Differentiation of subtypes of renal cell carcinoma with contrast-enhanced ultrasonography

Abstract

We aimed to assess the difference of enhancement patterns among the three RCC subtypes with contrast-enhanced ultrasound (CEUS). Two hundreds cases of pathologically proved clear cell renal cell carcinomas (ccRCC), 58 papillary renal cell carcinomas (pRCC) and 51 chromophobe renal cell carcinomas (chRCC) underwent preoperative conventional ultrasound and CEUS. The wash-in and wash-out pattern, peak enhancement degree and homogeneity, and the presence of pseudocapsule were evaluated by two blinded observers respectively. The interreader agreement in the characterization of CEUS features between two observers was good (κ = 0.649–0.775). Compared with pRCCs and chRCCs, ccRCCs demonstrated higher frequency of simultaneous wash-in pattern, hyperenhancement and heterogeneity with necrotic areas. Most pRCCs and chRCCs manifested hypoenhancement, homogeneity, fast wash-out and presence of pseudocapsule. The only difference we obtained between pRCC and chRCC was the wash-in pattern, with slow wash-in in pRCC and simultaneous wash-in in chRCC. In small lesions with long diameter≤3 cm, the majority of the three subtypes of RCC showed homogeneous enhancement and there was no difference among them. CEUS was a useful method to preoperatively differentiate the ccRCC from non-ccRCC subtypes. There were no distinguishing features identifid on CEUS that allowed reliable differentiation of pRCC from chRCC.

Keywords

Clear cell renal cell carcinoma papillary renal cell carcinoma chromophobe renal cell carcinoma contrast-enhanced ultrasonography differential diagnosis

1 Introduction

Widespread use of and improvement in imaging techniques such as sonography, CT, and MRI have increased the incidental discovery of asymptomatic RCCs during evaluation for unrelated or nonspecific symptoms [1].

Renal cell carcinoma (RCC) is the most common renal malignancy, with three common subtypes representing about 95% of all renal tumors: clear cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (pRCC) and chromophobe renal cell carcinoma (chRCC). The clear cell subtype is the most common histologic variant (approximately 70% of renal cell carcinomas) and tends to present at advanced stage and a higher rate of metastasis than other RCC subtypes with an overall 5-year survival rate of 55–60%. The papillary subtype represents 15–20% of cases and it tends to present at an early stage with a high 5-year survival rate of 80–90%. The chromophobe subtype accounts for 6–11% of cases and it has the best prognosis with a 5-year survival rate of approximately 80–100% [2 –6]. ccRCCs were often treated with radical nephrectomy while pRCCs and chRCCs with nephron-sparing surgery [13]. Therefore, presurgical classification has become an important theme due to different prognosis and tumor behavior for each subtype [8, 9].

As we all know, angiogenesis is necessary for tumor growth and metastases [10], and evaluating the vascularization of renal lesions is one of the most important role of imaging techniques for diagnosis. Contrast-enhanced CT (CECT) and MRI examination have played a great role in identification of RCC subtypes [8 , 12]. It has been reported that most ccRCCs were hypervascular lesions while pRCCs and chRCCs revealed hypovascular or avascular features [13, 14]. However, a lack of CT enhancement in a renal lesion is not sufficient to indicate that a renal mass is benign because pRCC has classically been described as a poorly enhancing type of RCC [15]. Nowadays, harmonic ultrasonography performed with second generation contrast agents can be used to manifest the perfusion patterns of lesions and it has revealed promising perspectives in the diagnosis of renal tumors [16 –20]. Ultrasound contrast agents are safe with a very low incidence of side effects including no cardio, hepato, or nephrotoxic effects [21]. Life threatening anaphylactoid reactions have been reported with a rate of less than 0.002% [22, 23].

To our knowledge, there was no literature to evaluate the CEUS enhancement patterns of pRCC and chRCC, as well as their difference from ccRCC by CEUS. A few studies in the literature that have examined this topic have either grouped pRCCs or chRCCs with other “non-clear cell” RCCs or consist of relatively low numbers of subjects [16 , 24]. In our study, the number of pathologically proved RCCs, especially pRCCs and chRCCs, which were evaluated with CEUS was the largest. The purpose of our study was, therefore, to describe difference of the enhancement features among pathologically proved ccRCC, pRCC and chRCC.

