Awide variety of benign stromal tumors may occur in

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1 Incidental Stromal-Predominant Mixed Epithelial-Stromal Tumors of the Kidney A Mimic of Intraparenchymal Renal Leiomyoma Parin Parikh, BA; Theresa Y. Chan, MD; Jonathan I. Epstein, MD; Pedram Argani, MD Context. Mixed epithelial-stromal tumor of the kidney is a recently recognized benign renal tumor that usually occurs in adult women and typically forms a sizable lesion with solid and cystic areas. The recognized morphologic spectrum of this recently described entity is evolving. Objective. To review the clinicopathologic features of 3 small mixed epithelial-stromal tumors of the kidney that were incidental findings in kidneys removed for other reasons. Design. The clinical presentation and morphologic findings of the 3 cases were reviewed. A panel of immunohistochemical stains was performed. Setting. Academic medical center. Results. All 3 lesions contained predominantly fascicles of smooth muscle mimicking leiomyoma, but they also had cellular subpopulations of smaller, müllerian-appearing stromal cells. Tubules present within the lesion were most abundant at the periphery, suggesting that they might be entrapped. Although only the spindled smooth muscle cells were immunoreactive for muscle markers desmin and actin, both the spindled smooth muscle cells and the cellular müllerian-appearing stromal cells demonstrated diffuse nuclear labeling for estrogen and progesterone receptors. Conclusions. Mixed epithelial-stromal tumor of the kidney may present as an incidental stromal-predominant lesion within the kidney. Such lesions are easily confused with leiomyomas or stromal-predominant angiomyolipomas. (Arch Pathol Lab Med. 2005;129: ) Awide variety of benign stromal tumors may occur in the adult kidney. These include renal medullary fibroma (renomedullary interstitial tumor), solitary fibrous tumor, schwannoma, muscle-predominant angiomyolipoma, metanephric stromal tumor, and leiomyoma. 1 Of these lesions, renal medullary fibroma and leiomyoma are commonly incidental findings, identified in kidneys resected for other lesions. A smaller number of benign biphasic stromal-epithelial tumors have been reported in the kidney. One such lesion is the metanephric adenofibroma, a lesion postulated to be a hyperdifferentiated biphasic stromal-epithelial Wilms tumor that combines the histology of metanephric stromal tumor and metanephric adenoma. 2 4 Metanephric adenofibroma, like metanephric stromal tumor, affects predominantly children, although adult cases are on record. Another benign biphasic lesion is the recently described mixed epithelial-stromal tumor (MEST) (also known in the literature as cystic hamartoma of the renal pelvis or adult mesoblastic nephroma), which predominantly affects adult women This complex lesion combines a benign epithelial component that may have cystic, microcystic, tubular, papillary, or complex branch- Accepted for publication February 10, From the Division of Surgical Pathology, Johns Hopkins University, Baltimore, Md. The authors have no relevant financial interest in the products or companies described in this article. Reprints: Pedram Argani, MD, The Johns Hopkins Hospital, Division of Surgical Pathology, Weinberg Building, 401 N Broadway/Room 2242, Baltimore, MD ( pargani@jhmi.edu). ing architecture with a stroma that may contain fascicles of smooth muscle, abundant collagen, or cellular foci resembling ovarian or endometrial (müllerian) stroma. Mixed epithelial-stromal tumors typically are centered on the renal medulla and form masses with solid and cystic areas. Although approximately 75% of patients present with symptoms, such as pain or hematuria, or signs of infection, the remaining 25% of lesions are identified by imaging. These lesions are typically sizable; the mean diameter in the largest series was 6 cm, with a size range of3to12cm. 5 We report herein 3 incidental, microscopic, stromal-predominant MESTs, each less than 1 cm in greatest dimension, occurring in kidneys resected for other lesions. These lesions may account for a subset of what has previously been termed renal leiomyoma. REPORT OF CASES Case 1 A 35-year-old white woman with a 5-year history of episodic right flank pain presented with dysuria and worsening episodes of flank pain. Ultrasonography demonstrated hydronephrosis, and a retrograde pyelogram showed ureteropelvic junction obstruction with a right kidney function of 10%. The patient underwent cystoscopy with placement of a ureteral stent, after which a repeat renal scan showed 20% kidney function. Computed tomographic scan revealed thin kidney parenchyma, consistent with the markedly diminished renal function. The patient subsequently underwent laparoscopic exploration and biopsy of the kidney. Intraoperative pathologic consultation revealed extensive glomerulosclerosis and chronic inflammation, 910 Arch Pathol Lab Med Vol 129, July 2005 Mixed Epithelial-Stromal Tumors of the Kidney Parikh et al

