Case 1 -

Mixed Epithelial and Stromal Tumor John N. Eble Indiana University School of Medicine Indianapolis, IN

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Clinical History: An incidentally-found 40 x 32 x 25 mm mass in the hilar region of the kidney of a 62-year-old woman was thought clinically to be a primary malignancy of the kidney. Gross examination in the pathology laboratory found a rubbery well-circumscribed solid and cystic tumor which protruded into the renal pelvic cavity. Case 1 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 1 - Figure 1 Mixed epithelial and stromal tumor with a mixture of collagenous and smooth muscle stroma and cysts of variable size lined by cuboidal and columnar epithelium A few fat cells are present in the upper right. Case 1 - Figure 2 Mixed epithelial and stromal tumor with irregular branching lumen lined by cuboidal and hobnail epithelium. Case 1 - Figure 3 Mixed epithelial and stromal tumor with collagenous stroma and cysts lined by urothelium. Case 1 - Figure 4 Mixed epithelial and stromal tumor with collagenous stroma and a cyst with spatulate papillae with cellular cores protruding into it. Histiocytes are present in the lumen of the cyst and in one of the papillary cores (upper right). Case 1 - Figure 5 Mixed epithelial and stromal tumor with cyst with spatulate papillae protruding into it. The stroma is smooth muscle and contains clustered small cysts of variable size lined by cuboidal epithelium. In upper left quadrant is a blood vessel with mural sclerosis on its way to becoming a fibrous lump resembling a corpus albicans of the ovary. Case 1 - Figure 6 Mixed epithelial and stromal tumor with smooth muscle stroma and clusters of minute cysts line by low cuboidal epithelium. Case 1 - Figure 7 Mixed epithelial and stromal tumor with smooth muscle stroma and a few fat cells. Case 1 - Figure 8 Mixed epithelial and stromal tumor with smooth muscle stroma interspersed with collections of small cystic glandular structures containing brightly eosinophilic proteinaceous fluid and lined by cuboidal epithelial cells. Case 1 - Figure 9 Mixed epithelial and stromal tumor with cyst lined by ciliated columnar epithelium. Case 1 - Figure 10 Mixed epithelial and stromal tumor with rounded blunt papillae with cellular stromal cores and a covering of cuboidal and flattened cuboidal cells. Case 1 - Figure 11 Mixed epithelial and stromal tumor with cyst lined by urothelium and by columnar epithelium. Differential Diagnosis: Mixed epithelial and stromal tumor Angiomyolipoma with cysts Cystic nephroma Final Diagnosis: Mixed epithelial and stromal tumor Mixed Epithelial and Stromal Tumor In 1993, descriptions of 6 examples of solid and cystic renal tumors composed of spindle cell stroma containing epithelial elements with a wide variety of growth patterns, were published. Subsequently, the name "mixed epithelial and stromal tumor" was proposed for these tumors and was adopted for the WHO classification. Clinical Features Of 76 mixed epithelial and stromal tumors reported in sufficient detail that one can be confident of the diagnoses, 67 occurred in women and 9 in men. The ages ranged from 18 to 78 years, with a median age of 46 years; a third of the patients were 41 years old or younger. The men ranged in age from 23 to 71 years (median 44 years). Presenting symptoms have been nonspecific: flank mass or hematuria; many have been asymptomatic and found radiographically in the course of work up for other conditions. At least one male was diagnosed after hormonal treatment for prostate cancer. The tumors have so far all been cured by surgery. Reports asserting malignant behavior in a few cases have been diagnostically unconvincing. Histologically similar tumors are part of the hyperparathyroidism-jaw tumor syndrome. Gross Pathologic Features Of 75 tumors for which gross descriptions are available, the most common descriptor is "solid and cystic."Gross photos were published for 36 of the 75 tumors. Of these 17 show a solid tumor without clear cysts; 7 show a small minority component of cysts, 6 were solid and cystic, and in 3 the cystic component appeared to predominate. The other