Case 2 -

Clear Cell Papillary Renal Cell Carcinoma Satish Tickoo Memorial Sloan Kettering Cancer Center New York, NY

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Clinical History A 67 year old male presented with left flank pain and microscopic hematuria. CT scan performed revealed a left UVJ calculus with mild hydronephrosis, along with a 2.5 cm enhancing mass in the lower pole of the left kidney. After the placement of left ureteral stent, subsequent MR revealed no hydronephrosis, but persistent complex cystic mass in the kidney. A partial nephrectomy was performed, and the photomicrographs are from the resected 2.5 cm, cystic and solid mass. Case 2 - Figure 1 Cystic areas in the tumor with papillary proliferations. Case 2 - Figure 2 Prominent papillary architecture. Note the clear cell cytology of the tumor. Case 2 - Figure 3 A solid area in the tumor showing closely packed tubular architecture. In addition to the clear cell cytology, the arrangement of nuclei away from basement membrane is prominantly present. Case 2 - Figure 4 A higher magnification image showing the characteristic linear arrangement of nuclei. Case 2 - Figure 5 This image illustrates the spectrum of morphologic features in this clear cell papillary RCC: tubular/acinar pattern with characteristically arranged nuclei, microcysts, solid sheet-like area composed of numerous mico- or "collapsed" acini, and smooth muscle metaplasia of the capsule with extension into the tumor. Case 2 - Figure 6 Diffuse positivity for CK7. Case 2 - Figure 7 Diffuse membranous positivity for CA-IX. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: Grossly, the tumor was well-circumscribed and partially encapsulated. Focally, the capsule was thick and fibrotic. Solid areas in the tumor had a pale-tan cut surface with small yellow foci. These solid areas merged with somewhat spongy cut-surface and grossly cystic areas. Cysts contained clear watery fluid. On microscopy, the cysts were lined by low-columnar cells with clear cytoplasm, with multiple papillary structures tufting into the lumina. In some non-cystic areas papillary structures appeared tightly packed giving rise to a solid appearance. The tumor also showed tubular/acinar and microcystic areas. Some foci appeared more solid, with sheet-like architecture. Careful examination of these revealed compact, "collapsed" micro- acini, containing scant cytoplasm. Because of the tight packing of these "collapsed' acini, such areas appeared highly vascular. All tumoral cells, other than in solid "collapsed" acinar areas, showed clear cytoplasm with low grade (equivalent to Fuhrman grade 2) nuclei. Because of scant cytoplasm in the "collapsed" acini,the cells in such foci had amphophilic or lightly eosinophilic appearance. The tumor nuclei in most of the tumor, but not in the collapsed acini, showed a linear arrangement away from the basal aspect of the cell, either in the middle of the cell or towards the apex. No necrosis or foamy macrophages were noted. Immunohistochemical stains showed diffuse positivity for CK7, carbonic anhydrase-IX (CA-IX) and 34BE12 (high molecular weight cytokeratin). The tumor cells were negative for CD10 and racemase (AMACR). Differential Diagnoses: The differential diagnostic possibilities that may be considered include clear cell renal cell carcinoma, papillary renal cell carcinoma with clear cell cytology, MiTF/TFE family translocation-associated renal carcinoma, and clear cell papillary renal cell carcinoma. Final Diagnosis: Clear cell papillary renal cell carcinoma Case Discussion: Clear cell-papillary RCC is a recently recognized distinctive renal tumor, initially described in the setting of end-stage kidneys. As was also suggested in its initial description, it is now amply clear that they also occur without evidence of impaired renal function. Although the tumors morphologically may mimic both the papillary and clear cell RCC, they immunohistochemically differ from both, and also lack the characteristic genetic signatures of either of these tumors. These tumors are usually unicentric, unilateral and small; the largest described being 5 cm in size. However in our experience, and as recently reported in literature, multifocality and bilaterality may be present in some cases. Review of the Literature/Treatment Options (if applicable): Grossly they are well circumscribed and often encapsulated. The cut surface may appear fibrotic. Some cases with grossly thick capsules and fibrotic-appearing cut surface show extensive myoid metaplasia of the capsule with extensions into tumor mass on microscopy. It is common for the tumor to be cystic, but many are predominantly solid with very few cystic areas. On microscopy, most tumors have variable, and sometimes prominent, papillary architecture. In some cases papillae are tightly packed giving rise to solid appearance. Sometimes these papillary structures are tufting into cystic spaces. Tubular/acinar features are also common, and some tumors have markedly crowded, very small "collapsed" acini, containing scant cytoplasm, and giving the tumor solid sheet-like appearance. Tumors with "collapsed" acini, variable tubular/acinar architecture, myoid metaplasia, and diffuse CK7 positivity have been considered to be separate tumor entities (renal angiomyoadenomatous tumor/RCC with diffuse CK7 immunoreactivity) by some. Since these morphologic features are not infrequent in otherwise typical clear cell papillary RCC, it is obvious that such features exist within the morphologic spectrum of clear cell papillary RCC. Aydin et