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Evaluation of upper tract urothelial carcinomas by contrast-enhanced ultrasound
Radiología. 2018;60(6):496---503
www.elsevier.es/rx
ORIGINAL ARTICLE
Evaluation of upper tract urothelial carcinomas by contrast-enhanced ultrasound夽 A.A. Painel Seguel ∗ , M.J. Martínez Pérez, T. Ripollés González, D.P. Gómez, J. Vizuete del Río, G. Martín Benítez Servicio de Radiodiagnóstico, Hospital Universitario Doctor Peset, Valencia, Spain Received 22 November 2017; accepted 25 July 2018
KEYWORDS Transitional cell carcinoma; Ureter; Upper urinary tract; Contrast agents; Contrast-enhanced ultrasound; Microbubbles
Abstract Aim: To describe the findings and behaviour of contrast-enhanced ultrasound in the study of upper tract urothelial tumours and to assess its usefulness for diagnosis. Material and methods: We reviewed our hospital’s database over a period of 45 months to identify patients diagnosed with upper tract urothelial carcinomas. We reviewed the findings on mode B-ultrasound, contrast-enhanced ultrasound (location and qualitative assessment of intensity and washout of enhancement), and made a comparison with other techniques (computed tomography or magnetic resonance), and with the surgical specimen. Results: We found 42 patients with a diagnosis of upper tract urothelial carcinoma confirmed with surgery over the period reviewed. Twenty-eight (67%) patients underwent contrastenhanced ultrasound. Baseline ultrasound showed hydronephrosis with or without ureteral dilatation with echogenic content occupying the renal calyx (6), pelvis (10) or ureter (12). After injection of contrast, enhancement was noticed in 100% of the lesions, with similar intensity to the cortex in 23, and less in 5. Twenty-four lesions showed early washout, before the cortex, between 40 and 55 s after the injection. The diagnosis was correct in 27 cases. Localisation coincided with the histological specimen in 28 cases, and 3 patients had additional distal carcinoma foci. Conclusion: Contrast-enhanced ultrasound is a useful technique for diagnosing upper tract urothelial tumours that increases confidence in the diagnosis. © 2018 SERAM. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
夽
Please cite this article as: Painel Seguel AA, Martínez Pérez MJ, Ripollés González T, Gómez DP, Vizuete del Río J, Martín Benítez G. Valoración del carcinoma urotelial de vías superiores mediante ecografía con contraste. Radiología. 2018;60:496---503. ∗ Corresponding author. E-mail address: [email protected] (A.A. Painel Seguel). 2173-5107/© 2018 SERAM. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
Evaluation of upper tract urothelial carcinomas by contrast-enhanced ultrasound
PALABRAS CLAVE Carcinoma de células transicionales; Uréter; Tracto urinario superior; Medios de contraste; Ecografía con contraste; Microburbujas
497
Valoración del carcinoma urotelial de vías superiores mediante ecografía con contraste Resumen Objetivo: Describir los hallazgos y el comportamiento de la ecografía con contraste en el estudio de los tumores uroteliales de vías superiores y evaluar su utilidad en el diagnóstico. Material y métodos: Se revisa la base de datos de nuestro hospital en un periodo de 45 meses para identificar los pacientes con diagnóstico de carcinoma urotelial de vías altas. Se revisan los hallazgos en la ecografía en modo B, ecografía con contraste (localización y valoración cualitativa de la intensidad y del lavado del realce) y se comparan con otras técnicas (tomografía computarizada o resonancia magnética) y con la pieza quirúrgica. Resultados: En el periodo revisado se encontraron 42 pacientes con diagnóstico de carcinoma urotelial de vías superiores confirmados con cirugía. Veintiocho (67%) pacientes tenían ecografía con contraste. La ecografía basal mostró hidronefrosis con o sin dilatación ureteral con ocupación por contenido ecogénico en cáliz renal (6), pelvis (10) o uréter (12). Tras la inyección de contraste se objetivó realce en el 100% de las lesiones, con intensidad similar a la cortical en 23 y menor en 5. Veinticuatro lesiones mostraron lavado precoz, antes que la cortical, entre los 40 y 55 segundos de la inyección. El diagnóstico fue correcto en 27 casos. La localización coincidió con la pieza histológica en 28 casos y 3 pacientes tenían focos de carcinoma distales adicionales. Conclusión: La ecografía con contraste es una técnica útil para el diagnóstico de tumor urotelial de vías altas que aumenta la confianza en el diagnóstico. © 2018 SERAM. Publicado por Elsevier Espa˜ na, S.L.U. Todos los derechos reservados.
Introduction Urothelial tumors are mostly found in the bladder being the 9th most common neoplasm of all.1 Upper tract urothelial carcinomas represent 5---10% and they are predominant in old males.2 Seventy five percent of these tumors are found in calyces and the renal pelvis, and only 25% of these carcinomas are found in the ureters.2,3 The diagnosis can be achieved incidentally or while studying micro or macroscopic hematuria as the most common symptom of presentation; flank pain is less common here. The computed tomography urography (CTU) and the magnetic resonance urography (MRU) are considered the most accurate diagnostic imaging modalities of all; the CTU is used as the first-line therapy while the MRU is used to avoid radiation in patients who should not be exposed to it or with declared allergies to iodinated contrasts.2 Yet despite these imaging modalities, diagnosis is sometimes based on indirect findings such as the thickening of reactive wall and the presence of ureterohydronephrosis, and not on the direct visualization of the lesion.3 The B mode ultrasound scan is the most commonly used imaging modality in the diagnostic study of patients with hematuria.4---7 Upper tract urothelial tumors appear as solid masses inside the echogenic renal sinus and they can be hyper, iso, or hypoechogenic with respect to it. Due to the fact that the echogenicity of pyelocalyceal tumors and renal sinus can be similar, the sensitivity of the ultrasound scan is limited and they are more easily seen as soft-tissue masses inside the echogenic renal sinus with associated hydronephrosis or
ureteral dilatation.4---6,8 The ultrasound scan makes suspicious or small sized-tumors4,8 and diffuse infiltrative renal masses difficult to find.8 On the other hand, the color Doppler ultrasound is not very useful for the identification of low flows and tumor vascularization is difficult to assess.8,9 The contrast-enhanced ultrasound is an imaging modality that has a established role in the characterization of hepatic masses and it is more and more widely used.9---12 It allows us to directly see the blood flow at the level of microvasculature and differentiate urothelial tumors from other causes of echogenic masses seen on the B mode ultrasound inside the excretory system such as blood clots or pus.3,8,9 The ultrasound contrast agent is merely intravascular, without the interstitial phase that iodinated or gadolinium-based contrast agents do have, and it is not cleared by the kidneys which is why there is no excretory phase. The advantages of this imaging modality are its lack of nephrotoxicity, the scarce incidence rate of adverse events, the lack of radiation involved, and the short time it takes to achieve diagnosis.9---14 Nevertheless, we should remember here that it is an operator-dependant technique and that in many nonhepatic uses, the applications of ultrasound contrast agents are usually off label.14 A few studies have been conducted to date assessing the utility of the ultrasound contrast agent in upper tract urothelial tumors though with a small number of patients or contradictory findings.3,8,15 We have not found any studies or papers published in Spanish language on this issue. The goal of this study is to describe the findings and evaluate the performance of the contrast-enhanced ultrasound
498 scan of upper tract urothelial carcinomas. Also, assess its diagnostic utility.