photos were indistinct. The tumors occur have involved the renal cortex and medullary pyramids and some have protruded into the pelvic cavity. The solid component is typically an off-white firm tissue, sometimes with a whorled texture, reminiscent of leiomyoma. Microscopic Features Individual mixed epithelial and stromal tumors typically contain a strikingly diverse array of stromal and epithelial elements. Once one has seen several examples, this diversity, unique among renal tumors, often permits the diagnosis to be made at the first glance at the first slide of the case. The stroma of mixed epithelial and stromal tumors very frequently resembles smooth muscle in routine sections. Sparsely cellular fibrous tissue also is common. Less frequently, there are more densely cellular areas composed of spindle cells without specific differentiation. Fat also is present occasionally. Some authors have been struck by a perceived resemblance of some of the stroma to ovarian stroma. The epithelial component is more variable than the stromal component. The most common finding is dense clusters of tiny glandular structures, some of which have only pinpoint or no visible lumens. These appear as islands of irregular contour embedded in the stroma. The epithelial cells in these are small cuboidal cells. Perhaps the second most common epithelial pattern is of irregular branching channels, almost like the antlers of an elk. These are usually lined by low columnar epithelium. Urothelium also often is present, lining larger cysts and covering broad spatulate papillae protruding into large cysts of the lumen fo the renal pelvis. Small and medium-sided cysts also are common and may be lined by cuboidal or columnar epithelium and filled with eosinophilic proteinaceous material or mucinous material. Occasionally there are foci in which the epithelium appears to have an apical brush of cilia. All of these stromal and epithelial elements appear mature and lack nuclear atypia and mitotic activity. Nothing resembling metanephric blastema has been seen in a mixed epithelial and stromal tumor. Skeletal muscle has not been reported in a mixed epithelial and stromal tumor. Immunohistochemistry In line with the appearance of smooth muscle differentiation in routine sections, the stroma of mixed epithelial and stromal tumors is almost always reactive with antibody to smooth muscle actin and in more than 50% of tumors the reaction is strong and diffuse. Positive reactions with antibody to desmin are found the stroma in more than 50% of tumors. Antibodies to estrogen receptor and progesterone receptor give positive reactions in the nuclei (mainly stromal nuclei) in 80% or more of tumors and these reactions are often strong and diffuse. Reactions with antibodies to inhibin and to angiomyolipoma markers HMB45 and melanA are consistently negative. The epithelial elements frequently react with antibodies to S100 protein, cytokeratin 7 and high molecular weight cytokeratin (34βE12). Differential Diagnosis Angiomyolipoma with Cysts Rarely, angiomyolipomas contain cysts. The smooth muscle component and fat should bring mixed epithelial and stromal tumor to mind. Angiomyolipomas also often give positive reactions with antibodies to estrogen and progesterone receptors. However, the lack of complexity of the epithelial elements and positive redactions with one or more angiomyolipoma markers (HMB45, melanA, microphthalmia transcription factor) should sort this out. Cystic Nephroma Cystic nephroma is a cystic renal tumor which has posed a variety of differential diagnostic problems in the more than 100 years we have known it. In the middle of the 20th century the problems were related to its differentiation from congenital and infectious cystic kidney diseases. At the end of the 20th century the differential diagnostic problems were with cystic partially differentiated nephroblastoma, and, to a much lesser extent, with multilocular cystic clear cell renal cell carcinoma. In the beginning of the 21st century, the differential diagnostic problem is with mixed epithelial and stromal tumor. In recent and forthcoming publications, some authors have proposed to resolve the