Clear Cell Tubulopapillary Renal Cell Carcinoma: A Study of 36 Distinctive Low-grade Epithelial Tumors of the Kidney

Abstract

Recently several low-grade renal cell tumors, distinct from those recognized by the 2004 World Health Organization classification of renal tumors, have been described. These tumors had similar clinicopathologic features, being low-stage tumors with cystic, tubuloacinar, and/or papillary architecture. The tumor cells were low grade with variable amounts of clear cytoplasm that was positive for cytokeratin 7 (CK7), but negative for CD10. Genetic changes characteristic of clear cell or papillary renal cell carcinoma were not seen in these tumors. We investigated the morphologic, immunohistochemical, and genetic features of 36 additional tumors. Immunohistochemistry was carried out for CK7, carbonic anhydrase 9, α-methylacyl-CoA racemase, CD10, TFE-3, and desmin. Interphase fluorescence in situ hybridization was carried out with centromeric probes for chromosomes 3, 7, 17, and a subtelomeric probe for 3p25. Sequencing of von Hippel-Lindau gene and analysis of the methylation status of the promoter region was also carried out in 2 tumors. Thirty-six tumors from 33 patients (mean age: 60.4 , range: 26 to 88; 17 men and 16 women) were studied. Three patients had bilateral tumors and 1 patient had von Hippel-Lindau disease. Follow-up was available in 60% (20/33) of the patients for a mean of 27.4 (range 1 to 85) months. No patient had evidence of the disease after surgery except for the patient with von Hippel-Lindau disease, who was alive with stable disease in the contralateral kidney. All 36 tumors were small (mean size 2.4 cm; range 0.9 to 4.5 cm) and low stage (pT1). The majority was cystic and had prominent fibrous capsule and stroma. The tumors were composed of variable amount of cysts, papillae, tubules, acini, and solid nests. The most characteristic histologic features were branching tubules and acini and anastomosing clear cell ribbons with low-grade nuclei. All tumors were strongly positive for CK7 and variably positive for CA9, but largely negative for CD10, and negative for α-methylacyl-CoA racemase and TFE-3. All but 1 tumor had no gains of chromosomes 7 and 17 and deletion of 3p. Only 1 tumor had low copy number gains of chromosomes 7 and 17. VHL gene mutation and promoter methylation were negative in 2 tumors analyzed. We show that these tumors, which we term as "clear cell tubulopapillary renal cell carcinoma," constitute a unique subtype in the spectrum of renal epithelial neoplasia based on their characteristic morphologic and immunohistochemical features.

Renal cell carcinoma with angioleiomyoma-like stroma: clinicopathological, immunohistochemical, and molecular features supporting classification as a distinct entity

“…[33][34][35] Comparison to Clear Cell Papillary Renal Cell Carcinoma It has been hypothesized that these renal cell carcinomas with smooth muscle stroma are part of the morphological spectrum of clear cell papillary renal cell carcinoma. 13 In keeping with such a possibility, we found the immunohistochemical profile of these two tumor types to overlap, including labeling for carbonic anhydrase IX (sometimes with a 'cup-shaped' staining pattern 8 ), CK7, 6,8,10 and cytokeratin 34bE12 8 and negative reactivity for AMACR. 6,8,10 As a point of contrast, the tumors in this study showed more diffuse labeling for CD10 than expected of clear cell papillary renal cell carcinoma.…”

“…13 In keeping with such a possibility, we found the immunohistochemical profile of these two tumor types to overlap, including labeling for carbonic anhydrase IX (sometimes with a 'cup-shaped' staining pattern 8 ), CK7, 6,8,10 and cytokeratin 34bE12 8 and negative reactivity for AMACR. 6,8,10 As a point of contrast, the tumors in this study showed more diffuse labeling for CD10 than expected of clear cell papillary renal cell carcinoma. 10 In our experience, clear cell papillary renal cell carcinoma usually shows an entirely negative reaction for CD10 or apical labeling of only the cyst-lining cells; however, others have occasionally observed focal labeling for CD10 in non-cystic areas.…”

“…10 In our experience, clear cell papillary renal cell carcinoma usually shows an entirely negative reaction for CD10 or apical labeling of only the cyst-lining cells; however, others have occasionally observed focal labeling for CD10 in non-cystic areas. 6,8,10 Genetically, absence of chromosome 3p deletion is also a point of similarity between these tumor types that contrasts both to clear cell renal cell carcinoma. 7,36 However, features contrasting these tumors included a higher nuclear grade in renal cell carcinoma with angioleiomyomalike stroma (grade 2-3) compared with clear cell papillary renal cell carcinoma (grade 1-2) and the absence of the 'secretory cell' pattern with nuclei aligned above the basement membrane in the former.…”

“…The staining reaction was considered 2 þ if labeling was easily recognized from low magnification but not diffuse or 1 þ if labeling was focal or weak, requiring high magnification to be identified. Immunohistochemical staining results were compared with those previously published for clear cell papillary renal cell carcinoma 6,8,10 and clear cell renal cell carcinoma. 16,17 Staining reactions for caldesmon, CD34, and cytokeratin 34bE12 were also studied in a control group of 10 tumors: 5 clear cell papillary renal cell carcinomas and 5 clear cell renal cell carcinomas.…”

“…4 As only a small number of tumors with these features have been reported and their clinicopathological, immunohistochemical, and molecular features are incompletely understood, it is unclear whether these lesions comprise a single distinct type of renal neoplasm or whether these reports encompass multiple entities. The relationships of these tumors to clear cell renal cell carcinoma 4 and clear cell papillary renal cell carcinoma [5][6][7][8][9][10][11] (also known as clear cell tubulopapillary renal cell carcinoma) 6,12 are also poorly understood. 13 To elucidate the characteristics of these tumors and assess whether they represent a distinct subcategory of renal neoplasia, we studied the clinicopathological, immunohistochemical, and molecular features of renal epithelial neoplasms noted to have a smooth muscle stromal component from our pathology archives.…”