The quantitative evaluation of contrast-enhanced ultrasound in the differentiation of small renal cell carcinoma subtypes and angiomyolipoma

Introduction

Renal cell carcinoma (RCC) is the most prevalent primary renal malignancy that usually requires invasive treatment such as nephrectomy or partial nephrectomy and accounts for nearly 2% of all adult cancers worldwide (1). The most common subtypes are clear cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (pRCC), and chromophobe renal cell carcinoma (chRCC), comprising 70–80%, 10–15%, and 5–10% of all RCC cases, respectively (2-4). ccRCC is the most frequent, with higher rates of invasiveness and metastasis, while pRCC and chRCC are relatively rare and have better prognoses, with 5-years survival rates of 55–60%, 80–90%, and 80–100%, respectively (5,6). Angiomyolipoma (AML) is the most common benign renal neoplasm, which requires only conservative management and active surveillance. Most scholars define renal tumors with a maximum diameter <4 cm as small renal masses (7). In recent years, increasing numbers of small RCC are being detected due to advancements in modern medical imaging technology (8). Differentiating histological classification of renal tumors is of great significance to clinical treatment decision-making and prognostic evaluation. However, it is independently difficult to characterize a small RCC using conventional magnetic resonance imaging (MRI) and computed tomography (CT) due to their low temporal resolutions. Thus, B-mode ultrasound (B-mode US) should be the preferred choice for renal tumor screening, but it is limited to differentiating a small RCC from an AML (9). Fortunately, contrast-enhanced ultrasound (CEUS), a relatively new imaging technology, has the advantage of being minimally invasive, real-time, dynamic, readily accessible, and free from the radioactive and nephrotoxic properties of contrast agents. Furthermore, CEUS has a high sensitivity for avoiding false-negative cases, which saves resources without compromising effectiveness and leaves more CT or MRI availabilities for other patients in need. Thus, CEUS is more cost-effective than MRI or CT (10-12).

At present, there are more reports on CEUS qualitative analysis for oncological imaging (13), cysts (14), solid lesions (15), and pseudotumors (16). Lu et al. (9) found that both centripetal enhancement in the cortical phase (71.9% vs. 23.2%) and homogeneous peak enhancement (100% vs. 27.5%) were important for differentiating an AML from a ccRCC. Some researchers have reported that ccRCC is mainly characterized by heterogeneous hyperperfusion, while pRCC and chRCC mostly feature homogeneous hypoperfusion (17,18). In our more recent study, it was found that hyperenhancement (64/81, 79.0%), homogeneous enhancement (54/81, 66.7%), fast wash-out (WO) (63/81, 77.8%), and peripheral rim-like enhancement (PRE) (45/81, 55.6%) were the typical features of small RCC (19). To the extent known, some imaging findings, including enhancement intensity (hyper-, iso-, hypo-), homogeneity (homogeneous, heterogeneous), and perilesional rim-like enhancement (present, absent), are all subject to examinations with low reproducibility. Therefore, an objective quantitative analysis is of great significance to the differentiation of small RCC subtypes and AML, and CEUS quantitative parameters are of significant importance to the differentiation of small RCC subtypes and AML (6,9,20).

Some studies have reported that CEUS has value in differentiating RCC subtypes and AML (21,22), but no reports investigate its benefit in the differentiation of different small renal lesions. Thus, the present study aims to investigate the usefulness of the quantitative parameters of CEUS in the differential diagnosis of small RCC subtypes and AML.

Methods

Patient selection

The ethical committee approved this single-institution retrospective study of Huadong Hospital (No.: 20160045) with written informed consent from all patients. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Between June 2015 and December 2019, 97 small renal masses in 97 consecutive patients were admitted to Huadong Hospital. Enrolled in the study were 85 RCCs (67 males and 18 females, ages ranging from 35–87 years, mean 60.5±12.1 years) and 12 AMLs (5 males and 7 females, ages ranging from 37–68 years, mean 54.8±8.6 years), with each patient having undergone preoperative B-mode US and CEUS. Inclusion criteria were as follows: (I) mass size less than 4 cm; (II) mass depth less than 10 cm; (III) patient having undergone CEUS before a radical or partial nephrectomy; (IV) mass pathologically confirmed the RCC or AML. Exclusion criteria were: (I) history of cardiac failure or respiratory disorders; (II) any patient having undergone invasive treatments before the CEUS; (III) incomplete video recordings of the CEUS procedure; (IV) mass was not pathologically confirmed or pathologically confirmed as another benign or malignant tumor.