problem by concluding that mixed epithelial and stromal tumor and cystic nephroma are one entity. Others (including this author) hold the view that the two are different and can be distinguished. As currently defined, cystic nephroma is a tumor of minimal complexity entirely composed of cysts and set off from the kidney by a fibrous capsule. The cysts are lined by epithelium which is usually flattened or hobnail and the stroma varies from hypocellular fibrous stroma to cellular stroma which may bear a resemblance to ovarian stroma in that the nuclei have a wavy contour. The cellular stroma usually reacts with antibodies to estrogen or progesterone receptors, or both. Reaction with antibody to inhibin also is common in the cellular stroma. Of 74 cases of cystic nephroma reported with sufficient detail to confirm the diagnosis, 15 (20%) occurred in men. The mean age overall was 52 years (range 17 to 87 years, median 54 years). There is no question that microscopic foci within a mixed epithelial and stromal tumor can be essentially indistinguishable from cystic nephroma. However, the gross appearance of the great majority of mixed epithelial and stromal tumors shows extensive solid areas rather than an expansile tumor composed entirely of cysts and set off from the kidney by a fibrous capsule. Thus, the gross pathologic findings usually distinguish the two immediately. In those rare situations in which the gross appearance is not helpful, the histology of routine sections is usually helpful, showing the simplicity of cystic nephroma or the complexity of mixed epithelial and stromal tumor. Branching complex epithelial structures, fat, urothelium, dense clusters of small glands, apical brushes of cilia, and so forth are not found in cystic nephroma but a complex mixture of elements is typical of mixed epithelial and stromal tumor. Immunohistochemistry is of limited assistance, but a positive reaction for inhibin in cellular stroma lends support to a diagnosis of cystic nephroma. Synovial Sarcoma Synovial sarcoma in the kidney can be a solid and cystic tumor with gross pathologic features similar to mixed epithelial and stromal tumor. However, at the microscopic level, the cytologic atypia, lack of complexity, lack of smooth muscle differentiation, and lack of estrogen an progesterone receptors make differentiating it from mixed epithelial and stromal tumor straightforward. Wilms' Tumor Cystic partially differentiated nephroblastoma and Wilms' tumor with cysts could have gross pathologic similarities to mixed epithelial and stromal tumor but the cystic partially differentiated nephroblastoma occurs only in the first 2 years of life and the lack of blastema and lack of mitotic activity should help to differentiate Wilms' tumor in an adult from mixed epithelial and stromal tumor. References Pawade J, Soosay GN, et al. Cystic hamartoma of the renal pelvis. Am.J.Surg.Pathol. 17:1169-1175, 1993. Michal M and Syrucek M. Benign mixed epithelial and stromal tumor of the kidney. Pathol.Res.Pract. 194:445-448, 1998. Teh BT, Farnebo F, et al. Autosomal dominant primary hyperparathyroidism and jaw tumor syndrome associated with renal hamartomas and cystic kidney disease: linkage to 1q21-q32 and loss of the wild type allele in renal hamartomas. J.Clin.Endocrinol.Metab 81:4204-4211, 1996. Adsay NV, Eble JN, et al. Mixed epithelial and stromal tumor of the kidney. Am.J.Surg.Pathol. 24:958-970, 2000. Davis CJ, Barton JH, and Sesterhenn IA. Cystic angiomyolipoma of the kidney, a clinicopathologic description of 11 cases. Mod.Pathol. 19:669-674, 2006. Fine SW, Reuter VE, et al. Angiomyolipoma with epithelial cysts (AMLEC): a distinct cystic variant of angiomyolipoma. Am.J.Surg.Pathol. 30:593-599, 2006. Eble JN and Bonsib SM. Extensively cystic renal neoplasms: cystic nephroma, cystic partially differentiated nephroblastoma, multilocular cystic renal cell carcinoma, and cystic hamartoma of renal pelvis. Semin.Diagn.Pathol. 15:2-20, 1998. Argani P, Faria PA, et al. Primary renal synovial sarcoma: molecular and morphologic delineation of an entity previously included among embryonal sarcomas of the kidney. Am.J.Surg.Pathol. 24:1087-1096, 2000.