Material and methods Retrospective study that reviewed our hospital database to identify the cases with a diagnosis of upper tract urothelial carcinoma including ureters from January 2009 through September 2013. Since this was a retrospective study with data anonymization and since the imaging modalities were used with diagnostic purposes only, our hospital ethics committee deemed it unnecessary to obtain the patients’ informed consent. Only patients with anatomo-pathologically confirmed urothelial carcinomas were included in the study. Both the B mode ultrasound and the contrast-enhanced ultrasound scans were reviewed retrospectively. Patients without an ultrasound contrast agent study were excluded, even if the tumor was found on the B mode ultrasound. Conducting the ultrasound contrast agent study was decided by the radiologist in a non-protocolized fashion after finding suspicious tumor images on the B mode ultrasound. The ultrasonographic study with contrast was conducted using two (2) ultrasound machines: Aplio 80 (Toshiba, Tokyo, Japan) and Acuson Sequoia 512 (Siemens, Munich, Germany). A second-generation ultrasound contrast agent was used ® (sulfur hexafluoride, Sonovue Bracco International B.V., Amsterdam, The Netherlands) through the injection of 1.2/2.4 ml of contrast via the antecubital vein, or through a three-way stopcock followed by one bolus of saline solution at 0.9%. Patients were examined using one 3---4 MHz convex transducer and the pulse-inversion technique and a 60 s video was recorded of it all whose timer started just when the contrast started to be administered. Image visualization using double layers was activated and arranged with the contrast image on the left whereas the gray-scale ultrasound images remained on the right. The contrast-enhanced ultrasound scans were conducted by four (4) radiologists with different experience conducting this imaging modality (between 6 and 12 years of experience). Two (2) observers reviewed both the images and the video by consensus and assessed the location of the tumor on the baseline ultrasound and the contrast-enhanced ultrasound scan, the presence of enhancement, the intensity of lesion enhancement in relation to the cortex and the washout in relation to the parenchyma. The intensity of enhancement and the washout were assessed qualitatively and no time intensity curve shape analysis was conducted. Both parameters were compared to the enhancement of the adjacent renal cortex and the peak enhancement of the lesions was considered of higher, equal, or lower intensity compared to the cortex.8 Similarly, the washout pattern was considered faster, equal or slower compared to the renal cortex.8 The correlation with the histological tumor grade or other imaging modalities such as the CTU or the MRU was studied too. The histological tumor grade was assessed according to the classification established by the World Health Organization (WHO) back in 2004.16 The CTU consisted of one phase without contrast and, after the administration of IV
A.A. Painel Seguel et al. contrast, one nephrographic phase at 90 s, and one excretory phase at 8 min. On the MRU, precontrast T1 and T2 sequences were used and, after the administration of contrast, coronal T1-weighted sequences at 40 s and then at 3 min, and the whole process was repeated until the entire ureter could be visualized. The data was stored in one database built for this purpose using basic descriptive statistical patterns (continuous variables: mean ± standard deviation and range; qualitative variables: absolute frequence and percentage). Fisher’s exact test was used to compare the degree of enhancement or washout of the histological tumor grades (high and low). The high and low degree measures of time and washout were compared using the Mann---Whitney U test. The statistical software SPSS version 20.0 was used to conduct all statistical calculations. P values <0.05 were considered statistically significant.
Results The period reviewed included 42 patients with a diagnosis of upper urinary tract urothelial carcinomas including surgical and anatomo-pathological confirmed ureters. The contrastenhanced ultrasound scan was not conducted in 14 patients --- in 3 of them because it had not been visualized on the B mode ultrasound. Twenty-eight (67%) patients underwent one contrastenhanced ultrasound scan after the tumor was found on the baseline ultrasound scan, corresponding to the patients included in the study. Twenty-two (78%) males and 6 females with an average age of 67 ± 10.6 years (range: 41---84 years old) were selected showing mostly monosymptomatic hematuria (18 cases, 64%), and less frequently back pain (n = 3), constitutional syndrome (n = 3), hematuria and back pain (n = 2) or incidental finding (2 cases). As part of the diagnostic study, one CT scan was conducted in all patients --- in one of them one MRI was conducted too. The anatomo-pathological analysis conducted on the specimen obtained through radical nephroureterectomy revealed that 21 (75%) patients suffered from high grade urothelial carcinomas and 7 (25%) patients from low grade urothelial carcinomas. The basaline ultrasound scan conducted confirmed the presence of hydronephrosis with or without ureteral dilatation filled with echogenic content that became enhanced after the administration of contrast in 100% of the lesions. After the contrast study, all patients except for one were given an ultrasound diagnosis of tract tumor with the ultrasound examination report stapled to the patient’s clinical history and available for his doctor. In the other patient and after conducting an ultrasound scan, a differential diagnosis between inflammatory process or upper tract tumor was proposed. These were the locations of the tumors: renal calyx (n = 6), renal pelvis (n = 10) and upper (n = 4), mid (n = 7) or distal (n = 1), ureter (n = 12). Three (3) patients showed additional distal carcinoma foci found on the CT scan and/or the surgical specimen. The location was consistent with the histological specimen and/or with the CTU/MRI in all the cases (Fig. 1). The intensity of enhancement at the moment of peak enhancement was similar or higher to the renal cortex in 23 (82%) cases and lower
Evaluation of upper tract urothelial carcinomas by contrast-enhanced ultrasound
499
Figure 1 77-year-old woman with high grade urothelial carcinoma located in a calyx. (A) B mode ultrasound with hypoechoic lesion in the renal sinus (arrow). (B) Contrast-enhanced ultrasound scan showing nodular enhancement similar to the cortex inside the dilated calyx. (C) Maximum intensity projection (MIP) image of a computed tomography urography (CTU) scan in the excretory phase showing the partial amputation of the upper calyx (arrow). (D) Surgical specimen with calyceal polypoid mass of irregular edge (arrow) with a great correlation with the image of the contrast ultrasound.
