Quantitative Differentiation of Renal Cell Carcinoma From Fat-Poor Angiomyolipoma and Between Renal Cell Carcinoma Subtypes by Using Three-Phase MDCT

Background: Renal cell carcinoma (RCC) can be differentiated from angiomyolipoma by detection of macroscopic fat at multidetector computed tomography (MDCT). Measurement of enhancement at MDCT help classifying between RCC subtypes, which possibly predict tumor prognosis. Objective: Retrospectively assess whether quantitative measurements (percentage enhancement ratio [PER] and absolute washout ratio [AWR]) of renal mass enhancement during three-phase MDCT help differentiating RCC from fat-poor angiomyolipoma and other RCC subtypes. Methods: The retrospective review of the preoperative three-phase MDCT (unenhanced, corticomedullary, and early excretory phases) performed between January 2008 and July 2017, a total of 75 renal lesions (74 consecutive patients) were assessed for attenuation values in each phase. The enhancement values (PER and AWR) were compared by ANOVA tests. Cutoff analysis of enhancement values was performed to determine optimal threshold for each histologic subtype. Results: The attenuation value of fat-poor angiomyolipoma was significantly higher than clear cell RCCs in unenhanced phase (P = .02). The PER of the clear cell RCCs was significantly lower than that of papillary RCCs, chromophobe RCCs, and fat-poor angiomyolipomas (P < .001). The AWR of the clear cell RCCs showed significantly greater than that of papillary RCCs and fat-poor angiomyolipoma (P < .001). The PER and AWR thresholds for differentiating RCCs from fat-poor angiomyolipoma were 93.0 and 31.6 with accuracy of 74.7% and 77.3%, respectively. Conclusions: Quantitative measurement of enhancement (PER and AWR) might help differentiating RCCs from fat-poor angiomyolipoma, and differentiating clear cell RCCs from papillary RCCs.

Non–Clear Cell Renal Cell Carcinomas: From Shadow to Light

Non–clear cell renal cell carcinomas (RCCs) account for up to 25% of kidney cancers and encompass distinct diseases with distinct pathologic features, different molecular alterations, and various patterns of response to systemic therapies. Recent advances in molecular biology and large collaborative efforts helped to better define the oncogenic mechanisms at play in papillary, chromophobe, collecting duct, medullary, translocation, and sarcomatoid RCCs. Papillary RCCs are divided into several subsets of tumors characterized by distinct gene expression profiles, chromatin remodeling genes, cell cycle changes, and alterations of the MET pathway. Chromophobe RCC genomic analysis revealed mostly metabolic pathway alterations with mitochondrial dysfunctions. Translocation RCCs are characterized by MITF fusions and wide genomic reprogramming. Collecting duct carcinomas are distinct entities from upper tract urothelial carcinomas associated with high T-cell infiltration and metabolic alterations. Medullary RCCs present alterations of the INI1 gene and rhabdoid features at pathologic analysis. Finally, sarcomatoid RCCs represent sarcomatoid differentiation for any subsets of RCCs with specific alterations associated with mesenchymal dedifferentiation. From the standpoint of systemic therapy, more than a decade of using VEGF and mTOR inhibitors showed that they generally had limited efficacy in non–clear cell RCCs compared with clear cell RCCs. MET inhibitors are actively being developed for papillary RCC with a specific focus on MET-driven tumors. Other strategies under investigation include CDK4/6 inhibitors in tumors with cell cycle alterations and EZH2 inhibitors in RCCs with INI1 loss. The emergence of immune checkpoint inhibitors and combination strategies enlarges the spectrum of investigational treatments. Better understanding of driver and passenger alterations and better patient stratification along with dedicated clinical networks will be key to improving the management of these rare tumors.

Suitability of clear cell renal cell carcinoma to heat shock proteins-inhibitors.

