Ultrasonography Significantly Overestimates Stone Size When Compared to Low-dose, Noncontrast Computed Tomography

Accepted Manuscript Title: Ultrasonography Significantly Overestimates Stone Size When Compared to Low-Dose Non-Contrast Computed Tomography Author: Kevan M. Sternberg, Brian Eisner, Troy Larson, Jullet Han, Natalia Hernandez, Vernon M. Pais Jr PII: DOI: Reference:

S0090-4295(16)30271-0 http://dx.doi.org/doi: 10.1016/j.urology.2016.06.002 URL 19841

To appear in:

Urology

Received date: Accepted date:

9-4-2016 3-6-2016

Please cite this article as: Kevan M. Sternberg, Brian Eisner, Troy Larson, Jullet Han, Natalia Hernandez, Vernon M. Pais Jr, Ultrasonography Significantly Overestimates Stone Size When Compared to Low-Dose Non-Contrast Computed Tomography, Urology (2016), http://dx.doi.org/doi: 10.1016/j.urology.2016.06.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Ultrasonography significantly overestimates stone size when compared to low-dose noncontrast computed tomography Kevan M. Sternberg MD, Brian Eisner MD, Troy Larson, Natalia Hernandez, Jullet Han MD, Vernon M. Pais Jr MD Kevan M. Sternberg MD- Division of Urology, University of Vermont Medical Center, Burlington Vermont Corresponding Author: [email protected] 111 Colchester Avenue Main Campus, East Pavillion, Level 5 Burlington, VT 05401 Phone: 802-847-2884 / Fax: 802-847-6020 Brian Eisner MD- Department of Urology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts Troy Larson- University of Vermont Medical Center, Burlington, Vermont Jullet Han- Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire Natalia Hernandez MD- Department of Urology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts Vernon M. Pais Jr MD- Section of Urology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire

Running head: Ultrasound to diagnosis and manage nephrolithiasis Key Words: calculi, nephrolithiasis, ultrasound

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OBJECTIVES To evaluate the differences between Low-dose Non-Contrast Computed Tomography (NCCT) and renal ultrasound (US) in the identification and measurement of urinary calculi.

METHODS A retrospective review was conducted at three institutions of patients evaluated for flank pain with both renal US and NCCT, within 1 day of one another, from 2012-2015. Stone presence and size were compared between imaging modalities. Stone size was determined by largest measured diameter. Stones were grouped into size categories ( 5 mm, 5.1-10 mm, and >10 mm) based on NCCT and compared with US. Statistical analysis was performed using 2-sided t-tests.

RESULTS 155 patients received both a renal US and NCCT within 1 day. In 79 patients (51.0%), both US and NCCT identified a stone for size comparison. 58 patients (37.4%) had a stone visualized on NCCT but not on US and 2 patients (1.3%) had a stone documented on US but not seen on NCCT. The average NCCT size of the stones missed on US was 4.5 mm. When comparing the average largest stone diameter for US (9.1 mm) vs. NCCT (6.9 mm), US overestimated stone size by 2.2 mm (p < 0.001). US overestimated stone size by 84.6% for stones  5 mm, 27.1% for stones 5.1-10 mm, and 3.0% for stones > 10 mm.

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CONCLUSIONS US significantly overestimated stone size and this was most pronounced for small (5 mm) stones. The potential for systematic over-estimation of stone size with standard US techniques should be taken into consideration when evaluating endourologic treatment options.

Non-contrast computerized tomography (NCCT) is the gold standard for the evaluation of nephrolithiasis 1, 2. The advantages of NCCT include superior sensitivity and specificity, the ability to identify ureteral calculi, the accurate assessment of stone size, and the ability to discover alternative pathology accounting for the clinical presentation. Despite these advantages, there is growing concern over increased cost and most importantly the cumulative risk of ionizing radiation exposure 3. For these reasons, recent research has been conducted to evaluate the safety of using renal ultrasound (US) as an alternative to NCCT for the evaluation of patients with suspected urolithiasis. Most notably, Smith-Bindman et al. 4, in a multicenter comparative effectiveness trial, showed that the use of initial diagnostic US had no significant differences in high-risk diagnoses, with complications or serious adverse events, when compared to NCCT for patients presenting to the emergency department (ED) with renal colic. With the possible expanding use of ultrasound as a first line diagnostic modality, it is important to evaluate not only the safety of this approach, but also the diagnostic accuracy needed to guide urologic management decisions. It is necessary to provide patient care throughout the entire stone episode, not only in the acute setting. While ensuring a safe discharge from the emergency department is the initial goal, the importance of follow-up care to ensure