Figure 2 65-year-old male with high grade papillary transitional cell carcinoma. (A) Baseline ultrasound showing one hypoechoic lesion in the pelvis and right proximal ureter (arrows). (B) After the administration of the ultrasound contrast agent one lesion appears more enhanced than the parenchyma. (C) Correlation with the excretory phase of CTU (MIP image) showing significant distorsion of the calyces with a mass occupying the entire renal pelvis (arrows).
in 5 cases (Figs. 2 and 3, Video 1). Twenty-four (86%) lesions showed an early washout prior to that of the renal parenchyma; this early washout was seen 40-55 s after the administration of contrast (Fig. 4). With contrast, two (2) patients showed reduced enhancement of most part of
the upper pole renal parenchyma associated with tumor infiltration. No significant differences were found in the intensity of enhancement or in the washout pattern between high and low grade tumors (p > 0.05). There were no statistically significant differences in the washout average time
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A.A. Painel Seguel et al.
Figure 3 54-year-old male with low grade urothelial carcinoma. (A) The B mode ultrasound shows a long hypoechoic mass in the renal sinus of the upper pole (arrows). (B) After the administration of the ultrasound contrast agent, we can see one mass in the renal sinus and upper pole infundibulum less enhanced than the parenchyma (arrows). CT scan in the corticomedullary (C) and excretory (D) phases confirming the presence of one hypodense urothelial carcinoma with respect to the parenchyma (arrows).
Figure 4 75-year-old male with low grade urothelial carcinoma with early washout. (A) B mode ultrasound showing echogenic content in the renal pelvis that conditions upper calyceal hydronephrosis. CTU in the nephrographic (B) and excretory (C) phases with MIP reconstruction showing one hypovascular mass in the renal sinus with amputation of part of the upper calyceal system and pelvis. (D and E) Ultrasound scan after the administration of IV contrast showing moderate enhancement of the mass with early washout at 40 s.
of any histological tumor grades. The findings are shown in Table 1.
Discussion The contrast-guided ultrasound allows us to make real time assessments of microvascularization8---11 with a tissue
perfusion resolution similar to that of the CT scan and the MRI.8,10 The use of the ultrasound contrast agent allows us to see the blood flow of small vessels3,8,9 to be able to identify urothelial tumors of urinary tract non-solid lesions such as blood clots or debris (Fig. 5).12 The use of the ultrasound contrast agent is limited by how difficult it is to
Evaluation of upper tract urothelial carcinomas by contrast-enhanced ultrasound
501
Table 1 Characteristics of the ultrasound contrast agent enhancement of upper tract urothelial tumors based on the histological tumor grade. Histological tumor grade
Phase of enhancement
Phase of contrast washout Washout time (s)
Same or more cortical intensity Less cortical intensity Early Late High grade (n = 21) Low grade (n = 7) p value
17 6 0.776
4 1 0.212
17 4 7 0 0.521
47 ± 10.9 43 ± 13.4
Figure 5 Comparison of two patients (A and B) one showing a blood clot in the tract and the other one (C and D) showing urothelial carcinoma. (A and C) B mode ultrasound of the two patients showing echogenic content inside both renal pelvis (arrows). (B and D) After the administration of the ultrasound contrast agent we can see the enhancement of the first patient (B) and confirm the presence of blood clots inside the urinary tract unlike the second patient whose enhancement suggests the presence of urothelial carcinoma (arrows) (D).
