Case 1 -

Multilocular Cystic Renal Cell Carcinoma David Grignon Wayne State University School of Medicine Detroit, MI

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Clinical history A 74 year old woman is found to have a 3 cm complex cystic mass involving the right kidney. A partial nephrectomy is performed. Grossly the lesion measures 2.8 x 1.8 x 1.8 cm and bulges from the cortical surface. It is multicystic with thin septae and no solid areas. The cysts contain translucent pale yellow fluid. Case 1 - Figure 1 - Low power photomicrograph illustrating multiloculated cystic mass with thin fibrous septae and adjacent renal parenchyma. Case 1 - Figure 2 - Additional low power photomicrograph illustrating multiloculated cystic mass with thin fibrous septae and adjacent renal parenchyma. Case 1 - Figure 3 - Center of mass illustrating the thin nature of the septae. Case 1 - Figure 4 - Tumor edge illustrating a fibrous capsule and the hypocellular, fibrotic appearance of the septae. Case 1 - Figure 5 - The thin fibrous septae are covered by a predominantly single layer of cuboidal cells with clear cytoplasm. Note the absence of cells within the septae. Case 1 - Figure 6 - High power photomicrograph illustrating the clear cells. Note the small, uniform hyperchromatic nuclei. Case 1 - Figure 7 - Photomicrograph highlighting the fibrous septae and clear cells. Case 1 - Figure 8 - In this septae there are nests of clear cells within the fibrous stroma some of which are forming tubules. Note again the low grade nuclei. Case 1 - Figure 9 - High power photomicrograph highlighting the clear cells with low grade nuclei in the stroma. Cystic degeneration is not uncommon in renal cell carcinoma. In a review of the AFIP experience, Hartman et al found that 15% of all renal cell carcinomas in their files were cystic [1]. They acknowledged that this likely represented an overestimation due to the nature of their practice. Hartman et al subclassified cystic renal cell carcinomas into 4 subtypes, (i) those resulting from an intrinsic multilocular pattern of growth, (ii) those resulting from an intrinsic unilocular pattern of growth; (iii) those resulting from cystic degeneration of a previously solid tumor; and (iv) those originating in a benign cyst. For the most part "cystic RCC" does not represent a specific entity but rather reflects a degenerative or unusual growth pattern in a tumor belonging to one of the recognized subtypes of RCC [2]. One specific cystic tumor, multiclocular cystic RCC has been included in current classifications as a subtype of clear cell RCC [3, 4]. Additionally, RCC frequently arises in the context of kidneys with cysts such as von Hippel Lindau disease, tuberous sclerosis and acquired cystic kidney disease. Multilocular cystic RCC is most frequent and is characterized by variably sized, noncommunicating cysts, separated by irregular, thick fibrous septae. The septae usually show marked hyalinization and may contain calcifications or even foci of ossification. Nests of tumor cells can be found which most often are of the clear cell type. The cysts are lined by tumor cells but in some areas may be markedly attenuated or even absent. This group of tumors is usually of low nuclear grade, confined to the kidney and associated with an excellent prognosis [5, 6, 7]. In those cases meeting the criteria listed in the table below, no examples of metastases have been recorded [6, 7]. This has led to uncertainty as to the actual nature of these tumors [6]. We have found high expression of G250, a tumor associated protein expressed highly in clear cell RCC in these tumors supporting the current classification [8] and recently have identified mutations of the VHL gene in tumor cells microdissected from these lesions adding greater strength to the current approach [9]. Diagnostic Criteria For Multilocular Cystic Renal Cell Carcinoma Tumor growth as an expansile mass surrounded by a fibrous pseudocapsule Tumor interior composes of cysts and septae without grossly visible expansile nodules Septae containg aggregates of clear cells The unilocular variant has a thick irregular wall and a lining of tumor cells that is also usually clear. Papillary excrescenses are seen with the papillae covered by clear cells. In cases resulting from cystic necrosis of a previously solid tumor the cyst contains old and recent hemorrhage as well as necrotic tissue. The cyst wall is thickened and irregular. Papillary renal cell carcinoma frequently has this appearance. These cases may be the most problematic as an epithelial lining is often absent. Any cystic mass in the kidney containing hemorrhagic or necrotic material should be suspected as malignant and extensive sampling performed for evidence of tumor. In these cases viable tumor may be only focally present and the identification of any clear or papillary cell areas indicates a malignant diagnosis. Finally carcinomas may arise in benign cysts in the kidney. Brinker et al [2] described a pathologic classification for RCC with extensive cystic change. In 2 types the cystic change was related to near compete tumor necrosis or to partial