2 and the decision was made to perform a laparoscopic nephrectomy. The resected kidney was somewhat nodular and measured cm. Serial sectioning revealed a dilated collecting system, but no masses or cysts were identified grossly. Microscopic examination revealed end-stage renal disease with extensive glomerulosclerosis (80% 90% globally sclerotic glomeruli), marked interstitial fibrosis and chronic inflammation, and hydronephrosis consistent with the clinical history of obstruction. In addition, a 0.3-cm solid lesion was noted in the medulla; the lesion is described in the Results section. Case 2 The patient was a 59-year-old woman with a long history of renal lithiasis. She had passed stones on at least 5 occasions, had undergone lithotripsy many years ago, and had undergone ureteroscopy. She presented with flank pain; computed tomographic scan showed a complex cystic calcified lesion. A small midpole lesion was commented upon but was not described further. The cyst increased by 0.5 cm during the next 9 months. The patient subsequently underwent laparoscopic partial nephrectomy to remove the right renal mass and the midpole lesion in the right kidney. The excised renal cyst wall consisted of pink-tan soft tissue measuring cm. A cm tan-brown renal calculus was identified. The partial nephrectomy specimen was morsellated and measured cm in aggregate. A cm tan-white solid lesion was identified, with the remainder of the specimen consisting of a pale brown parenchyma. Microscopic examination of the renal cyst wall showed atrophic renal parenchyma with multiple globally sclerotic glomeruli. No tumor was identified. The 0.5-cm lesion within the partial nephrectomy specimen is described in the Results section. Case 3 The patient was a 76-year-old woman with a right renal mass that was suspected to be a carcinoma. She subsequently underwent a right nephrectomy. The nephrectomy specimen measured cm with attached perinephric adipose tissue. The inferior pole revealed a mass that measured cm and was golden yellow and centrally hyperemic. There was also a cm circumscribed, tan-white, rubbery nodule in the superior pole. The remaining parenchyma was tan-red, with multiple cortical cysts measuring up to cm. The inferior pole mass proved to be a renal cell carcinoma of the clear cell type, Fuhrman nuclear grade II of IV. Vascular and ureteral margins were negative for tumor, and the tumor was confined within the renal capsule. The 0.7-cm superior pole solid lesion is described in the Results section. MATERIALS AND METHODS Paraffin-embedded, formalin-fixed tissue sections 5 m in thickness were stained with hematoxylin-eosin for light microscopic examination. Immunohistochemical labeling was performed on the Ventana Benchmark XT automated stainer (Ventana, Tucson, Ariz) using the avidin-biotin method. All immunohistochemical assays were performed after steam-mediated antigen retrieval. The antibodies, vendors, and dilutions were as follows: smooth muscle actin (Dako Corporation, Carpinteria, Calif; 1:500), desmin (Dako; 1:100), estrogen receptor (ER) clone 6F11 (Novocastra Laboratories Ltd, Newcastle upon Tyne, United Kingdom; 1:50), progesterone receptor (PR) clone PGR636 (Dako; 1:60), HMB-45 (Dako; 1:500), Melan-A (Dako; 1:200), S100 protein (Dako; 1:6000), and CD34 (Ventana; prediluted). RESULTS On microscopic examination, all 3 lesions were unencapsulated and consisted predominantly of spindled cells, with scattered tubules present at the periphery (Figures 1, A through D, and 2, A and B). The spindle cells had several appearances. The most common appearance was that of short intersecting fascicles of cells with rectangular nuclei and eosinophilic cytoplasm, consistent with smooth muscle. In foci most prominent at the periphery of each lesion, the spindled cells were more crowded, had less cytoplasm, and did not form fascicles. In these areas, the spindle cells had a nondescript, primitive appearance somewhat resembling ovarian stroma, whereas other areas had a more edematous appearance and resembled endometrial stroma. Capillary blood vessels were prominent in the latter areas. Such a morphology is typical of MEST. 5 Intermixed within these areas were benign tubules lined by cuboidal cells like those of the surrounding kidney, although the tubules often had eosinophilic luminal contents resembling thyroid colloid. In all 3 cases, the spindle cells with abundant eosinophilic cytoplasm labeled diffusely and strongly for smooth muscle actin and desmin (Figure 2, C), whereas the müllerian-appearing stromal cells were negative. Both the eosinophilic and the müllerian-appearing spindle cells were diffusely and strongly immunoreactive for ERs and PRs (Figure 2, D). The spindle cells were negative for HMB- 45, Melan-A, and S100 protein in all cases and were negative for CD34 in the 1 case tested. Tubules within the lesion were negative for all of these markers, including ER and PR. COMMENT We report 3 renal tumors with morphologic features most consistent with a stromal-predominant MEST, all of which were identified incidentally in adult women whose kidneys were resected for other reasons. All 3 lesions noted were confined to the kidney medulla, with sizes ranging from 0.3 to 0.7 cm. Grossly, the lesions were either inapparent or identified as a small white-tan lesion, and microscopically the 3 lesions consisted predominantly of spindle cells with scattered tubules. Assuming that these lesions reflect earliest MEST, one wonders if most MESTs begin as predominantly stromal lesions, with the epithelial component arising secondarily, perhaps by entrapment and induction of normal tubules. The absence of labeling for ER and PR in the epithelial component of most MESTs reported to date would support this hypothesis. 