2 Materials and methods

2.1 Patients

A retrospective review was performed on patients who underwent CEUS examination for evaluation of renal masses and who also had pathologic confirmation of the renal cell carcinoma during 2004 to 2014. Between October 2004 and September 2014, 57 consecutive patients (41 males and 16 females, mean age: 52.4±12.7 years) with 58 renal lesions underwent preoperative CEUS and their lesions were pathologically proven as pRCC after surgery. During the same period, 51 patients (26 males and 25 females, mean age: 53.5±12.2 years) with 51 lesions were proved as chRCCs. From January 2012 to September 2014, 197 consecutive patients (149 males and 48 females, mean age: 54.1±11.7 years) with 200 renal lesions also underwent CEUS and lesions were proven positive for ccRCC by pathological examination. All of the lesions were surgically removed and definite pathologic diagnosis was obtained. All of the patients had no contraindication against CEUS, and informed patient consent for CEUS examination had been obtained. Institutional Ethics Committee approval was obtained to retrospectively review images and patient medical records.

Of the 305 patients, 303 underwent unilateral nephrectomy and two underwent bilateral nephrectomy for bilateral renal masses. Of the 309 lesions, 86 (27.8%) were resected with partial nephrectomy and 223 (72.2%) with radical nephrectomy.

2.2 Examination technique

US and CEUS were conducted two to fourteen days before surgery. Examinations were performed with one of the following US systems: IU22 (Philips Medical Systems, Netherlands; C5-1, 1–5 MHz), E9 (GE Healthcare, England; C1-5, 1–5 MHz) or Technos DU8 (Esaote Clinical Solutions, Genoa, Italy; CA6217-2, 2.5–5 MHz). Gray-scale ultrasound was conducted to localize and assess the size and the echostructural characteristics of renal masses, while color Doppler ultrasound was used to examine blood flow in the tumors. In each patient, CEUS was performed after conventional US examination with the same scanning technique. In the contrast-enhanced study, low-acoustic power modes were used with mechanical index (MI) of 0.05–0.11 [25]. Every patient received an intravenous 1.2 mL bolus injection of the second-generation contrast agent SonoVue^® (Bracco, Italy), followed by a flush of 5 mL of 0.9% (w/v) sodium chloride. The timer was activated at the beginning of contrast agent administration. At the same time, patients were asked to hold their breath as long as possible. Slow shallow breathing was allowed for patients unable to hold their breath. During each CEUS study, we swept through the lesion to obtain the information about enhancement of the whole lesion. Repeated injections of SonoVue were performed at an interval of more than 15 min if necessary. The duration of CEUS from the administration of SonoVue to the end of the video must be more than 4 min. Digital video clips of entire examination were recorded on hard disc for imaging interpretation [26].

2.3 Image analysis

The videos were retrospectively reviewed by two readers (with 22 and 14 years of experience in CEUS imaging, respectively) independently who were blinded to any clinical or pathologic data. Discrepant interpretations were resolved by consensus after involvement of another reader with 22 years of experience in CEUS. Location, size, echogenicity, border, shape and vascularization of the lesions were evaluated on conventional US. The definitions of enhancement patterns and features of CEUS were as follows: (A) as for wash-in enhancement pattern, “synchronous-in” or “slow-in” meant that the arrival time of the contrast agent in the lesions was the same as or slower than that in the adjacent renal cortex, respectively. (B) Similarly, with the respect to washout pattern, “fast-out”, “synchronous-out”, or “slow-out” indicated that the outflow of the contrast agent from the tumors was faster than, simultaneous with, or slower than that from the adjacent cortex, respectively. (C) As for the homogeneity at peak enhancement, homogenous enhancement was defined as a lesion occupied by a full enhancement without any defects. Heterogeneous enhancement was defined as a lesion with unenhanced areas, regardless various enhancement degree. (D) At peak enhancement of lesions, according to the lesions enhancement degree compared with that of the renal cortex, hyper, iso- and hypo-enhancement were defined [27]. (E) A rim of perilesional enhancement after SonoVue injection was considered to represent a pseudocapsule [1]. According to the maximum diameter of lesions by CEUS, they were classified as two groups: ≤3 cm and >3 cm. The above CEUS features of the two groups were characterized respectively.

