Papillary renal cell carcinoma (RCC) is an established

Solid Variant of Papillary Renal Cell Carcinoma With Spindle Cell and Tubular Components N The solid variant of papillary renal cell carcinoma, when strictly defined as a tumor in which no true papillae can be identified, is extremely rare, with only a few cases reported in the literature. This tumor is characterized histologically by solid sheets of cells without true papillae; nevertheless, immunohistochemical and genetic analysis supports the classification of this tumor as a variant of papillary renal cell carcinoma. We report a case of solid variant of papillary renal cell carcinoma affecting a young man and provide histologic and clinical follow-up data, adding an additional case of this extremely rare pathology to the literature. In addition, we describe the first case, to our knowledge, of a solid variant of papillary renal cell carcinoma to contain a high-grade (sarcomatoid) spindle cell component. (Arch Pathol Lab Med. 2010;134:1210 1214) Papillary renal cell carcinoma (RCC) is an established subtype of RCC with characteristic histologic, immunohistochemical, and cytogenetic features that separate it from other types of RCC. Papillary RCC traditionally has been defined histologically as tumors with at least 50% true papillae. 1 Papillary RCC is separated into a type 1 histologic variant, which features papillae lined by a 1- to 2-cell layer of cuboidal cells with scant cytoplasm, and a type 2 histologic variant, which displays papillae covered by a pseudostratified layer of large eosinophilic cells. 2 The type 2 histologic variant is typically associated with a worse prognosis. Several subtypes of papillary RCC had been described, including typical, trabecular, tubular, sclerotic, and high-grade papillary RCC, all of which still contain at least 50% papillary architecture. 3 Additionally, a solid component of papillary RCC had been described, reported as a solid architectural growth pattern in tumors, which still contained at least 50% true papillae. 3 However, in 1997, Renshaw et al 1 identified 6 renal tumors composed of solid sheets of cells with foci of ill-defined tubular formation, but without true papillae, that otherwise resembled papillary RCC by immunohistochemical and genetic analysis. Renshaw et al 1 concluded that these 6 Accepted for publication December 31, 2009. From the Department of Pathology, Rush University Medical Center, Chicago, Illinois. The authors have no relevant financial interest in the products or companies described in this article. Reprints: David Cimbaluk, MD, Department of Pathology, Rush University Medical Center, 1653 W Congress Pkwy, Chicago, IL 60612 (e-mail: David_ J_Cimbaluk@rush.edu). Richard Cantley, MD; Paolo Gattuso, MD; David Cimbaluk, MD tumors represented solid variants of papillary RCCs, which lacked true papillae, and the authors more strictly defined the solid variant of papillary RCC to include only RCCs that lack true papillae but that contain the characteristic immunohistochemical and genetic features of papillary RCC. Encountering a minor solid component in an otherwise traditional papillary RCC is not uncommon in practices that routinely analyze renal tumors, and this controversial designation proposed by Renshaw et al 1 was never incorporated into the literature. However, a universally accepted definition as to what percentage of solid elements must be comprised by papillary RCC to qualify as a solid variant is still lacking. Reports continue to use the term solid variant of papillary RCC in describing tumors with variable percentages of solid and papillary components. Although the entirely solid variant of papillary RCC was first described 1 in 1997, to our knowledge, only 2 additional cases 4,5 have been reported since the first case series by Renshaw et al. 1 Here, we present the clinical, histopathologic, immunohistochemical, and genetic findings of another such case of a solid variant of papillary RCC, in which no true papillae could be identified. In addition, we report a high-grade spindle cell histologic pattern that was not present in any of the tumors reported in the case series by Renshaw et al, 1 and is, to our knowledge, previously undescribed. REPORT OF A CASE A 31-year-old man presented with left flank pain. The patient s medical history and physical examination were unremarkable. Computed tomography scan