480 Background: Heat shock proteins (HSP) HSP27 and HSP90 are expressed in response to a wide variety of insults, thus allowing the cell to adapt to stress. In cancer cells, both HSP27 and HSP90 may participate to carcinogenesis, suggesting these chaperones as an appealing target for cancer therapeutics. The role of HSP in the development and progression of renal-cell carcinomas (RCCs) remains to be defined. We sought to evaluate a series of clear cell RCCs. Methods: 388 RCCs with clear cell histology available on 10 tissue microarrays were recruited. Each case was represented by 3 neoplastic cores. All these cases were stratified according to the Mayo Clinic SSIGN (Size, Staging, Grading, Necrosis) score into five prognostic groups with increasing worse prognosis (1 to 5). Immunostainings for HSP27 and 90 were performed. A mean score number from the three cores was set per case (percentage x intensity). Results were detailed per number of scorable cases per SSIGN category (1 to 5). Results: 117 and 122 RCCs were respectively available for HSP90 and HSP27 scoring. The remaining samples were lost due to the lack of tissue sections or to the absence of adequate neoplastic cells scorable. HSP90 scored 4,9 in 32 with SSIGN1, 3,5 in 41 SSIGN2, 4,8 in 11 SSIGN3, 4,2 in 22 SSIGN4 and 5 in 3 SSIGN5 patients. HSP27 scored 4,6 in 33 with SSIGN1, 3,1 in 43 SSIGN2, 2,6 in 11 SSIGN3, 3,6 in 24 SSIGN4 and 2,7 in 3 SSIGN5 patients. A significant trend of increasing value for HSP90 has been observed when comparing cases tabled SSIGN1-2 versus SSIGN3-5 (4,2 to 4,6 mean values) (p=0.05); a minor stratification has been observed for HSP27 (3,8 to 3,9) (p=0.08). Conclusions: In conclusion, HSP90 and HSP27 are variable immunoexpressed in a subset of clear cell RCCs, with a trend to higher prognostic SSIGN score. At light of new emerging targeted-therapies in kidney cancer, we report an increasing suitability of these patients to therapies that target the pathways of heat shock protein molecules. Additional learning of the HSP role in clear cell RCCs carcinogenesis is required to guide future therapeutic developments.

Survival outcomes in metastatic renal carcinoma based on histological subtypes: SEER database analysis.

381 Background: Renal cell cancer (RCC) represents a heterogeneous group of tumors with distinct histopathologic, genetic, and clinical features. This study was conducted to evaluate the prognostic value of histology in RCCs. Methods: 3,062 patients with metastatic RCC from year 1998-2007 were identified from Surveillance Epidemiology and End Results (SEER) database. Data regarding their age, sex, race, treatment modality utilized and cancer specific survival was extracted and analyzed. Results: Clear cell, sarcomatoid, adenocarcinoma NOS, papillary, collecting duct, chromophobe and cyst associated renal carcinoma accounted for 2,166 (70%), 433 (14%), 216 (7%), 160 (52%), 47 (1.5%), 35 (1.14%), and 5 (0.01%) respectively. The mean age of presentation was 63.5 in clear cell RCC and 62.7 years in non-clear cell RCC. Surgery was performed in 57.23% of all clear cell cancers and 50.84% in non-clear cell-RCC group. 27.34% of all clear cell cancer patients received radiation in contrast to 34.53% in the other group. Both clear cell RCC (64.54%) and non-clear cell RCC (69.52%) occurred commonly in males. Incidence of clear cell RCC was 4.67% in Asians, 7.01% in Blacks, 88.32% in Whites. The incidence of non-clear cell RCC was 3.81% in Asians, 14.78% in Blacks, and 81.41% in Whites. Cancer-specific survival was calculated in all histologic subtypes. Median survival for clear cell RCC was 8 months, 3 months for adenocarcinoma NOS, 7 months for cyst associated renal carcinoma, 8 months for papillary carcinoma, 7 months for chromophobe type, 4 months for sarcomatoid and 4 months for collecting duct RCC. Median overall survival was significantly better for clear cell cancer as compared to non-clear cell RCCs (8 months vs. 4 months; p< 0.0001). Conclusions: Non-clear histology RCCs represent 30% of metastatic RCC and are associated with poor prognosis when compared to clear cell RCC.While development of novel targeted therapies has improved survival in clear cell RCC, it has not made a impact in survival of non-clear RCCs. An indepth understanding of the genetic and molecular changes associated with non-clear cell RCCs is important to improve their prognosis. No significant financial relationships to disclose.