2.4 Statistical analysis

Statistical analyses were performed with the SPSS 16.0 software package (SPSS Inc., Chicago, IL, USA). Continuous variables were expressed as mean values±standard deviation, and discrete variables as numbers and percentages. An unweighted kappa (κ) statistic was used to evaluated the interreader agreement for the features and κ values were interpreted as: poor (κ< 0.20), fair (κ = 0.20–0.40), moderate (κ = 0.40–0.60), good (κ= 0.61–0.80) and excellent (κ> 0.80). The Pearson chi-square test or Yates continuity correction was used to compare the terms of enhancement pattern as well as enhancement homogeneity among pRCC, ccRCC and chRCC. To reduce the risk of type II error, the significance level for multiple comparisons was controlled by applying the Bonferroni correction for multiple comparisons (test-wise significance level divided by the number of tests performed) and variables were deemed significant if P≤0.0167.

3 Results

There were 309 histopathologically proved RCCs, ranging in diameter from 1.0 cm to 28.0 cm (mean 4.0 cm±2.5). The diameter of each RCC subtype was shown in Table 1. Histopathologic analysis was obtained from radical nephrectomy (n = 223) or partial nephrectomy (n = 86) specimens. More percentage of patients with chRCC were female than patients with ccRCC (49.0% vs. 24.4%, P = 0.001). There was no statistical difference of age distribution among three subtypes (Table 2).

On conventional US, 152/200 (76.0%) lesions of ccRCC were hyperechoic compared with the surrounding renal parenchyma, 20/200 (10.0%) were isoechoic, and 28/200 (14.0%) were hypoechoic. Thirty-three cases of 58 pRCCs (56.9%) showed hyperchoic, 7/58 (12.1%) isoechoic, and 18 /58 (31.0%) hypoechonic. Twenty-nine lesions of 51 chRCCs (56.9%) were hyperchoic, 2/51 (3.9%) were isoechoic, and 20/51 (39.2%) were hypoechonic. There was no difference of echogenicity among the three subtypes.

There was good agreement between the readers regarding these enhancement features, as evidenced by κ statistics that ranged from 0.649 to 0.775 (Table 3).

All of the RCCs were detected enhancement with CEUS and the enhancement features were shown in Table 4. The enhancement patterns of ccRCC were quite different from that of pRCC and chRCC. After injection of the contrast agent, a higher proportion of ccRCC (187/200, 93.5%) showed simultaneous wash-in pattern than chRCC (32/51, 62.7%) (P < 0.001), while most pRCCs showed slow wash-in (36/58, 62.1%). There was statistical difference between pRCC and chRCC (P = 0.010). As for peak enhancement degree, hyperenhancement was observed in the majority of ccRCCs (124/200, 62%), while the main feature of peak enhancement in pRCC and chRCC was hypoenhancement (34/58, 58.6% and 24/51, 47.1%, respectively) (P all < 0.001). There was no statistical difference of peak enhancement degree between pRCC and chRCC (P = 0.150). As for the wash-out pattern, the frequencies of fast-out pattern in pRCC (52/58, 89.7%) and chRCC (39/51, 76.5%) were higher than in ccRCC (95/200, 47.5%) (P all <0.001). Meanwhile, most ccRCCs (145/200, 72.5%) were detected heterogeneous enhancement with enhancing solid component and nonenhancing necrosis or cystic degeneration (Fig. 1). On the contrary, most pRCCs (32/58, 55.2%) and chRCCs (35/51, 68.6%) showed homogeneous enhancement without necrotic area (Figs. 2, 3). More percentage of pseudocapsule was detected in pRCCs (27/58, 46.6%) and chRCCs (28/51, 54.9%) than in ccRCCs (40/200, 20%) (P all <0.001).

The CEUS features of three subtypes that were divided in two groups by the long diameter were showed in Table 5. Most features were similar with that observed without diameter classification in Table 2 except the homogeneity. In the group of small lesion with diameter no more than 3 cm, the three RCC subtypes mainly manifested as homogeneous enhancement without statistical difference among them. Meanwhile, in the group with lesions >3 cm, a high proportion of heterogeneity was revealed in ccRCCs than in pRCCs and chRCCs (P all <0.001), and the latter two subtypes were not statistically different.

4 Discussion

It is well known that patients with clear cell RCC have a poorer prognosis compared with patients with papillary and chromophobe RCC, and there was no significant difference in cancer-specific survival between patients with papillary and chromophobe RCC [9]. This demonstrates that there are significant differences in outcome for the different histologic subtypes of RCC, so classification is of great significance [9, 28]. The results of our study showed that pRCC, in comparison to ccRCC, was more often observed in female patients, which was in accordance with previous researches [5, 29]. Other research reported that chRCC was observed in younger patients than ccRCC or pRCC [5], but in our series there was no difference of age distribution among RCC subtypes.