detect lesions on the B mode ultrasound, especially when no tract dilatation is found.8 The clinical guidelines established by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) back in 2017 include a recommendation to use contrast-enhanced ultrasound scans to distinguish solid renal lesions from pseudo-tumors. However, no reliable criteria have been published to date to achieve differential diagnosis among various solid lesions due to overlapping findings both in the qualitative and quantitative analyses without an explicit reference to urinary tract tumors.14 In the same year, Xue et al.8 conducted a retrospective study of 52 patients that did not include ureters in which practically all tumors showed enhancement (94.2%). Among them 77.6% became less enhanced, 12.2% equally enhanced and 10.2% more enhanced than the renal cortex. In our study, all tumors became enhanced after the administration of the ultrasound contrast agent, but unlike Xue’s study, most of them (86%) did so equally or more than the renal cortex --- a fact that may be due to the high sensitivity of the contrast agent when it comes to finding microvascularization. Xue’s study also conducted the qualitative assessment of washout time that was more precocious in the cortex
in 93.9% of the cases, something similar to our study that confirmed the early washout of the parenchyma in 24 cases (86%). Several studies have analyzed the value of ultrasound contrast agents to distinguish between high and low grade urothelial tumors. The findings published to date are contradictory. The degree of enhancement with time-intensity curve-shape analysis of high grade tumors was higher compared to low grade tumors in two (2) studies3,17 whereas in Fan Li et al.’s study, low grade tumors became more enhanced.15 Washout time was faster in low grade tumors in two (2) studies3,17 and no differences were found in a third study.15 Our study showed no statistically significant differences in the degree of enhancement or washout time reported between both histological grades. From a practical point of view, the differentiation between high and low histological grade can be important for the management of vesical tumor, but it will probably not change the therapeutic approach of upper tract tumors. Ultrasound contrast agents can identify unclear tumors found on the B mode ultrasound scan and significantly improve our trust in the diagnosis of tumors in the excretory duct. The characteristics of the initial enhancement of
502 the lesion found in the excretory duct and the early washout of contrast allow easier detections of this type of tumors.8 Conducting ultrasound scans our series found a large number of tumors in the ureter. It is generally thought that the value of the ultrasound scan in the assessment of ureteral cancer is limited since the ureter is never seen in completely.6,18 Due to its limited sensitivity, a negative ultrasound scan does not rule out the presence of upper tract urothelial carcinomas. However, in our opinion, if the ureter is dilated as it is the case with almost all ureteral neoplasms, we can see the cause in a large number of cases. When the ultrasound scan is the initial imaging modality for the assessment of hematuria, the upper tracts need to be carefully looked into because finding a tumor will shorten the times required for its diagnosis, staging and management. The findings of this study support the idea that the contrast-enhanced ultrasound scan may be used to diagnose upper tract tumors as an additional imaging modality to the CTU or MRU in cases of renal failure or contrast allergies. We think it may play a relevant role in the screening of patients with hematuria or other suspicious symptoms since it distinguishes between tumor and pseudo-tumor disease (such as the presence of blood clots or debris) in CT scans and MRIs without contrast.15 The fact that the real time analysis of the ultrasound contrast agent is more sensitive than the CT scan for the detection of tumor microperfusion may be useful for diagnostic purposes in cases where tumors do not become clearly enhanced on the CTU.15,19 One of the limitations that the contrast-enhanced ultrasound scan, the CTU or the MRU share is their incapacity to distinguish urothelial carcinomas from other less common types of tract tumors such as epidermoid tumors, adenocarcinomas or lymphomas, or even benign lesions such as tuberculosis. For instance, diffuse urothelial tumors infiltrating the renal parenchyma aggressively may be taken for renal cell carcinomas damaging the collecting system. Other limitations of the study have to do with its retrospective nature including the relatively small number of patients, and also that the evaluation of the contrast findings was qualitatively assessed by two (2) observers by consensus. Future studies may include independent qualitative evaluations conducted by several observers to assess variability in the interpretation of enhancement, or quantitative evaluations of tumor enhancement and its correlation with the histological tumor grade --- an issue only studied so far in urothelial tumors of the bladder.17,20 In sum, the findings of this study let us conclude that the use of ultrasound contrast agents is a promising imaging technique that improves diagnostic accuracy compared to the B mode ultrasound. This technique available in our setting is also easy to implement, and consolidates the diagnosis of upper tract urothelial tumors when observing lesions in enhanced pyelocaliceal systems and ureters being early washout with respect to the renal parenchyma a common phenomenon.
Authors 1. Manager of the integrity of the study: AAPS, MJMP and TRG. 2. Study idea: AAPS, MJMP, TRG, AAPS, DPG, JVR and GMB.
A.A. Painel Seguel et al. 3. Study design: AAPS, MJMP, TRG, DPG, JVR and GMB. 4. Data mining: AAPS, MJMP, TRG, DPG, JVR and GMB. 5. Data analysis and interpretation: AAPS, MJMP, TRG, DPG, JVR and GMB. 6. Statistical analysis: AAPS, MJMP, TRG and DPG. 7. Reference: AAPS, TRG and DPG. 8. Writing: AAPS, MJMP, TRG, DPG, JVR and GMB. 9. Critical review of the manuscript with intellectually relevant remarks: AAPS, MJMP, TRG, DPG, JVR and GMB. 10. Approval of final version: AAPS, MJMP, TRG, DPG, JVR and GMB.
Conflicts of interests The authors declare no conflicts of interests associated with this article whatsoever.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j. rxeng.2018.10.001.
References 1. Ploeg M, Aben KK, Kiemeney LA. The present and future burden of urinary bladder cancer in the world. World J Urol. 2009;27:289---93. 2. Roupret M, Babjuk M, Comperat E, Zigeuner R, Sylvester RJ, Burger M, et al. European Association of Urology guidelines on upper urinary tract urothelial cell carcinoma: 2015 update. Eur Urol. 2015;68:868---79. 3. Drudi FM, Di Candio G, Di Leo N, Malpassini F, Gnecchi M, Cantisani V, et al. Contrast-enhanced ultrasonography in the diagnosis of upper urinary tract urothelial cell carcinoma: a preliminary study. Ultraschall Med. 2013;34:30---7. 4. O’Connor OJ, Fitzgerald E, Maher MM. Imaging of hematuria. AJR Am J Roentgenol. 2010;195:W263---7. 5. Browne RF, Meehan CP, Colville J, Power R, Torreggiani WC. Transitional cell carcinoma of the upper urinary tract: spectrum of imaging findings. Radiographics. 2005;25:1609---27. 6. Vikram R, Sandler CM, Ng CS. Imaging and staging of transitional cell carcinoma: Part 2, upper urinary tract. AJR Am J Roentgenol. 2009;192:1488---93. ® 7. National Guideline C. ACR Appropriateness Criteria ; hematuria. Rockville MD: Agency for Healthcare Research and Quality (AHRQ); 2014. Available at: https://www.guideline.gov/ summaries/summary/49082 [updated in 2014; accessed on 18.11.17]. 8. Xue LY, Lu Q, Huang BJ, Li CL, Yan CJ, Wen JX, et al. Evaluation of renal urothelial carcinoma by contrast-enhanced ultrasonography. Eur J Radiol. 2013;82:e151---7. 9. Nicolau Molina C, Fontanilla Echeveste T, Del Cura Rodriguez JL, Cruz Villalon F, Ripolles Gonzalez T, Baudet Naveros B, et al. Usefulness of contrast-enhanced ultrasonography in daily clinical practice: a multicenter study in Spain. Radiologia. 2010;52:144---52. 10. Wilson SR, Greenbaum LD, Goldberg BB. Contrast-enhanced ultrasound: what is the evidence and what are the obstacles? AJR Am J Roentgenol. 2009;193:55---60. 11. Ripolles T, Puig J. Update on the use of contrast agents in ultrasonography: a review of the clinical guidelines of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB). Radiologia. 2009;51:362---75.