demonstrated a solitary, large mass lesion in the midpole of the left kidney. The right kidney was without abnormality, and other radiographic findings were normal. Abdominal exploration revealed no evidence of metastases, and left-sided radical nephrectomy was performed. Grossly, the kidney measured 9.5 3 7.0 3 5.0 cm, and the external surface was unremarkable. The cut surface showed a solid, homogeneous, tan tumor that was centered on the renal cortex and measured 4.5 cm in greatest dimension (Figure 1). The tumor was not grossly encapsulated, had illdefined edges, and protruded from the renal cortex but remained confined within the renal capsule. Microscopically, the tumor was separated from the surrounding tissue by a fibrous pseudocapsule. The tumor was composed predominately of solid sheets of cells with an ill-defined tubular pattern (Figures 2 and 3). The tumor cells had scant, basophilic cytoplasm and round, high-grade nuclei, with finely dispersed chromatin and distinct nucleoli. Additionally, foci containing spindle cells were seen (Figure 4). These 1210 Arch Pathol Lab Med Vol 134, August 2010 Solid Variant of Papillary Renal Cell Carcinoma Cantley et al

Figure 1. Gross photograph showing a solid, firm, tan tumor protruding from the renal cortex as a solitary, rounded mass. The interface of the tumor and the adjacent kidney is well demarcated, and the tumor abuts the renal pelvis. Figure 2. Solid variant of papillary renal cell carcinoma, composed of solid sheets of cells (hematoxylin-eosin, original magnification 3100). Figure 3. Solid variant of papillary renal cell carcinoma, showing an ill-defined tubular pattern (hematoxylin-eosin, original magnification 3400). Figure 4. A spindle cell component was present in focal areas (hematoxylin-eosin, original magnification 3400). Figure 5. Immunohistochemical analysis for cytokeratin 8/18 shows strong reactivity in the tubular component (original magnification 3400). Figure 6. Spindled neoplastic cells are diffusely immunoreactive for cytokeratin 8/18 (original magnification 3400). Arch Pathol Lab Med Vol 134, August 2010 Solid Variant of Papillary Renal Cell Carcinoma Cantley et al 1211

spindle cells contained elongated nuclei but, otherwise, demonstrated a similar appearance to the cells seen in the remaining tumor, with scant basophilic cytoplasm and highgrade nuclear features, with moderate pleomorphism, finely dispersed chromatin, and distinct nucleoli. Fibrovascular cores, foamy macrophages, and necrosis were not present. By immunohistochemistry, the tumor was strongly reactive for cytokeratin AE1/AE3, cytokeratin 7, cytokeratin 8/18, and vimentin, both in the tubular and spindle cell elements (Figures 5 and 6). Immunohistochemical analysis for CD10 showed focal positivity in both areas, and c-kit showed cytoplasmic staining. The tumor was negative for WT-1, cytokeratin 20, CD57, synaptophysin, desmin, smooth muscle actin, myogenin, and leukocyte common antigen (CD45). Fluorescence in situ hybridization using CEP7/LSI D7S486 (Abbott Molecular, Abbott Park, Illinois) showed gain of chromosome 7 (trisomy 7). Therefore, based on the morphologic features and in accordance with the immunohistochemical and genetic findings, a diagnosis of solid variant of papillary RCC with spindle cell and tubular components was rendered. The postoperative course was uneventful. Last follow-up, 24 months after excision, the patient was well and without any evidence of recurrence or metastasis. COMMENT Papillary RCC is an established subtype of renal cell carcinoma, with distinctive histologic, immunohistochemical, and cytogenetic features. When defined histologically as tumors composed of more than 50% true papillae, papillary RCCs comprise approximately 10% of renal cell carcinoma in surgical series. 5 Morphologically, papillary RCCs are composed predominately of papillary or tubulopapillary structures lined by small, cuboidal cells with basophilic cytoplasm or by larger cells with eosinophilic cytoplasm. 3 These tumors often show collections of foamy macrophages within the papillary stalks, iron deposition, and psammoma bodies. Although papillary RCC was originally defined histologically, it is clear that these tumors also have characteristic immunohistochemical and genetic features. Chromosomal trisomies, most often of chromosomes 7 or 17, are seen in most papillary RCCs, and gains in chromosomes 12, 16, and 20, as well as loss of Y, may also be observed. 