It has been reported that, for the differentiation of the subtypes of RCC, degree of enhancement is the most valuable parameter [2]. We concluded that the peak enhancement degree of ccRCC was much higher than that of pRCC and chRCC (P < 0.001). Our findings are concordant with previous investigations in which investigators observed less avid enhancement of lower-grade malignant tumors [8, 14]. Some studies reported that ccRCC showed higher enhancement degree, as well as higher tumor-to-aorta and tumor-to-kidney ratios in the arterial and delayed phases than pRCC and chRCC, when assessed with CECT or dynamic contrast-enhanced MRI [14 , 31]. Zhang et al. [14] found that clear cell RCCs tended to be hypervascular with CECT, chromophobe lesions tended to enhance moderately, and papillary lesions were mostly hypovascular. In our qualitative study, the enhancement degree of both pRCC and chRCC was lower than that of ccRCC, but there was no difference between the former two subtypes.

Furthermore, the perfusion process of renal lesions with CEUS was real-time, continuous and dynamic, so we could observe the whole course of contrast agent wash into and wash out of the lesions. This is an advantage of CEUS over CT and MRI which only provide discontinuous pictures of lesion enhancement. In our study, ccRCC and chRCC mainly manifested as simultaneous-in while pRCC mainly showed slow-in. As for wash-out pattern, more proportion of pRCC and chRCC showed fast-out than ccRCC lesions.

Histopathologically, tumors with homogeneous enhancement were chiefly composed of solid elements, whereas tumors with heterogeneous enhancement had both solid elements and necrosis or hemorrhage. The presence of heterogeneity has been known to be associated with tumor aggressiveness and poor clinical outcomes [9]. We found that ccRCCs most commonly manifested with a heterogeneous pattern with of both enhancing soft-tissue components and nonenhancing areas. On the contrary, more than half of the pRCCs and chRCCs manifested with homogeneous enhancement without cystic degeneration or necrosis. There has been investigation reporting that, evaluated with CECT, the frequency of homogeneous enhancement was higher in chRCC than in pRCC [2]. However, in our study, the proportion of homogeneity in chRCC was a litter higer than in pRCC (chRCC 35/51, 68.6% vs. pRCC 32/58, 55.2%), but there was no statistical difference (P = 0.150).

We found that most small lesions ≤3 cm showed homogeneous enhancement and there was no difference among the three subtypes. Similarly, Jiang et al. [32] have reported that homogeneity of enhancement correlated well with the tumor size and the frequency of homogeneity in small ccRCC lesions (≤3 cm) was higher than in big ccRCCs (>3 cm). It has been reported that the small tumors grow slowly with rare necrosis change. However, with the size of tumor increasing continually, necrotic areas will be observed frequently within the tumors due to the accelerating grow speed and the subsequent lack of blood supply [33]. Jung et al. [28] assessed the feature of 149 small (<4 cm) RCCs withthree-phase multidetector-row CT, and concluded that heterogeneity of enhancement showed a significant difference between clear cell and non-clear cell types on the corticomedullary phase, meantime, there was no significant difference between chRCC and pRCC. The result was a little different with our finding, and a possible reason may be that the size criterion of lesions was different: lesions in their study were bigger (<4 cm) than in our study (≤3 cm).

It is reported that pseudocapsule results from tumor growth producing compression, ischemia, and necrosis of adjacent normal parenchyma, with subsequent deposition of fibrous tissue [1]. It is almost exclusively seen in early-stage, low grade RCC. In our study, more percentage of pseudocapsule was detected in pRCC and chRCC than in ccRCC. Investigators have reported that CEUS imaging could improve the sonographic visualization of pseudocapsule, which could be useful both in the preoperative diagnosis and in the choice of conservative surgery for RCC [1, 34].

It should be acknowledged that there are several limitations in our study. First, it was a retrospective study and might have some degree of selection bias because we studied only pathologically confirmed RCC cases. Second, this is a qualitative and subjective study, further quantitative analysis with special software is necessary, especially for the differentiation between pRCC and chRCC. Third, we only studied three most common subtypes of RCC, and other rare subtypes were not included.

In conclusion, CEUS was a useful method to preoperatively differentiate the ccRCC from non-ccRCC subtypes. The value of CEUS in distinguish between pRCC and chRCC was limited, and further quantitative analysis is urgently needed.

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