Image examination

All included patients underwent B-mode US and CEUS examinations before surgery, using an ultrasound scanner (Aplio 500, Toshiba Medical Systems, Otawara, Japan) with a convex array transducer (4C1 probe, 3–5 MHz, mechanical index <0.10). Both B-Mode US and CEUS examinations were performed by the same radiologist from our hospital (CL), who has 18 years of experience in kidney US and 14 years in kidney CEUS. B-mode US and color Doppler flow imaging (CDFI) were used to obtain the tumors' location, size, shape, margin, orientation, echogenicity, homogeneity, and blood flow signals. The B-mode US examinations obtained the optimal view presenting the renal lesions and normal surrounding adjacent parenchyma. For each patient, CEUS was performed after a B-Mode US examination, using the same scanning system. During the CEUS examination, the US contrast agent, SonoVue (Bracco, Milan, Italy), which is a sulfur hexafluoride (SF6) microbubble stabilized by phospholipids, was shaken with 5 mL normal saline into a microbubble suspension. The amount of contrast agent ranged from 1.6–2.4 mL depending on patient height, weight, and age. A bolus of contrast agent was injected into the antecubital vein via a 20-gauge needle, followed by a 5 mL flush of 0.9% saline. A timer and video recorder were started at the same time as the contrast agent was injected. Patients were required to hold their breaths for as long as possible, with slow, shallow breathing allowed for any patient unable to hold their breath. Real-time dynamic images were observed continuously for at least 2–3 minutes following each injection. If necessary, repeat injections were administered after the contrast dissipated. The images and video recordings of each completely recorded CUS and CEUS examination were stored on the hard disk for subsequent analysis.

Quantitative imaging analysis of CEUS

Clicking the key of time curve analysis (TCA), the quantitative analysis software equipped within Aplio 500 systems was used to analyze every complete CEUS cine-loop for each renal lesion by a different radiologist from the previous clinician and was unaware of the identities of the patients. First, a region of interest (ROI) was, as much as possible, placed in the tumor’s maximum enhanced region (ROI_max), avoiding any surrounding renal parenchyma or large feeding vessels. Then, the adjacent renal cortex (ROI_refer) was selected from normal renal tissue around the mass in the same depth. In very small lesions, the ROI_max would cover the whole tumor. Thus, a ROI_tumor was used instead of a ROI_max. In relatively large lesions, especially in ccRCC, areas of necrosis are more likely to occur in the mass. Therefore, a ROI_max was used to represent a tumor's most vascularized area. The software's motion tracking technology was used to track the movement of an ROI in real-time (the error caused by tissue movement in the scanning plane can be corrected manually if necessary). We also obtained the quantitative parameters of the TIC of the ROI_max and the ROI_refer, which included: the peak intensity (PI), slope (SL), area under the curve (AUC), area under the wash-in curve (AWI), area under the wash-out curve (AWO), time to peak intensity (TTP) and mean transit time (MTT). Then we calculated subtractions of the TIC parameters between the ROI_max and the ROI_refer, including the △PI, △TTP, △MTT, △SL, △AUC, △AWI, and △AWO. The differences between the subtractions of the ROI_max and the ROI_refer parameters were compared among different small renal lesions.

Reference standard

Fifty-six patients underwent radical nephrectomy, and 41 patients underwent a partial nephrectomy depending to the size and location of their renal lesion. The specimens of 97 renal lesions were obtained, and histopathological examinations were performed on each. The histopathological results for the renal lesions were used as a reference standard.

Statistical analysis

IBM SPSS software (Version 22.0, IBM Corp., Armonk, NY, USA) and MedCalc software (Version 15.2.2, Ostend, Belgium) were used for all statistical analyses, and continuous variables were expressed as mean values ± standard deviation (SD). Discrete variables were expressed as numbers and percentages, and the differences of clinical features between RCC, AML, and RCC subtypes were analyzed using the χ² test. A paired sample t-test compared the quantitative parameters of CEUS between the ROI_max and the ROI_refer. Subtractions in CEUS quantitative parameters between the ROI_max and the ROI_refer of benign renal masses, malignant renal masses, and different RCC subtypes were examined by a normality test. Variables following normal distribution were compared using an independent sample t-test, while variables not following normal distribution were compared using a Mann-Whitney U test. Finally, a receiver operating characteristic (ROC) curve of the single parameter subtraction and combined parameter subtractions between the ROI_max and the ROI_refer was drawn based on the pathological diagnosis. The sensitivity, specificity, and AUC for differentiating small RCC subtypes and AML were then obtained, with a P value <0.05 considered statistically significant.