6 Papillary RCC is typically immunoreactive for cytokeratin AE1/AE3, cytokeratin 8/18, cytokeratin 7, CAM 5.2, callus keratin, CD10, epithelial membrane antigen, and vimentin. 7,8 Papillary RCC containing foci of solid areas admixed with more conventional tubulopapillary areas is not an uncommon finding in routine practice. In this report, we describe a tumor with a solid growth pattern completely lacking true papillae. Nonetheless, the tumor retains the genetic features and immunophenotype of papillary RCC, showing gain of chromosome 7 by fluorescence in situ hybridization and immunoreactivity for cytokeratin 7, cytokeratin 8/18, vimentin, CD10, and c-kit, supporting classification as a papillary RCC. The positivity for cytokeratin 7, cytokeratin 8/18, and vimentin is useful in differentiating papillary RCC from other primary renal neoplasms, including metanephric adenoma, chromophobe RCC, oncocytoma, and urothelial cell carcinoma of the renal pelvis. 8 In addition, cytoplasmic distribution of c-kit has been reported in papillary RCC 9 and was immunoreactive in this tumor. Immunohistochemical analyses for cytokeratin 20, CD57, and WT-1 were negative, all of which, are known to be absent in papillary RCC. 10,11 Although tumors containing a minor solid component are not uncommon, the solid variant of papillary RCC composed of solid sheets of cells without true papillae is extremely rare, previously described in a small case series by Renshaw et al 1 They identified 6 renal tumors composed of solid sheets of cells without true papillae but that otherwise resembled papillary RCCs by immunohistochemical and genetic analysis. Renshaw et al 1 concluded that these 6 tumors represented solid variants of papillary RCCs, which lack true papillae, and they more strictly defined the solid variant of papillary RCC to include only RCCs that lack true papillae but that contain the characteristic immunohistochemical and genetic features of papillary RCC. Other histologic variants of papillary RCC that have been described (all containing $50% true papillae) include typical, trabecular, tubular, sclerotic, and high-grade papillary RCC. 3 From the time Renshaw et al 1 first described the solid variant of papillary RCC, which lacks true papillae, only 2 additional cases have been reported, the first by Ngan et al 4 in 2001. They describe a solid variant of papillary RCC composed of solid sheets of cells with intervening micronodules and abortive papillae, but no true papillae were present. By immunohistochemistry, the tumor had immunoreactivity characteristic of papillary RCC with positivity for epithelial membrane antigen and cytokeratin 7. Genetic studies were not performed. Regarding histologic pattern, 4 of the 6 tumors (67%) in the Renshaw et al 1 series were composed of solid sheets of cells containing distinct micronodules microscopically, which, in some cases, resembled abortive papillae. The other 2 tumors consisted of solid sheets of cells with an ill-defined tubular pattern, and that is the configuration that was present in the tumor we are reporting (Figure 3). Additionally, our case displayed a high-grade spindle cell component randomly intermixed with the tubular pattern. This sarcomatoid configuration comprised a minor element of the tumor and consisted of cellular fascicles of spindle-shaped tumor cells with scanty cytoplasm and hyperchromatic, moderately pleomorphic nuclei (Figure 4). We interpret this spindle cell pattern to represent a form of spindle cell dedifferentiation from the parenteral tubular element because both components expressed matching immunostaining patterns, showing positivity for cytokeratin, vimentin, and CD10. The spindle cell component in papillary RCC has been described recently by Argani et al, 5 who reported 5 cases of papillary RCC with low-grade spindle cell foci. All cases were diffusely immunoreactive for cytokeratin 7 and showed trisomy of chromosome 7 or chromosome 17 or both by fluorescence in situ hybridization, supporting classification as papillary RCC. Furthermore, all 5 tumors were predominately solid, demonstrating at least an 80% solid growth pattern. Four of the 5 neoplasms (80%) demonstrated areas of papillary architecture, comprising between 5% and 20% of the neoplasm, and 1 neoplasm (20%) demonstrated no papillary formations. This 1 neoplasm matches the description of our case, a solid growth pattern without true papillae; however, low-grade spindle cell foci were present in the previous case, in contrast to the high-grade sarcomatoid features in our case. The significance of these spindle cell foci in papillary 1212 Arch Pathol Lab Med Vol 134, August 2010 Solid Variant of Papillary Renal Cell Carcinoma Cantley et al