al have recently suggested the designation of "clear cell tubulopapillary renal cell carcinoma" for the morphologic spectrum of these tumors, although we do not see any specific advantages for this longer nomenclature (similar to papillary RCC with tubulopapillary features being designated as papillary RCC). Except in solid "collapsed" acinar areas, almost all tumoral cells have clear cytoplasm with low grade (equivalent to Fuhrman grade 2) nuclei. One of the most characteristic features of the tumor is the linear arrangement of nuclei away from the basal aspect of the cell, either in the middle of the cell or more towards the apex. Such nuclear arrangement is prominantly present in all clear cell RCCs. Stromal hyalinization is frequently evident within the lesion. Foamy macrophages, tumor necrosis and vascular invasion are not the features of these tumors. Most tumors are small and confined to the renal parenchyma, although rare cases extending into the renal sinus have been described. The number of cases in the literature with extended clinical follow up information is small; however, our experience, and as recently reported by Aydin et al, suggests that these tumors have an indolent clinical behavior. The immunohistochemical features of the tumor are quite characteristic. Tumor cells express carbonic anhydrase-IX (CA-IX) in a diffuse membranous distribution. However, it is common to see absence of staining along the luminal aspect of the tumor cells (cup-shaped distribution). There is diffuse staining with CK7, but AMACR is negative. CD10 is negative in most cases, while it is common to see patchy to diffuse immunoreactivity for high molecular weight cytokeratin (34βE12). Clear cell papillary RCC reveals no evidence of 3p25.3 losses, VHL gene mutations, or promoter hypermethylations that are common in clear cell RCC. Additionally, polysomy of chromosomes 7 and 17 is also not seen, as would be expected in many papillary RCC. These molecular features support its distinctive nature. Clear cell papillary RCC needs to be differentiated from papillary RCC with focal to extensive cytoplasmic clarity. The "clear" cytoplasm in papillary RCCs, unlike that in clear cell papillary RCC, is not optically transparent, but is finely granular and bubbly. Careful examination often reveals dusty hemosiderin granules within the cytoplasm. Additionally, papillary RCC does not have the linear and away-from-basement-membrane nuclear arrangement, frequently shows foamy macrophages and necrosis, and a different immunophenotype that is typically AMACR positive, 34 BE12 negative and CA-IX negative or at the most focally positive. Distinction from clear cell RCC is also primarily based on the characteristic nuclear arrangement and immunoprofile of clear cell papillary RCC. Genetic profile in clear cell RCC is also different. MiTF/TFE family translocation- associated renal carcinoma may also have papillary architecture with clear cell cytology. However, these tumors often bear accompanying eosinophilic cells, and have high nuclear grade, absent or at the most focal staining for epithelial markers, and positive nuclear staining for TFE3 or TFEB. Conclusion(s): Clear cell papillary RCC is a distinctive renal cell tumor, with characteristic morphologic and immunohistochemical features, and a genetic profile different from clear cell and papillary RCC. As more familiarity with the tumor is being gained, and more cases are recognized, the morphologic spectrum of the tumor has expanded, and will likely expand further. Further molecular studies are needed to identify characteristic signature, if any, of the tumor. References: Tickoo SK, dePeralta-Venturina MN, Harik LR, Worcester HD, Salama ME, Young AN, Moch H, Amin MB. Spectrum of epithelial neoplasms in endstage renal disease: an experience from 66 tumor-bearing kidneys with emphasis on histologic patterns distinct from those in sporadic adult renal neoplasia. Am J Surg Pathol. 2006;30:141-53. Tickoo SK, Reuter VE. Clear cell papillary renal cell carcinoma: Kidney tumors and tumor-like conditions. In: Diagnostic Pathology: Genitourinary. Eds., Amin, McKenney, Tickoo, Paner, Shen, Velazquez, Cubilla, Ro and Reuter. Amirsys Publishing, Inc. 2010. p 1-106 to 1-111. Tickoo SK, Gopalan A. Pathologic features of renal cortical tumors. Urol Clin North Am. 2008;35:551-61. Gobbo S, Eble JN, Maclennan GT, Grignon DJ, Shah RB, Zhang S, Martignoni G, Brunelli M, Cheng L. Clear cell papillary renal cell carcinoma: a distinct histopathologic and molecular genetic entity. Am J Surg Pathol. 2008;32:1239-45. Aydin H, Chen L,Cheng L, Vaziri SHe H GanapathiR, Delahunt BMagi-Galluzzi C, Zhou M Clear Cell Tubulopapillary Renal Cell Carcinoma: A study of 36 distinctive low-grade epithelial tumors of the kidney. Am J Surg Pathol. 2010;34:1608-21. Michal M, Hes O, Nemcova J, Sima R, Kuroda N, Bulimbasic S, Franco M, Sakaida N, Danis D, Kazakov DV, Ohe C, Hora M. Renal angiomyoadenomatous tumor: morphologic, immunohistochemical, and molecular genetic study of a distinct entity. Virchows Arch. 2009;454:89-99. Verine J. Renal angiomyoadenomatous tumor: morphologic, immunohistochemical, and molecular genetic study of a distinct entity. Virchows Arch. 2009;454:479-80. Michal M, Hes O, Kuroda N, Kazakov DV, Hora M. Difference between RAT and clear cell papillary renal cell carcinoma/clear renal cell carcinoma. Virchows Arch. 2009;454:719. Mai KT, Kohler DM, Belanger EC, Robertson SJ, Wang D. Sporadic clear cell renal cell carcinoma with diffuse cytokeratin 7 immunoreactivity. Pathology 2008;40:481-6.