Results

Clinical and pathological findings

In this study, pathology results were obtained following the radical (n=56) or partial nephrectomy (n=41) procedures of 97 small renal masses in 97 patients (Table 1). Of the 97 masses, 85 were RCCs (size ranging from 13–40 mm, mean size of 28.8±7.1 mm), including 71 ccRCCs, 7 pRCCs, 7 chRCCs, and several AMLs (size ranging from 11–40 mm, mean size of 22.5±9.7 mm). Significant differences were noted between RCC and AML in terms of gender (P=0.016), with males having higher RCC percentages than AML (78.8% versus 41.7%). However, there were no significant differences in location (left, right, upper, middle, lower) or surgical methods (radical or nephrectomy) among the different histological types of small renal masses (P>0.05).

The results of the quantitative parameters of CEUS

The quantitative parameters of the different small renal lesions between the ROI_max and the ROI_refer are shown in Table 2. All ROI_max from the different types of small renal lesions were compared with a ROI_refer found at the same depth. In the cases of RCC or ccRCC, the PI, SL, AUC, AWI, and AWO of the ROI_max were higher than those seen in the ROI_refer (all P=0.000), while the TTP and MTT of the ROI_max were shorter than those from the ROI_refer (all P=0.000) (Figure 1). In the cases of pRCC, the MTT of the ROI_max was shorter than in the ROI_refer (P=0.032), and the AUC and AWO of the ROI_max were lower than in the ROI_refer (P=0.025, 0.014, respectively) (Figure 2). In chRCC, the TTP and MTT of the ROI_max were shorter than that of the ROI_refer (P=0.020, 0.026, respectively) (Figure 3). As for AML, the SL of the ROI_max was lower than seen in the ROI_refer (P=0.031), while the TTP and MTT of the ROI_max were longer than in the ROI_refer (P=0.013, 0.017, respectively) (Figure 4).

Figure 1 A 57-year-old woman with clear cell renal cell carcinoma. (A) B-Mode US showing a hypoechoic mass located in the lower pole of the left kidney (arrows); (B) color Doppler flow imaging show rich blood flow signals in and around the tumor; (C) time-intensity curve showing comparison of ROI_refer(green) and ROI_tumor(magenta). ROI_max (yellow) is fast wash-in, fast wash-out and hyper-enhanced; (D) photomicrograph showing the tumor pseudocapsule (asterisk) between the mass (M) and normal kidney (N). (Hematoxylin and eosin stain, ×80). ROI, region of interest.

Figure 2 Forty-six-year-old man with papillary renal cell carcinoma. (A) B-Mode US showing a hypoechoic mass located in the middle of the left kidney (arrows); (B) color Doppler flow imaging show there was no blood flow signal in the tumor; (C) time-intensity curve showing comparison of ROI_refer(green). ROI_tumor(magenta) is fast wash-in, fast wash-out and hypoenhanced; (D) photomicrograph showing the tumor pseudocapsule (asterisk) between the mass (M) and normal kidney (N). (Hematoxylin and eosin stain, ×80). ROI, region of interest.

Figure 3 Sixty-two-year-old man with chromophobe renal cell carcinoma. (A) B-Mode US showing a hypoechoic mass located in the lower of the right kidney (arrows); (B) color Doppler flow imaging show there was no blood flow signal in the tumor; (C) time-intensity curve showing comparison ofROI_refer(green) and ROI_tumor(magenta). ROI_max (yellow) is fast wash-in, fast wash-out and hypoenhancd; (D) photomicrograph showing the tumor pseudocapsule (asterisk) between the mass (M) and normal kidney (N). (Hematoxylin and eosin stain, ×80). ROI, region of interest.

Figure 4 Sixty-five-year-old woman with renal angiomyolipoma. (A) B-Mode US showing a hyperechoic mass located in the lower of the left kidney (arrows); (B) color Doppler flow imaging showing no sign of blood flow in the tumor; (C) time-intensity curve showing comparison of ROI_refer(green). ROI_tumor(magenta) is slow wash-in, slow wash-out and hypoenhanced; (D) photomicrograph showing the tumor contained thick-walled blood vessels, smooth muscle, and fat tissue. (Hematoxylin and eosin stain, ×100). ROI, region of interest.