Evaluation of upper tract urothelial carcinomas by contrast-enhanced ultrasound 12. Nicolau C, Ripolles T. Contrast-enhanced ultrasound in abdominal imaging. Abdom Imaging. 2012;37:1---19. 13. Malhi H, Grant E, Duddalwar V. Contrast-enhanced ultrasound of the liver and kidney. In: Scoutt LM, editor. Update in ultrasound, vol. 52. Radiol Clin North Am; 2014. p. 1177---90. 14. Sidhu PS, Cantisani V, Dietrich CF, Gilja OH, Saftoiu A, Bartels E, et al. The EFSUMB guidelines and recommendations for the clinical practice of Contrast-Enhanced Ultrasound (CEUS) in non-hepatic applications: update 2017 (long version). Ultraschall Med. 2018;39:e2---44. 15. Li F, Bai M, Wu Y, He Y, Gu J, Xing J, et al. Comparative diagnostic performance of contrast-enhanced ultrasound versus baseline ultrasound for renal pelvis lesions. Ultrasound Med Biol. 2015;41:3109---19. 16. Lopez-Beltran A, Sauter G, Gasser T, Hartmann A, SchmitzDrager J, Helpap B, et al. Infiltrating urothelial carcinoma. In: Eble JN, Sauter G, Epstein JI, Sesterhenn IA, editors. World
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Health Organization Classification of Tumours. Pathology and genetics of tumours of the urinary system and male genital organs. Lyon: IARC Press; 2004. p. 93---9. Guo S, Xu P, Zhou A, Wang G, Chen W, Mei J, et al. Contrast-enhanced ultrasound differentiation between low- and high-grade bladder urothelial carcinoma and correlation with tumor microvessel density. J Ultrasound Med. 2017;36:2287---97. Froemming A, Potretzke T, Takahashi N, Kim B. Upper tract urothelial cancer. Eur J Radiol. 2018;98: 50---60. Ignee A, Straub B, Brix D, Schuessler G, Ott M, Dietrich CF. The value of contrast enhanced ultrasound (CEUS) in the characterisation of patients with renal masses. Clin Hemorheol Microcirc. 2010;46:275---90. Li Q, Tang J, He E, Li Y, Zhou Y, Wang B. Differentiation between high- and low-grade urothelial carcinomas using contrast enhanced ultrasound. Oncotarget. 2017;8:70883---9.
www.elsevier.es/rx
ORIGINAL ARTICLE
Evaluation of upper tract urothelial carcinomas by contrast-enhanced ultrasound夽 A.A. Painel Seguel ∗ , M.J. Martínez Pérez, T. Ripollés González, D.P. Gómez, J. Vizuete del Río, G. Martín Benítez Servicio de Radiodiagnóstico, Hospital Universitario Doctor Peset, Valencia, Spain Received 22 November 2017; accepted 25 July 2018
KEYWORDS Transitional cell carcinoma; Ureter; Upper urinary tract; Contrast agents; Contrast-enhanced ultrasound; Microbubbles
Abstract Aim: To describe the findings and behaviour of contrast-enhanced ultrasound in the study of upper tract urothelial tumours and to assess its usefulness for diagnosis. Material and methods: We reviewed our hospital’s database over a period of 45 months to identify patients diagnosed with upper tract urothelial carcinomas. We reviewed the findings on mode B-ultrasound, contrast-enhanced ultrasound (location and qualitative assessment of intensity and washout of enhancement), and made a comparison with other techniques (computed tomography or magnetic resonance), and with the surgical specimen. Results: We found 42 patients with a diagnosis of upper tract urothelial carcinoma confirmed with surgery over the period reviewed. Twenty-eight (67%) patients underwent contrastenhanced ultrasound. Baseline ultrasound showed hydronephrosis with or without ureteral dilatation with echogenic content occupying the renal calyx (6), pelvis (10) or ureter (12). After injection of contrast, enhancement was noticed in 100% of the lesions, with similar intensity to the cortex in 23, and less in 5. Twenty-four lesions showed early washout, before the cortex, between 40 and 55 s after the injection. The diagnosis was correct in 27 cases. Localisation coincided with the histological specimen in 28 cases, and 3 patients had additional distal carcinoma foci. Conclusion: Contrast-enhanced ultrasound is a useful technique for diagnosing upper tract urothelial tumours that increases confidence in the diagnosis. © 2018 SERAM. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
夽
Please cite this article as: Painel Seguel AA, Martínez Pérez MJ, Ripollés González T, Gómez DP, Vizuete del Río J, Martín Benítez G. Valoración del carcinoma urotelial de vías superiores mediante ecografía con contraste. Radiología. 2018;60:496---503. ∗ Corresponding author. E-mail address: [email protected] (A.A. Painel Seguel). 2173-5107/© 2018 SERAM. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
Evaluation of upper tract urothelial carcinomas by contrast-enhanced ultrasound
PALABRAS CLAVE Carcinoma de células transicionales; Uréter; Tracto urinario superior; Medios de contraste; Ecografía con contraste; Microburbujas
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Valoración del carcinoma urotelial de vías superiores mediante ecografía con contraste Resumen Objetivo: Describir los hallazgos y el comportamiento de la ecografía con contraste en el estudio de los tumores uroteliales de vías superiores y evaluar su utilidad en el diagnóstico. Material y métodos: Se revisa la base de datos de nuestro hospital en un periodo de 45 meses para identificar los pacientes con diagnóstico de carcinoma urotelial de vías altas. Se revisan los hallazgos en la ecografía en modo B, ecografía con contraste (localización y valoración cualitativa de la intensidad y del lavado del realce) y se comparan con otras técnicas (tomografía computarizada o resonancia magnética) y con la pieza quirúrgica. Resultados: En el periodo revisado se encontraron 42 pacientes con diagnóstico de carcinoma urotelial de vías superiores confirmados con cirugía. Veintiocho (67%) pacientes tenían ecografía con contraste. La ecografía basal mostró hidronefrosis con o sin dilatación ureteral con ocupación por contenido ecogénico en cáliz renal (6), pelvis (10) o uréter (12). Tras la inyección de contraste se objetivó realce en el 100% de las lesiones, con intensidad similar a la cortical en 23 y menor en 5. Veinticuatro lesiones mostraron lavado precoz, antes que la cortical, entre los 40 y 55 segundos de la inyección. El diagnóstico fue correcto en 27 casos. La localización coincidió con la pieza histológica en 28 casos y 3 pacientes tenían focos de carcinoma distales adicionales. Conclusión: La ecografía con contraste es una técnica útil para el diagnóstico de tumor urotelial de vías altas que aumenta la confianza en el diagnóstico. © 2018 SERAM. Publicado por Elsevier Espa˜ na, S.L.U. Todos los derechos reservados.
