEST; in these cases careful sampling will disclose the epithelial component of MEST. In difficult cases, immunohistochemistry for HMB-45 and CD34, both characteristically absent in MEST (with the exception of the above-mentioned PEComatous variant), may be of utility.
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