The comparison of quantitative parameter subtractions between a ROI_refer and the ROI_max of different small renal lesions is shown in Table 3. The △PI, △SL, △AUC, △AWI, △AWO, △TTP, and △MTT differed significantly for AML and RCC (all P<0.05). Compared with pRCC and chRCC, in ccRCC, the △PI, △SL, △AUC, and △AWO were all larger (all P<0.05), while there was no statistical significance in the △TTP, △MTT, and △AWI. Likewise, there were no significant differences between pRCC and chRCC (all P>0.05).

The results show that the sensitivity, specificity, and AUC of the combination of quantitative parameter subtractions for differentiating small RCC from AML were 100%, 81.2%, and 0.965, respectively (Table 4), while the AUC of the combination of quantitative parameter subtractions for differentiating ccRCC from pRCC and chRCC was 0.911, with 85.71% sensitivity, and 85.92% specificity (Table 5).

Discussion

CEUS has unique advantages over other imaging modalities. Quantitative CEUS provides objective perfusion characteristics of renal lesions with excellent reproducibility, reducing the operator dependency of beginners by decreasing subjective errors and contributing to stable and reliable results (20,23). In our study, compared with a ROI_refer, the degree of RCC perfusion was higher and the contrast enhancement mode used was “fast-in and fast-out” (Figures 1-3). As for AML, the degree of perfusion was lower, and the contrast enhancement mode used was “slow-in and slow-out” (Figure 4). These characteristics were due to a correlation with the neovascularization of renal lesions. Neovascularization is closely related to tumor growth, invasion, metastasis, and recurrence (24) and is significantly different from what is seen in normal blood vessels. Blood volume is a direct marker reflecting tumor angiogenesis (25). Micro-vessel density (MVD) is the “gold standard” for the quantitative evaluation of neovascularization in tumors, but it is an invasive operation that obtains tissue specimens by surgery or puncture (26). Fortunately, TIC parameters reflect the change of ROI enhancement intensity with the time-variation after the injection of the contrast medium. Multiple parameters of blood perfusion can be extracted for quantitative analysis.

RCC is an abundant blood supply tumor with high density and thin-walled blood vessels, leading to an accelerated circulation of contrast medium and shortening perfusion and clearance. AML is characterized by malformed blood vessels, irregularly thickened walls, and narrow lumens, resulting in the slow circulation of the contrast agent and long perfusion and clearance (17,18,27). Dai et al. (28) demonstrated that the peak intensity of a tumor (PI_t) and the time to peak intensity of a tumor (TTP_t) between benign and malignant lesions were both statistically significant (P=0.003. P=0.000, respectively), indicating that the perfusion of malignant lesions was higher and the time to intensity was shorter, compared with benign lesions. Our study obtained similar results to these. Sun et al. (6) used the Δ PI% [PI% = (PI_t – PI_refer)/PI_refer ×100%] to correct the enhancement degree and compared the Δ PI% of 74 malignant lesions and 19 benign lesions. The results showed a significant difference between RCC and AML in terms of Δ PI% (P<0.001). Common findings of an RCC include intratumoral necrosis, hemorrhage, and calcification, which could not reflect the perfusion of tumor parenchyma. Therefore, in our study, a ROI_max representing the most vascularized area within the tumor has a unique advantage over a tumor’s enhanced region (ROI_tumor) when compared with a ROI_refer. Further analysis of the ROI_tumor among renal histotypes was not performed. We concluded that all indices (△PI, △SL, △AUC, △AWI, △AWO, △TTP, and △MTT) differed significantly between RCC and AML, with reliable diagnosis efficiency. The sensitivity, specificity, and AUC of the combination of parameter subtractions for differentiating RCC from AML were 100%, 81.2%, and 0.965, respectively (Table 4).