Introduction Urothelial tumors are mostly found in the bladder being the 9th most common neoplasm of all.1 Upper tract urothelial carcinomas represent 5---10% and they are predominant in old males.2 Seventy five percent of these tumors are found in calyces and the renal pelvis, and only 25% of these carcinomas are found in the ureters.2,3 The diagnosis can be achieved incidentally or while studying micro or macroscopic hematuria as the most common symptom of presentation; flank pain is less common here. The computed tomography urography (CTU) and the magnetic resonance urography (MRU) are considered the most accurate diagnostic imaging modalities of all; the CTU is used as the first-line therapy while the MRU is used to avoid radiation in patients who should not be exposed to it or with declared allergies to iodinated contrasts.2 Yet despite these imaging modalities, diagnosis is sometimes based on indirect findings such as the thickening of reactive wall and the presence of ureterohydronephrosis, and not on the direct visualization of the lesion.3 The B mode ultrasound scan is the most commonly used imaging modality in the diagnostic study of patients with hematuria.4---7 Upper tract urothelial tumors appear as solid masses inside the echogenic renal sinus and they can be hyper, iso, or hypoechogenic with respect to it. Due to the fact that the echogenicity of pyelocalyceal tumors and renal sinus can be similar, the sensitivity of the ultrasound scan is limited and they are more easily seen as soft-tissue masses inside the echogenic renal sinus with associated hydronephrosis or
ureteral dilatation.4---6,8 The ultrasound scan makes suspicious or small sized-tumors4,8 and diffuse infiltrative renal masses difficult to find.8 On the other hand, the color Doppler ultrasound is not very useful for the identification of low flows and tumor vascularization is difficult to assess.8,9 The contrast-enhanced ultrasound is an imaging modality that has a established role in the characterization of hepatic masses and it is more and more widely used.9---12 It allows us to directly see the blood flow at the level of microvasculature and differentiate urothelial tumors from other causes of echogenic masses seen on the B mode ultrasound inside the excretory system such as blood clots or pus.3,8,9 The ultrasound contrast agent is merely intravascular, without the interstitial phase that iodinated or gadolinium-based contrast agents do have, and it is not cleared by the kidneys which is why there is no excretory phase. The advantages of this imaging modality are its lack of nephrotoxicity, the scarce incidence rate of adverse events, the lack of radiation involved, and the short time it takes to achieve diagnosis.9---14 Nevertheless, we should remember here that it is an operator-dependant technique and that in many nonhepatic uses, the applications of ultrasound contrast agents are usually off label.14 A few studies have been conducted to date assessing the utility of the ultrasound contrast agent in upper tract urothelial tumors though with a small number of patients or contradictory findings.3,8,15 We have not found any studies or papers published in Spanish language on this issue. The goal of this study is to describe the findings and evaluate the performance of the contrast-enhanced ultrasound
498 scan of upper tract urothelial carcinomas. Also, assess its diagnostic utility.
Material and methods Retrospective study that reviewed our hospital database to identify the cases with a diagnosis of upper tract urothelial carcinoma including ureters from January 2009 through September 2013. Since this was a retrospective study with data anonymization and since the imaging modalities were used with diagnostic purposes only, our hospital ethics committee deemed it unnecessary to obtain the patients’ informed consent. Only patients with anatomo-pathologically confirmed urothelial carcinomas were included in the study. Both the B mode ultrasound and the contrast-enhanced ultrasound scans were reviewed retrospectively. Patients without an ultrasound contrast agent study were excluded, even if the tumor was found on the B mode ultrasound. Conducting the ultrasound contrast agent study was decided by the radiologist in a non-protocolized fashion after finding suspicious tumor images on the B mode ultrasound. The ultrasonographic study with contrast was conducted using two (2) ultrasound machines: Aplio 80 (Toshiba, Tokyo, Japan) and Acuson Sequoia 512 (Siemens, Munich, Germany). A second-generation ultrasound contrast agent was used ® (sulfur hexafluoride, Sonovue Bracco International B.V., Amsterdam, The Netherlands) through the injection of 1.2/2.4 ml of contrast via the antecubital vein, or through a three-way stopcock followed by one bolus of saline solution at 0.9%. Patients were examined using one 3---4 MHz convex transducer and the pulse-inversion technique and a 60 s video was recorded of it all whose timer started just when the contrast started to be administered. Image visualization using double layers was activated and arranged with the contrast image on the left whereas the gray-scale ultrasound images remained on the right. The contrast-enhanced ultrasound scans were conducted by four (4) radiologists with different experience conducting this imaging modality (between 6 and 12 years of experience). Two (2) observers reviewed both the images and the video by consensus and assessed the location of the tumor on the baseline ultrasound and the contrast-enhanced ultrasound scan, the presence of enhancement, the intensity of lesion enhancement in relation to the cortex and the washout in relation to the parenchyma. The intensity of enhancement and the washout were assessed qualitatively and no time intensity curve shape analysis was conducted. Both parameters were compared to the enhancement of the adjacent renal cortex and the peak enhancement of the lesions was considered of higher, equal, or lower intensity compared to the cortex.8 Similarly, the washout pattern was considered faster, equal or slower compared to the renal cortex.8 The correlation with the histological tumor grade or other imaging modalities such as the CTU or the MRU was studied too. The histological tumor grade was assessed according to the classification established by the World Health Organization (WHO) back in 2004.16 The CTU consisted of one phase without contrast and, after the administration of IV
A.A. Painel Seguel et al. contrast, one nephrographic phase at 90 s, and one excretory phase at 8 min. On the MRU, precontrast T1 and T2 sequences were used and, after the administration of contrast, coronal T1-weighted sequences at 40 s and then at 3 min, and the whole process was repeated until the entire ureter could be visualized. The data was stored in one database built for this purpose using basic descriptive statistical patterns (continuous variables: mean ± standard deviation and range; qualitative variables: absolute frequence and percentage). Fisher’s exact test was used to compare the degree of enhancement or washout of the histological tumor grades (high and low). The high and low degree measures of time and washout were compared using the Mann---Whitney U test. The statistical software SPSS version 20.0 was used to conduct all statistical calculations. P values <0.05 were considered statistically significant.