RCC is unclear because of the limited clinical follow-up (maximum follow-up period 8 months in the Argani et al 5 series), but with our patient remaining disease-free at 2 years following diagnosis, we presume that it does not carry the same dismal prognostic implications as traditional sarcomatoid carcinomas. Regarding terminology, the existence of papillary RCCs that lack papillae is not the ideal designation for this group of tumors. We agree with Renshaw et al 1 that this semantic problem is somewhat analogous to the situation in the thyroid, where the follicular variant of papillary carcinoma lacks papillae but can still be recognized as papillary carcinoma by its other characteristic features. 1 Despite the term papillary being a misnomer, this descriptive approach is probably best for this rare tumor, which constitutes a very small percentage of cases, at most less than 3% of all papillary RCCs. 1 The differential diagnosis of this tumor includes metanephric adenoma, adult Wilms tumor, synovial sarcoma, mucinous tubular and spindle cell carcinoma of the kidney, and the oncocytic and clear cell variants of papillary renal cell carcinoma. Metanephric adenoma is typically well circumscribed on gross examination and displays a solid, tan mass, similar to the solid variant papillary RCC. However, metanephric adenoma is composed of small, uniform, round acini and long branching tubular structures in an edematous or hyalinized stroma. 12 Furthermore, metanephric adenoma is typically immunoreactive for WT-1 and CD57, markers that were not expressed in our tumor, and chromosomal gains are not seen in metanephric adenoma. 11 Wilms tumor is a malignant embryonal neoplasm of nephrogenic blastemal cells. Although an adult variant is known, nearly all cases occur in the third decade of life or earlier. Adult Wilms tumor is a triphasic neoplasm composed of a mixture of blastema, epithelium, and/or stroma. The blastemal component is composed of sheets of round to oval cells with scant cytoplasm, coarse chromatin, and small nucleoli. 13 The epithelial component is typically composed of small tubules lined by columnar or cuboidal cells, and the tumor may demonstrate rosetting, tubular, and papillary patterns. 13 In contrast to the solid variant of papillary RCC, the blastemal component is reactive for antibodies against WT-1 and CD56, the epithelial component is reactive for antibodies against CD57, and chromosomal gains are not typically seen. 13 Primary synovial sarcoma of the kidney is an extremely rare tumor with approximately 33 cases reported to date 14 but the monophasic variant can be confused with other spindle cell tumors. Grossly, synovial sarcoma is a well-circumscribed, solid, tan tumor, often with cystic and necrotic areas. Histologically, the monophasic variant of synovial sarcoma is composed of spindle cells arranged in fascicles and sheets. Synovial sarcoma shows reactivity to antibodies against CD56 and CD57 and has a unique chromosomal translocation t(x;18)(p11.2;q11.2), that can be detected in paraffin-embedded material using in situ polymerase chain reaction. 15 Mucinous tubular and spindle cell carcinoma of the kidney is a rare renal neoplasm that may show significant morphologic and immunohistochemical overlap with our case. Both are circumscribed lesions featuring solid areas and tubules; however, the mucinous stroma, highlighted with stains for acid mucins, generally distinguishes mucinous tubular and spindle cell carcinoma from the solid variant of papillary RCC. Furthermore, genetic analysis is most definite because mucinous tubular and spindle cell carcinoma typically demonstrates losses of multiple different chromosomes 5 and lacks the trisomies of chromosomes 7 and 17, which are characteristic of papillary RCC. Oncocytic papillary renal cell carcinoma is a recently described 16 variant of renal cell carcinoma that may exhibit areas of solid growth. However, the tumor cells contain abundant oncocytic cytoplasm, and spindle cell foci are not expected. 