5 Given that the tubules within these lesions did not label for ER or PR, were most prominent at the edge of the lesions, and merged morphologically with normal renal tubules, we believe that they were most likely entrapped within the spindle cell proliferation. Their morphologic similarity to the adjacent renal tubules supports this interpretation. However, because the epithelial component of a MEST has been reported to have many appearances, including that of renal tubules, the alternative interpretation is that the tubules represent minor components of the lesions. Although these tumors were unusually small, their occurrence in adult women (the usual patient population affected by MEST), their distinctive stromal appearance consisting of both overt smooth muscle cells and more müllerian-appearing cells, and their diffuse labeling for ER and PR support their classification as MEST. The differential diagnosis for these tumors is broad and includes medullary fibroma, metanephric stromal tumor, solitary fibrous tumor, mucinous tubular and spindle carcinoma, stroma-rich angiomyolipoma, and leiomyoma. Medullary fibromas, also known as renomedullary interstitial cell tumors, are usually incidental autopsy find- Arch Pathol Lab Med Vol 129, July 2005 Mixed Epithelial-Stromal Tumors of the Kidney Parikh et al 911

3 Figure 1. A, Intermediate-power view of case 2 showing spindled component (left) and müllerian-appearing stromal cells admixed with tubules (right) (hematoxylin-eosin, original magnification 100). B, High-power view of case 2, highlighting the contrast between the spindled component resembling smooth muscle (left) and the müllerian-appearing stromal cells (right) (hematoxylin-eosin, original magnification 200). C, Intermediatepower view of case 1, showing spindled component (upper right) and müllerian-appearing stromal cells intermixed with renal tubules (lower right) (hematoxylin-eosin, original magnification 100). D, High-power view of case 1, highlighting the contrast between the spindled component resembling smooth muscle (left) and the müllerian-appearing stromal cells (right) (hematoxylin-eosin, original magnification 200). ings. They are found equally in men and women and have an unclear association with hypertension. 1 Microscopically, the medullary fibroma consists of bland stellate cells set in a variably loose to densely sclerotic background. The current lesion differs from medullary fibroma in that it features cells with well-developed eosinophilic cytoplasm that label for desmin and smooth muscle actin, indicating smooth muscle differentiation. Metanephric stromal tumor usually presents as an abdominal mass in children but also rarely may present in adults. Characteristic histologic features of metanephric stromal tumor include a nodular low-power appearance, concentric ( onion-skin ) cuffing around entrapped renal tubules, heterologous differentiation, and angiodysplasia. 2 Metanephric stromal tumors label for CD34, but not for desmin. Solitary fibrous tumors are well-circumscribed masses consisting of a mixture of dense collagenous bands and a haphazard proliferation of bland spindle cells. A hemangiopericytoma-like growth pattern is often seen. Solitary fibrous tumors label for CD34, but not for desmin. 1 Mucinous tubular and spindle cell carcinoma is a recently described entity composed of tightly packed, collapsed tubules that may mimic smooth muscle fascicles. These lesions are keratin positive and desmin negative. 1 Stromal-rich angiomyolipomas consist predominantly of unusual smooth muscle cells that often have clear cytoplasm. Incidental small stroma-rich angiomyolipomas are often found in kidneys with larger, overt angiomyolipoma, and in this setting they suggest the possibility of tuberous sclerosis. Abnormally formed blood vessels and a small component of fat cells may be present, and these provide clues to the diagnosis. Stromalrich angiomyolipomas label for HMB-45. The lesions we describe are negative for HMB-45 and did not demonstrate abnormally formed blood vessels. Leiomyomas are the closest mimic of these lesions. Leiomyomas are benign smooth muscle neoplasms, found most commonly in the kidney capsule or, less commonly, within the parenchyma. They are generally reported to be circumscribed neoplasms, 1,12 so tubules should not be found within. They are usually incidental findings, present in up to 5% of autopsies. 12 The current lesions differ from leiomyomas in that they have tubules within, and 912 Arch Pathol Lab Med Vol 129, July 2005 Mixed Epithelial-Stromal Tumors of the Kidney Parikh et al