Results The period reviewed included 42 patients with a diagnosis of upper urinary tract urothelial carcinomas including surgical and anatomo-pathological confirmed ureters. The contrastenhanced ultrasound scan was not conducted in 14 patients --- in 3 of them because it had not been visualized on the B mode ultrasound. Twenty-eight (67%) patients underwent one contrastenhanced ultrasound scan after the tumor was found on the baseline ultrasound scan, corresponding to the patients included in the study. Twenty-two (78%) males and 6 females with an average age of 67 ± 10.6 years (range: 41---84 years old) were selected showing mostly monosymptomatic hematuria (18 cases, 64%), and less frequently back pain (n = 3), constitutional syndrome (n = 3), hematuria and back pain (n = 2) or incidental finding (2 cases). As part of the diagnostic study, one CT scan was conducted in all patients --- in one of them one MRI was conducted too. The anatomo-pathological analysis conducted on the specimen obtained through radical nephroureterectomy revealed that 21 (75%) patients suffered from high grade urothelial carcinomas and 7 (25%) patients from low grade urothelial carcinomas. The basaline ultrasound scan conducted confirmed the presence of hydronephrosis with or without ureteral dilatation filled with echogenic content that became enhanced after the administration of contrast in 100% of the lesions. After the contrast study, all patients except for one were given an ultrasound diagnosis of tract tumor with the ultrasound examination report stapled to the patient’s clinical history and available for his doctor. In the other patient and after conducting an ultrasound scan, a differential diagnosis between inflammatory process or upper tract tumor was proposed. These were the locations of the tumors: renal calyx (n = 6), renal pelvis (n = 10) and upper (n = 4), mid (n = 7) or distal (n = 1), ureter (n = 12). Three (3) patients showed additional distal carcinoma foci found on the CT scan and/or the surgical specimen. The location was consistent with the histological specimen and/or with the CTU/MRI in all the cases (Fig. 1). The intensity of enhancement at the moment of peak enhancement was similar or higher to the renal cortex in 23 (82%) cases and lower
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499
Figure 1 77-year-old woman with high grade urothelial carcinoma located in a calyx. (A) B mode ultrasound with hypoechoic lesion in the renal sinus (arrow). (B) Contrast-enhanced ultrasound scan showing nodular enhancement similar to the cortex inside the dilated calyx. (C) Maximum intensity projection (MIP) image of a computed tomography urography (CTU) scan in the excretory phase showing the partial amputation of the upper calyx (arrow). (D) Surgical specimen with calyceal polypoid mass of irregular edge (arrow) with a great correlation with the image of the contrast ultrasound.
Figure 2 65-year-old male with high grade papillary transitional cell carcinoma. (A) Baseline ultrasound showing one hypoechoic lesion in the pelvis and right proximal ureter (arrows). (B) After the administration of the ultrasound contrast agent one lesion appears more enhanced than the parenchyma. (C) Correlation with the excretory phase of CTU (MIP image) showing significant distorsion of the calyces with a mass occupying the entire renal pelvis (arrows).
in 5 cases (Figs. 2 and 3, Video 1). Twenty-four (86%) lesions showed an early washout prior to that of the renal parenchyma; this early washout was seen 40-55 s after the administration of contrast (Fig. 4). With contrast, two (2) patients showed reduced enhancement of most part of
the upper pole renal parenchyma associated with tumor infiltration. No significant differences were found in the intensity of enhancement or in the washout pattern between high and low grade tumors (p > 0.05). There were no statistically significant differences in the washout average time
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Figure 3 54-year-old male with low grade urothelial carcinoma. (A) The B mode ultrasound shows a long hypoechoic mass in the renal sinus of the upper pole (arrows). (B) After the administration of the ultrasound contrast agent, we can see one mass in the renal sinus and upper pole infundibulum less enhanced than the parenchyma (arrows). CT scan in the corticomedullary (C) and excretory (D) phases confirming the presence of one hypodense urothelial carcinoma with respect to the parenchyma (arrows).
Figure 4 75-year-old male with low grade urothelial carcinoma with early washout. (A) B mode ultrasound showing echogenic content in the renal pelvis that conditions upper calyceal hydronephrosis. CTU in the nephrographic (B) and excretory (C) phases with MIP reconstruction showing one hypovascular mass in the renal sinus with amputation of part of the upper calyceal system and pelvis. (D and E) Ultrasound scan after the administration of IV contrast showing moderate enhancement of the mass with early washout at 40 s.
of any histological tumor grades. The findings are shown in Table 1.