16 Clear cell papillary renal cell carcinoma may also demonstrate areas that appear solid because of closely packed and folded papillae, but areas of cystic and papillary formation are clearly identified, and the tumor cells exhibit abundant clear cytoplasm and low nuclear grade without foci of spindle cells. 17 In conclusion, we have described a case of RCC in which the tumor cells were arranged in solid sheets, with ill-defined tubules and focal spindle cell areas. Reactivity for cytokeratin 7 and vimentin, and trisomy 7 by fluorescence in situ hybridization, were characteristics. Despite the lack of true papillae, we believe this tumor is best classified as a solid variant of papillary RCC, and using a strict designation in which only tumors that contain no true papillae are included, this case is only the eighth reported in the literature, including the 6 cases described in the series by Renshaw et al, 1 the 1 case reported by Ngan et al 4,and1caseby Argani et al. 5 In addition, we have illustrated a highgrade spindle cell histologic pattern that we interpret to represent spindle cell dedifferentiation from the parental tubular element. References 1. Renshaw AA, Zhang H, Corless CL, Fletcher JA, Pins MR. Solid variants of papillary (chromophil) renal cell carcinoma: clinicopathologic and genetic features. Am J Surg Pathol. 1997;21(10):1203 1209. 2. Pignot G, Elie C, Conquy S, et al. Survival analysis of 130 patients with papillary renal cell carcinoma: prognostic utility of type 1 and type 2 subclassification. Urology. 2007;69(2):230 235. 3. Lager DJ, Huston BJ, Timmerman TG, Bonsib SM. Papillary renal tumors: morphologic, cytochemical, and genotypic features. Cancer. 1995;76(4):669 673. 4. Ngan KW, Ng KF, Chuang CK. Solid variant of papillary renal cell carcinoma. Chang Gung Med J. 2001;24(9):582 586. 5. Argani P, Netto GJ, Parwani AV. Papillary renal cell carcinoma with lowgrade spindle cell foci: a mimic of mucinous tubular and spindle cell carcinoma. Am J Surg Pathol. 2008;32(9):1353 1359. 6. Brunelli M, Eble JN, Zhang S, Martignoni G, Cheng L. Gains of chromosomes 7, 17, 12, 16, and 20 and loss of Y occur early in the evolution of papillary renal cell neoplasia: a fluorescent in situ hybridization study. Mod Pathol. 2003;16(10):1053 1059. 7. Eble JN, Sauter G, Epstein JI, Sesterhenn IA, eds. Pathology and Genetics of Tumors of the Urinary System and Male Genital Organs. Lyon, France: IARC Press; 2004. World Health Organization Classification of Tumours; vol 6. 8. Skinnider BF, Folpe AL, Hennigar RA, et al. Distribution of cytokeratins and vimentin in adult renal neoplasms and normal renal tissue: potential utility of a cytokeratin antibody panel in the differential diagnosis of renal tumors. Am J Surg Pathol. 2005;29(6):747 754. 9. Lin ZH, Han EM, Lee ES, et al. A distinct expression pattern and point mutation of c-kit in papillary renal cell carcinomas. Mod Pathol. 2004;17(6): 611 616. 10. Langner C, Wegscheider BJ, Ratschek M, Schips L, Zigeuner R. Keratin immunohistochemistry in renal cell carcinoma subtypes and renal oncocytomas: a systematic analysis of 233 tumors. Virchows Arch. 2004;444(2):127 134. 11. Muir TE, Cheville JC, Lager DJ. Metanephric adenoma, nephrogenic rests, and Wilms tumor: a histologic and immunophenotypic comparison. Am J Surg Pathol. 2001;25(10):1290 1296. 12. Jennette JC, Olsen JL, Schwartz MM, Silva FG. 2007. Heptinstall s Pathology of the Kidney. Philadelphia, PA: Lippincott Williams and Wilkins. 13. Srigley JR, Delahunt B. 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14. Dassi V, Das K, Singh BP, Swain SK. Primary synovial sarcoma of kidney: a rare tumor with an atypical presentation. Indian J Urol. 2009;25(2): 269 271. 15. Shannon BA, Murch A, Cohen RJ. Primary renal synovial sarcoma confirmed by cytogenetic analysis: a lesion distinct from sarcomatoid renal cell carcinoma. Arch Pathol Lab Med. 2005;129(2):238 240. 16. Mai KT, Kohler DM, Robertson SJ, Belanger EC, Marginean EC. Oncocytic papillary renal cell carcinoma with solid architecture: mimic of renal oncocytoma. Pathol Int. 2008;58(3):164 168. 17. Gobbo S, Eble JN, Grignon DJ, et al. Clear cell papillary renal cell carcinoma: a distinct histopathologic and molecular genetic entity. Am J Surg Pathol. 2008;32(8):1239 1245. 1214 Arch Pathol Lab Med Vol 134, August 2010 Solid Variant of Papillary Renal Cell Carcinoma Cantley et al