Tumor grade of clear cell renal cell carcinoma assessed by contrast-enhanced computed tomography

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCC, accounting for approximately 70 - 80% of RCC (Leibovich et al.2010; Teloken et al.2009; Kim et al.2002). It has a poorer prognosis than other subtypes of RCC, such as papillary and chromophobe RCC (Leibovich et al.2010; Teloken et al.2009), and its biological aggressiveness significantly affects prognosis.

The system most widely employed to classify RCC is the Fuhrman grading system, which uses the characteristics of the nuclei and nucleoli of tumor cells as its basis for grading (Fuhrman et al.1982; Novara et al.2007; Ficarra et al.2005). Fuhrman grade 1 is the least aggressive type, with grade 4 being the most aggressive (Fuhrman et al.1982). Grades 1–2 and 3–4 are classified as low and high grades, respectively (Novara et al.2007; Ficarra et al.2005). Higher grade tumors have an elevated risk of postoperative recurrence (Novara et al.2007); thus, postoperative surveillance for these patients should be more rigorous. The Fuhrman grade is one of the most effective parameters used in predicting the biological aggressiveness and metastatic potential of ccRCC and papillary RCC (Novara et al.2007; Sukov et al.2012; Nishikimi et al.2011), although it lacks prognostic significance for chromophobe RCC (Cheville et al.2012).

Imaging assessment of tumor grades in RCC may aid in clinical management decisions. For example, less invasive procedures (e.g., nephron-sparing surgery and radiofrequency ablation) or close observation may be considered for low grade RCC.

There have been few previous reports citing use of magnetic resonance imaging (MRI) to compare Fuhrman grade with imaging characteristics, and the number of cases reported was relatively small (Vargas et al.2013; Goyal et al.2012; Rosenkrantz et al.2010). Computed tomography (CT) is most often used for preoperative evaluation of RCC, and image quality is generally similar across institutions. Therefore, CT may be more applicable in evaluating significant numbers of cases.

The purpose of this study was to clarify the association between contrast-enhanced CT findings and Fuhrman grade of ccRCC.

Tumor morphology and Fuhrman grade are shown in Table 1. Nineteen of 22 (86.4%) cystic ccRCC were low grade (Fuhrman grades 1 or 2) (Figure 1) (Tables 1 and2). All of the three cystic ccRCC with grade 3 were Bosniak IV (Figure 2). There was a significant difference in tumor grade between cystic ccRCC and well-circumscribed ccRCC (P = 0.025). Thirty-eight of 43 (88.4%) infiltrative ccRCC were high grade (Fuhrman grades 3 or 4) (Figure 3). There were significant differences in tumor grades between well-circumscribed (Figure 4) and lobulated ccRCC (Figure 5) (P = 0.018), and between lobulated and infiltrative RCC (P = 0.00029).

In cystic ccRCC, there was no significant correlation between tumor size and Fuhrman grade. Spearman’s rank correlation Rho was -0.179 (P = 0.43, Figure 6a). By contrast, in predominantly solid ccRCC, there was significant correlation between tumor size and Fuhrman grade. Spearman’s rank correlation Rho was 0.51 (P <0.0001, Figure 6b).

Receiver operating characteristic (ROC) curves showed the cut-off value of 5.0 cm in the diagnosis of Fuhrman grades 3-4 ccRCC. The sensitivity, specificity, and the area under the ROC curve were 69.4%, 69.8%, and 0.740, respectively.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCC, followed by papillary and chromophobe RCCs. Characteristics of ccRCC are possible to differentiate from papillary and chromophobe RCCs on diagnostic imaging (Kim et al.2002), although it is not 100% accurate. Because papillary RCC is generally more indolent than ccRCC (Leibovich et al.2010; Teloken et al.2009), and Fuhrman grade lacks prognostic significance for chromophobe RCC (Cheville et al.2012), papillary and chromophobe RCCs were not considered in this study. Oncocytoma, a less common benign renal tumor, was beyond the scope of this study because it can be difficult to prospectively differentiate it from ccRCC on diagnostic imaging. For these reasons, we focused solely on the imaging findings of ccRCC and their relationship to Fuhrman grade.

In our study, cystic ccRCC was more likely (88.5%) to be low grade (Fuhrman grades 1–2), and no correlation was found between the size of cystic ccRCC and Fuhrman grade (Figure 6a). These results were in keeping with previous studies that showed cystic RCC to have a better prognosis than solid RCC (Koga et al.2000; Han et al.2004) and can be explained by the fact that fewer malignant cells are present in cystic RCC than predominantly solid RCC. Our results suggest that less invasive procedures such as nephron-sparing surgery or close observation may be considered for cystic RCC.

Our study did include a small percentage of high grade (Fuhrman grades 3–4) cystic ccRCC, although it was not statistically significant by multivariate analysis. RCC with cystic necrosis has the worst prognosis among the cystic RCCs (Han et al.2004; Hartman et al.1986), and one previous study showed the presence of tumor necrosis correlated with aggressive histology (Beddy et al.2014). Distinguishing cystic ccRCC from ccRCC with extensive central necrosis can be a problematic in some cases, although we did not evaluate interobserver variability on this study. When ccRCC is equivocal for solid or cystic type, it is recommended that the type be considered predominantly solid to avoid underestimation.

The increased likelihood of high grade tumors in infiltrative ccRCC (88.4%) may reflect biological tumor aggressiveness (Figure 3). For example, RCCs with aggressive histology, such as type 2 papillary RCC (Yamada et al.2008; Rosenkrantz et al.2013) and collecting duct RCC (Yoon et al.2006), commonly show an infiltrative appearance on imaging. Similarly, it has been reported that a histopathological finding of infiltrative growth was a factor indicating poor prognosis in ccRCC (Nishikimi et al.2011). Our results suggest that careful post-operative surveillance may be necessary for RCC with infiltrative growth on imaging findings.

The association of larger tumor size with higher grade, stage and metastasis has been described in previous reports (Umbreit et al.2012; Zhang et al.2012). However, it should be recognized that there can be some overlap in CT findings between Fuhrman grades 2 and 3 ccRCC.

Calcification and 60% or more non-enhancing area were commonly present in large tumors, which may explain why these findings were not significant by multivariate analysis in our study. In addition, one previous study showed that decreased tumor vascularity was associated with high grade RCCs (Vargas et al.2013). Because the CT protocols of our study group varied somewhat, our ability to evaluate tumor enhancement may have been limited. Further study to clarify the association between tumor neo-vascularity in ccRCC and tumor grade may be necessary.

The limitations of this study include 1) a retrospective study at a single institution, 2) non-uniform CT acquisition techniques, 3) no correlation of CT findings with histopathology results except Fuhrman grade of ccRCC, 4) a retrospective review of CT findings by a single experienced radiologist without assessment of interobserver variability, 5) inclusion of surgically proved clear cell RCC only and exclusion of other primary renal neoplasms, and 6) Fuhrman grades obtained from pathology reports without re-review.

In summary, cystic ccRCC tended to be low grade (Fuhrman grades 1–2), and tumor size did not correlate with tumor grade. For predominantly solid ccRCC, infiltrative growth and larger tumor size may increase the likelihood of high grade ccRCC (Fuhrman grades 3–4).