Discussion The contrast-guided ultrasound allows us to make real time assessments of microvascularization8---11 with a tissue
perfusion resolution similar to that of the CT scan and the MRI.8,10 The use of the ultrasound contrast agent allows us to see the blood flow of small vessels3,8,9 to be able to identify urothelial tumors of urinary tract non-solid lesions such as blood clots or debris (Fig. 5).12 The use of the ultrasound contrast agent is limited by how difficult it is to
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Table 1 Characteristics of the ultrasound contrast agent enhancement of upper tract urothelial tumors based on the histological tumor grade. Histological tumor grade
Phase of enhancement
Phase of contrast washout Washout time (s)
Same or more cortical intensity Less cortical intensity Early Late High grade (n = 21) Low grade (n = 7) p value
17 6 0.776
4 1 0.212
17 4 7 0 0.521
47 ± 10.9 43 ± 13.4
Figure 5 Comparison of two patients (A and B) one showing a blood clot in the tract and the other one (C and D) showing urothelial carcinoma. (A and C) B mode ultrasound of the two patients showing echogenic content inside both renal pelvis (arrows). (B and D) After the administration of the ultrasound contrast agent we can see the enhancement of the first patient (B) and confirm the presence of blood clots inside the urinary tract unlike the second patient whose enhancement suggests the presence of urothelial carcinoma (arrows) (D).
detect lesions on the B mode ultrasound, especially when no tract dilatation is found.8 The clinical guidelines established by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) back in 2017 include a recommendation to use contrast-enhanced ultrasound scans to distinguish solid renal lesions from pseudo-tumors. However, no reliable criteria have been published to date to achieve differential diagnosis among various solid lesions due to overlapping findings both in the qualitative and quantitative analyses without an explicit reference to urinary tract tumors.14 In the same year, Xue et al.8 conducted a retrospective study of 52 patients that did not include ureters in which practically all tumors showed enhancement (94.2%). Among them 77.6% became less enhanced, 12.2% equally enhanced and 10.2% more enhanced than the renal cortex. In our study, all tumors became enhanced after the administration of the ultrasound contrast agent, but unlike Xue’s study, most of them (86%) did so equally or more than the renal cortex --- a fact that may be due to the high sensitivity of the contrast agent when it comes to finding microvascularization. Xue’s study also conducted the qualitative assessment of washout time that was more precocious in the cortex
in 93.9% of the cases, something similar to our study that confirmed the early washout of the parenchyma in 24 cases (86%). Several studies have analyzed the value of ultrasound contrast agents to distinguish between high and low grade urothelial tumors. The findings published to date are contradictory. The degree of enhancement with time-intensity curve-shape analysis of high grade tumors was higher compared to low grade tumors in two (2) studies3,17 whereas in Fan Li et al.’s study, low grade tumors became more enhanced.15 Washout time was faster in low grade tumors in two (2) studies3,17 and no differences were found in a third study.15 Our study showed no statistically significant differences in the degree of enhancement or washout time reported between both histological grades. From a practical point of view, the differentiation between high and low histological grade can be important for the management of vesical tumor, but it will probably not change the therapeutic approach of upper tract tumors. Ultrasound contrast agents can identify unclear tumors found on the B mode ultrasound scan and significantly improve our trust in the diagnosis of tumors in the excretory duct. The characteristics of the initial enhancement of
502 the lesion found in the excretory duct and the early washout of contrast allow easier detections of this type of tumors.8 Conducting ultrasound scans our series found a large number of tumors in the ureter. It is generally thought that the value of the ultrasound scan in the assessment of ureteral cancer is limited since the ureter is never seen in completely.6,18 Due to its limited sensitivity, a negative ultrasound scan does not rule out the presence of upper tract urothelial carcinomas. However, in our opinion, if the ureter is dilated as it is the case with almost all ureteral neoplasms, we can see the cause in a large number of cases. When the ultrasound scan is the initial imaging modality for the assessment of hematuria, the upper tracts need to be carefully looked into because finding a tumor will shorten the times required for its diagnosis, staging and management. The findings of this study support the idea that the contrast-enhanced ultrasound scan may be used to diagnose upper tract tumors as an additional imaging modality to the CTU or MRU in cases of renal failure or contrast allergies. We think it may play a relevant role in the screening of patients with hematuria or other suspicious symptoms since it distinguishes between tumor and pseudo-tumor disease (such as the presence of blood clots or debris) in CT scans and MRIs without contrast.15 The fact that the real time analysis of the ultrasound contrast agent is more sensitive than the CT scan for the detection of tumor microperfusion may be useful for diagnostic purposes in cases where tumors do not become clearly enhanced on the CTU.15,19 One of the limitations that the contrast-enhanced ultrasound scan, the CTU or the MRU share is their incapacity to distinguish urothelial carcinomas from other less common types of tract tumors such as epidermoid tumors, adenocarcinomas or lymphomas, or even benign lesions such as tuberculosis. For instance, diffuse urothelial tumors infiltrating the renal parenchyma aggressively may be taken for renal cell carcinomas damaging the collecting system. Other limitations of the study have to do with its retrospective nature including the relatively small number of patients, and also that the evaluation of the contrast findings was qualitatively assessed by two (2) observers by consensus. Future studies may include independent qualitative evaluations conducted by several observers to assess variability in the interpretation of enhancement, or quantitative evaluations of tumor enhancement and its correlation with the histological tumor grade --- an issue only studied so far in urothelial tumors of the bladder.17,20 In sum, the findings of this study let us conclude that the use of ultrasound contrast agents is a promising imaging technique that improves diagnostic accuracy compared to the B mode ultrasound. This technique available in our setting is also easy to implement, and consolidates the diagnosis of upper tract urothelial tumors when observing lesions in enhanced pyelocaliceal systems and ureters being early washout with respect to the renal parenchyma a common phenomenon.
Authors 1. Manager of the integrity of the study: AAPS, MJMP and TRG. 2. Study idea: AAPS, MJMP, TRG, AAPS, DPG, JVR and GMB.
A.A. Painel Seguel et al. 3. Study design: AAPS, MJMP, TRG, DPG, JVR and GMB. 4. Data mining: AAPS, MJMP, TRG, DPG, JVR and GMB. 5. Data analysis and interpretation: AAPS, MJMP, TRG, DPG, JVR and GMB. 6. Statistical analysis: AAPS, MJMP, TRG and DPG. 7. Reference: AAPS, TRG and DPG. 8. Writing: AAPS, MJMP, TRG, DPG, JVR and GMB. 9. Critical review of the manuscript with intellectually relevant remarks: AAPS, MJMP, TRG, DPG, JVR and GMB. 10. Approval of final version: AAPS, MJMP, TRG, DPG, JVR and GMB.
Conflicts of interests The authors declare no conflicts of interests associated with this article whatsoever.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j. rxeng.2018.10.001.
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