necrosis. The third pattern corresponds to the multilocular cystic pattern (Hartmann type 1). In their series none of the 6 multilocular cystic tumors developed progression in keeping with previous series. The differential diagnosis of multilocular cystic kidney tumors is with cystic nephroma (multilocular cyst) and a recently defined tumor of presumed collecting duct origin that also has a complex multicystic gross appearance (tubulocystic carcinoma). In the 3rd series AFIP fascicle, Farrow [10] illustrated an unusual tumor with a multicystic gross appearance and striking mixture of tubules and micro/macro cysts histologically. Similar cases were subsequently included in the low-grade collecting duct carcinoma paper of MacLennan et al [11].We have seen a large number of cases now that are remarkable for the uniformity on gross and microscopic characteristics [12]. The tubules and cysts are lined by cuboidal to columnar cells with eosinophilic cytoplasm. Nuclei are uniform and contain nucleoli. In our experience approximately 10% metastasize. Whether these truly derive from the collecting system is uncertain. This tumor is not recognized as a distinct entity in the current classification systems but likely will be in the next few years. Clinically it occurs predominantly in men and in the limited cases reported has demonstrated a low rate of metastases [13]. Cystic nephroma may occur at any age but shows a distinctive bimodal age distribution with about 50% of cases occurring before 2 years of age and 40% of cases between 40 and 69 years [4]. In the latter age group there is a striking predominance of females; 7:1 in one series [6]. The tumors are unilateral, solitary, and surrounded by a thick fibrous capsule. The cysts do not communicate and have a smooth, glistening lining. The cysts are lined by a single layered epithelium that typically is made up of cells with eosinophilic cytoplasm and a "hob nail" morphology. In larger cysts the epithelium may be more cuboidal or attenuated; clear cells restricted to the lining epithelium are acceptable but nests of clear cells in the septae indicate a diagnosis of renal cell carcinoma. Stromal cellularity is quite variable and in most is hypocellular and fibrotic – similar to multilocular cystic RCC. In many cases the stroma is at least focally more cellular and often has an ovarian-like appearance. The latter is a useful differential diagnostic feature. There is currently debate concerning the relationship between this tumor and mixed epithelial stromal tumor with some considering these to represent the same lesions while others believe they are 2 distinct entities. References Hartman DS, Davis CJ Jr., Johns T, Goldman SM. Cystic renal cell carcinoma. Urology 28: 145-153, 1986 Brinker DA, Amin MB, Peralta-Venturina M, Reuter V, Chan DY, Epstein JI. Extensively necrotic cystic renal cell carcinoma: a clinicopathologic study with comparison to other cystic and necrotic renal cancers. Am J Surg Pathol24:988-995, 2000 Eble JN, Sauter G, Epstein JI, Sesterhenn IA (Eds). World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. IARC Press. Lyons, 2004. Murphy WM, Grignon DJ, Perlman E. Tumors of the kidney, bladder, and related urinary structures. Washington: Armed Forces Institute of Pathology, 4th series fascicle, 2004. Murad T, Komaiko W, Oyasu R, Bauer K. Multilocular cystic renal cell carcinoma. Am J Clin Pathol 95:633-637, 1991 Eble JN, Bonsib SM. Extensively cystic renal neoplasms: cystic nephroma, cystic partially differentiated nephroblastoma, multilocular cystic renal cell carcinoma and cystic hamartoma of the renal pelvis. Semin Diagn Pathol 15:2-20, 1998 Nassir A, Jollimore J, Gupta R, Bell D, Norman R. Multilocular cystic renal cell carcinoma: a series of 12 cases and review of the literature. Urology 60:421-7, 2002 Bismar TA, Bianco FJ, Zhang H, Li X, Sarkar FH, Sakr WA, Grignon DJ, Che M. Quantification of G250 mRNA expression in renal epithelial neoplasms by real-time reverse transcription-PCR of dissected tissue from paraffin sections. Pathology 35:513-517, 2003 Grignon DJ, Bismar TA, Bianco F, et al. VHL gene mutations in multilocular cystic renal cell carcinoma: evidence in support of its classification as a type of clear cell renal cell carcinoma (abstract). Mod Pathol17:154A, 2004. Murphy WM, Beckwith JB and Farrow GM. Tumors of the kidney, bladder, and related structures. Washington: Armed Forces Institute of Pathology, 3rd series fascicle, 1994 MacLennan GT, Farrow GM, Bostwick DG. Low-grade collecting duct carcinoma of the kidney: Report of 13 cases of low-grade mucinous tubulocystic renal carcinoma of possible collecting duct origin. Urology 50:679-684, 1997 Amin MB, MacLennan GT, Paraf F, Cheville JC, Vieillefond A, Radhakrishnan A, Che M, Srigley JR, Grignon DJ. Tubulocystic carcinoma of the kidney: clinicopathologic analysis of 29 cases of a distinctive rare subtype of renal cell carcinoma (abstract). Mod Pathol 17:137A, 2004 MacLennan GT, Bostwick DG. Tubulocystic carcinoma, mucinous tubular and spindle cell carcinoma, and other recently described rare tumors. 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