Expression of Galectin-3 in Renal Neoplasms: A Diagnostic, Possible Prognostic Marker

Context. Galectin-3, a member of the lectin family, was shown to be expressed in normal distal tubular cells and in renal cell carcinomas (RCC). However, its diagnostic and prognostic significance in RCC is as yet undefined. Objectives. To describe the expression of Galectin-3 among different histologic subtypes of renal neoplasms and to determine their diagnostic and prognostic significances. Design. The expression of Galectin-3 was evaluated in 217 renal neoplasms by tissue microarray and immunohistochemistry with semiquantitative analysis. Results. Strong expression of Galectin-3 was observed in 92 of 217 of renal neoplasms (42.4%). Although 22 of 23 oncocytomas (95.7%) and 19 of 21 chromophobe RCCs (90.5%) express Galectin-3, only 4 of 32 papillary RCCs (12.5%) and 47 of 137 clear cell RCCs (34.3%) express Galectin-3, suggesting that it may be used as a potential diagnostic marker. Galectin-3 expression was seen in 55% of high-grade (Fuhrman nuclear grades 3 and 4) versus 21% low-grade (grades 1 and 2) clear cell RCCs (P &lt; .001). Conclusions. This study confirms that Galactin-3 is strongly overexpressed in renal cell neoplasms of distal tubular differentiation, that is, oncocytoma and chromophobe RCCs, suggesting it might be used as a possible differential diagnostic tool for renal cell neoplasm with oncocytic or granular cells. Furthermore, we observed a strong association of overexpression of Galectin-3 and high nuclear grade in clear cell RCC. These results also suggest a possible pivotal role for Galectin-3 in the differentiation and prognosis of clear cell RCC.

Claudin-7 Immunohistochemistry in Renal Tumors: A Candidate Marker for Chromophobe Renal Cell Carcinoma Identified by Gene Expression Profiling

Context.—The differential diagnosis of eosinophilic renal tumors can be difficult by light microscopy. In particular, chromophobe renal cell carcinoma (RCC) is difficult to distinguish from oncocytoma. This differential diagnosis is important because chromophobe RCC is malignant, whereas oncocytoma is benign. Furthermore, chromophobe RCC has distinct malignant potential and prognosis compared with eosinophilic variants of other RCC subtypes. Immunohistochemistry is useful for distinguishing chromophobe RCC from other subtypes of renal carcinoma, but no expression marker reliably separates chromophobe RCC from oncocytoma. Objective.—In a previous gene expression microarray analysis of renal tumor subtypes, we found the distal nephron markers claudin-7 and claudin-8 to be overexpressed in chromophobe RCC versus oncocytoma and other tumor subtypes. We have confirmed similar findings in independent microarray data and validated differential claudin-7 protein expression by immunohistochemistry. Design.—Immunohistochemical analysis of claudin-7 in 36 chromophobe RCCs, 43 oncocytomas, 42 clear cell RCCs, and 29 papillary RCCs. Results.—Membranous claudin-7 expression was detected in 67% chromophobe RCCs, compared with 0% clear cell RCCs, 28% papillary RCCs, and 26% oncocytomas (P &lt; .001). Conclusions.—Based on microarray and immunohistochemical data, we propose claudin-7 to be a candidate expression marker for distinguishing chromophobe RCC from other renal tumor subtypes, including the morphologically similar oncocytoma. The clinical utility of claudin-7 should be validated in independent studies of renal tumors, possibly in combination with additional targets in a multiplex immunohistochemical panel.