The incidence rate of ccRCC is the highest of the RCC subtypes, with high malignancy and a poor prognosis, while the incidence rates of pRCC and chRCC are relatively low and have lower malignancies and better prognoses. Li et al. (21) compared the △PI and △MTT obtained from the CEUS quantitative analysis of 341 RCCs (280 ccRCCs, 28 pRCCs, and 33 chRCCs) and 88 AMLs. The results showed that the △PI of the different histological types of renal tumors presents a trend of ccRCC > AML > pRCC = chRCC, and a trend of △MTT was AML > pRCC = chRCC = ccRCC. Similar results were obtained in our study. On this basis, we calculated the TIC parameter subtractions between the ROI_max and the ROI_refer and drew a ROC curve based on the pathological diagnosis to get the sensitivity, specificity, and AUC of the combination of parameters subtractions to diagnose RCC subtypes and AML. Lu et al. (22) compared the tumor-to-cortex intensity ratio (TOC-ratio) obtained by the CEUS quantitative analysis of 106 ccRCCs, 25 pRCCs, 28 chRCCs, and 34 AMLs. The results showed that pRCC = chRCC < AML < ccRCC. Our study found that the △PI, △SL, △AUC, △and AWO of ccRCC were significantly larger than in pRCC and chRCC. The △TTP, △MTT, and △AWI showed no significant difference, and there was also no significant difference between pRCC and chRCC. Our study showed that the blood volume parameters of ccRCC were higher than in other RCC subtypes, while blood volume time-correlated parameters were shorter, reflecting the maximum blood volume and the highest micro-vessel density. These features were associated with ccRCC, a rich blood supply tumor with a large microvascular diameter, and distorted, interrupted, irregular, and dense blood vessels, and arteriovenous fistulas (29). pRCC and chRCC are low-grade RCC with low enhancement, with characteristics relating to pRCC being a hypovascular tumor with a small microvascular caliber and no large vessels or arteriovenous fistulas. chRCC cells show compact growth and parameters of perfusion intensity that are most consistent with those of pRCC. In this study, compared with pRCC and chRCC, the △TTP, △MTT, △AWI of ccRCC were not statistically significant (P>0.05), potentially related to the selection bias of the recruited cases or similar poor vascularization. Larger △PI, △SL, △AUC, and △AWO can differentiate a ccRCC from both pRCC and chRCC with a reliable diagnosis efficiency (the area under the ROC curve was 0.849, 0.854, 0.905, and 0.900, respectively). The sensitivity, specificity, and AUC of the combination of these parameter subtractions for differentiating ccRCC from pRCC and chRCC were 85.71%, 85.92%, and 0.911, respectively.

It is worth noting that CEUS alone will not fully identify benign and malignant renal masses. For example, an AML can be expressed as high enhancement, which is difficult to identify with an RCC. Therefore, it is necessary to identify AML from RCC with hyperechogenicity in the B-Mode US and without circular perfusion in CEUS qualitative features (30). Furthermore, although it is difficult to distinguish between pRCC and chRCC by CEUS qualitative characteristics and quantitative parameters, chRCC is more likely to have a central scar, cystic changes, and necrosis than pRCC (31). Therefore, in clinical work, a combination of B-mode US, CEUS qualitative characteristics, and TIC quantitative parameters are needed to evaluate renal tumors comprehensively.

In recent research, Spiesecke et al. (32) indicated that a shrunken kidney, which gives the kidney and lesion a greater distance from the body’s surface and smaller lesion size, may impair the image quality of CEUS examinations, while exophytic growth of a focal renal lesion results in better image quality. In our study, a “mass depth of less than 10 cm” and a “mass size of less than 4 cm” were included, and lesion sizes ranged from 11–40 mm, corresponding to a better TIC assessment. The TIC parameters can be used to study the perfusion of RCC subtypes and AML, making the results more objective (19). However, there are some limitations. First, the numbers of AML were fewer than the RCC, and the numbers of pRCC and chRCC were also fewer than the ccRCC. Therefore, prospective studies with larger numbers of AML, pRCC, and chRCC are required to verify our results. Second, the Gain value was considerably different in our study, which may influence the intensity parameters of CEUS and represent a technical limitation. Due to individual variations such as a patient’s girth and the penetration depth of renal lesions, the Gain value varied in the imaging of different lesions. Therefore, we used a Q Scan to avoid this difference to acquire the highest quality image possible. Third, in very small lesions, the ROI was placed to cover the whole tumor, but in relatively large lesions, the ROI should be placed in the highest vascularized areas as possible, avoiding areas of necrosis. These limitations may influence the assessment of tumor vascularization in general and represent a technical limitation. We performed a pathological diagnosis on all cases by radical or partial nephrectomy, but tumor microvessel density was not detected. Therefore, prospective studies are needed to verify our results. Moreover, our study did not include other benign masses (for example, oncocytoma) or other malignant (for example, metastases or lymphoma) histotypes. Further studies should be performed for the differentiation of additional renal tumor histotypes.

Conclusions

In summary, CEUS quantitative parameters can help the differentiation of small RCC and AML. Although it cannot distinguish between pRCC and chRCC, these parameters help to distinguish ccRCC, which has relatively higher malignancy, from pRCC and chRCC, which have higher △PI, △SL, △AUC, and △AWO.

Acknowledgments

Funding: This work was supported by funds from the Shanghai Municipal Health and Family Planning Commission of China (201640285).

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/qims-21-248). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the ethical committee of Huadong Hospital with written informed consent from all included patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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