4 Figure 2. Case 3. A, Low-power view showing circumscribed nature of the lesion that abuts the medulla (lower right) (hematoxylin-eosin, original magnification 20). B, Higher-power view showing müllerian-appearing cellular areas at the periphery, associated with bland tubules, and fascicles of eosinophilic spindled cells (hematoxylin-eosin, original magnification 100). C, Immunohistochemical assay for desmin labels the spindled cells with abundant pink cytoplasm, but not the müllerian-appearing stromal cells or the tubules at the periphery (immunoperoxidase, original magnification 200). D, Immunohistochemical assay for estrogen receptor labels the nuclei of both the spindled and the müllerian-appearing stromal cells (immunoperoxidase, original magnification 200). they also contain the population of primitive, müllerianappearing stromal cells characteristic of MEST. The strong, diffuse labeling for ER and PR also supports a relationship with MEST, although it should be stated that retroperitoneal leiomyomas also often label for ER and PR. 13 Interestingly, what have been termed renal capsular leiomyomas have been shown to label for HMB-45, 14 raising the possibility that they are more closely related to stromarich angiomyolipomas. The current lesions were noncapsular and could easily be confused with intraparenchymal leiomyoma if the müllerian-appearing stromal component were overlooked or dismissed as insignificant, and if hormone receptor studies were not performed. Because MEST has only recently been recognized, it may be that some previously reported leiomyomas of the renal parenchyma were in fact small MESTs. Along these lines, the 1 noncapsular renal leiomyoma reported in 1 series was described as unusual and as contain[ing] abundant collagen, within which were slender fascicles of smooth muscle cells and native medullary tubules entrapped in a manner similar to a medullary fibroma. This description suggests that the lesion might in fact have been a MEST. 14 Hence, when capsular angiomyolipomas and parenchymal MESTs are excluded, true renal leiomyomas may be more rare than previously thought. In summary, we characterize 3 lesions as incidental, stromal-predominant MESTs. These lesions were all incidentally found in women who had nephrectomies for other medical reasons. The spindle cell component demonstrates smooth muscle differentiation, as evidenced by its labeling for desmin and smooth muscle actin, whereas the more cellular, müllerian-appearing component and the overall diffuse labeling for ER and PR support classification as MEST. The absence of labeling for HMB-45, Melan- A, and S100 protein helped exclude other lesions in the differential diagnosis. We thank Mary Owens, BA, and Jon Christofersen, BA, for outstanding support. References 1. Eble JN, Sauter G, Epstein JI, Sesterhenn IA, eds. Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. Lyon, France: IARC Press; World Health Organization Classification of Tumours; vol 7. Arch Pathol Lab Med Vol 129, July 2005 Mixed Epithelial-Stromal Tumors of the Kidney Parikh et al 913

5 2. Argani P, Beckwith JB. Metanephric stromal tumor: report of 31 cases of a distinctive pediatric renal neoplasm. Am J Surg Pathol. 2000;24: Hennigar RA, Beckwith JB. Nephrogenic adenofibroma: a novel kidney tumor of young people. Am J Surg Pathol. 1992;16: Arroyo MR, Green DM, Perlman EJ, Beckwith JB, Argani P. The spectrum of metanephric adenofibroma and related lesions: clinicopathologic study of 25 cases from the National Wilms Tumor Pathology Center. Am J Surg Pathol. 2001;24: Adsay NV, Eble JN, Srigley JR, Jones EC, Grignon DJ. Mixed epithelial and stromal tumor of the kidney. Am J Surg Pathol. 2000;24: Pawade J, Soosay GN, Delprado W, Parkinson MC, Rode J. Cystic hamartoma of the renal pelvis. Am J Surg Pathol. 1993;13: Durham JR, Bostwick DG, Farrow GM, Ohorodnik JM. Mesoblastic nephroma of adulthood: report of three cases. Am J Surg Pathol. 1993;17: Troung LD, Williams R, Ngo T, et al. Adult mesoblastic nephroma: expansion of the morphologic spectrum and review of the literature. Am J Surg Pathol. 1998;22: Trillo AA. Adult variant of congenital mesoblastic nephroma. Arch Pathol Lab Med. 1990;114: Mensch LS, Trainer TD, Plante MK. Cystic hamartoma of the renal pelvis: a rare pathologic entity. Mod Pathol. 1999;12: Beiko DT, Nickel JC, Boag AH, Srigley JR. Benign mixed epithelial stromal tumor of the kidney of possible mullerian origin. J Urol. 2001;166: Steiner M, Quinlan D, Goldman SM, et al. Leiomyoma of the kidney: presentation of 4 new cases and the role of computed tomography. J Urol. 1990; 143: Billings SD, Folpe AL, Weiss SW. Do leiomyomas of deep soft tissue exist: an analysis of highly differentiated smooth muscle tumors of deep soft tissue supporting two distinct subtypes. Am J Surg Pathol. 2001;25: Bonsib SM. HMB-45 immunoreactivity in renal leiomyomas and leiomyosarcomas. Mod Pathol. 1996;9: Arch Pathol Lab Med Vol 129, July 2005 Mixed Epithelial-Stromal Tumors of the Kidney Parikh et al