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stone passage or recommend surgical removal must not be overlooked. The latter relies on accurate diagnosis and stone measurement obtained through imaging. One proposed limitation of ultrasound is the inability to accurately determine stone size 5. Stone size is the main factor used to predict spontaneous stone passage, as smaller stones < 5 mm are more likely to pass without surgical intervention 6, 7. In the absence of infection or compromised renal function, observation can therefore be recommended for most small stones. Previous studies have looked at the comparative sensitivity, specificity, and size concordance between ultrasound and NCCT with mixed results. In general, ultrasound is thought to have inferior sensitivity and specificity, while overestimating stone size 5, 8-10. The existing literature has compared standard dose computerized tomography (CT) with ultrasonography. More recently, low dose CT has become the standard of care at many institutions for the evaluation of urolithiasis. In fact, low dose CT is now the preferred imaging modality in patients with acute flank pain and suspicion of stone disease according to the American College of Radiology Appropriateness Criteria 11. While low dose CT has been shown to compare favorably with standard dose CT in terms of sensitivity and specificity for the diagnosis of urolithiasis, it may miss small stones (< 3 mm) 12, 13. In addition, concern regarding image quality in obese patients may limit the effectiveness in this patient population. The American Urological Association currently recommends low dose CT only in patients with a BMI < 30 kg/m2 14. With the use of low dose CT imaging, it is possible that the previously reported differences between standard dose CT and ultrasound would be less pronounced. In our contemporary series, low dose CT protocols were used for all patients further expanding the body of literature to include this current paradigm.

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To address these timely questions, we performed a multi-center retrospective study to compare the concordance between ultrasound and NCCT in patients who received both imaging modalities within one day for the work-up of suspected renal colic.

MATERIAL AND METHODS After obtaining institutional review board approval, we performed a multicenter retrospective review of patients who obtained renal ultrasound and NCCT imaging within 1 day at 3 academic institutions (University of Vermont Medical Center, Massachusetts General Hospital, DartmouthHitchcock Medical Center) between 2012 and 2015. Inclusion was limited to adult patients > 18 years of age. Only formal radiologic ultrasound, not bedside-ultrasound, were included. CT images were obtained using a low dose stone protocol with an estimated dose between 1.5 to 5 millisieverts (mSv). Patients were excluded if images were obtained > 1 day apart, if imaging was of poor quality for interpretation, and/or if staghorn calculi were present (Figure 1). Data collected from review of patient charts was used to quantify baseline patient characteristics (sex, age, body mass index(BMI)). All NCCT images were independently reviewed to document stone presence and measure the size of the predominant stone of interest. One reviewer from each center performed the stone measurements. A standard protocol was followed using abdominal windows and zooming in to best visualize the stone of interest. Three measurements were made (length, width, height) using axial, sagittal, and coronal sections. Stone size was determined using the largest measured diameter. Renal ultrasound results

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were obtained from the official radiology reports. NCCT was used as the reference standard for determining stone size. Stones were grouped into 3 size categories: 5 mm, 5.1-10 mm, and > 10 mm. These size classifications are often used clinically and have been used in previous studies looking at stone measurements 5.

Statistical Analysis Stone presence was recorded as a dichotomous variable based on direct observation and radiology reports of imaging tests. These parameters were quantified as proportions and compared between imaging modalities using descriptive statistics. Stone size and stone number was collected as a continuous variable, which was independently measured on NCCT or collected from ultrasound radiology reports. This data was quantified in several ways, including the arithmetic mean of each data set. The largest diameter size measurements of renal ultrasound and NCCT were compared using two-sided t-tests, with a set statistical significance level of p < 0.05. Each stone measured on NCCT was placed into a categorical size range (5 mm, 5.1-10 mm, > 10 mm) and compared with its respective size measurement on ultrasound. The ultrasound measurement was evaluated with respect to the average magnitude and frequency of over-estimation or underestimation, as well as the comparison of the arithmetic means between each imaging modality.

RESULTS

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155 patients were included in the analysis. Stone size data was analyzed from 79 patients who received both renal ultrasound and NCCT within the 1 day time period and in whom both ultrasound and NCCT detected a stone. There were 60 patients where a stone was only identified on one imaging modality and these were not included for the size comparison analysis. Specifically, 58 patients (37.4%) had a stone visualized on NCCT but not on ultrasound and 2 patients (1.3%) had a stone documented on US but not seen on NCCT. Of the 58 patients where ultrasound missed a stone, the average size of those stones on NCCT was 4.5 mm (standard deviation (SD) = 3.2 mm). 83 patients (53.5%) were female. The mean age of the group was 44.5 years (SD 15.6 years) with a mean BMI of 28.6 kg/m2 (SD 8.5 kg/m2). With ultrasound measurement, the average largest diameter of the predominant stone was 9.1 mm (SD = 4.0 mm) and on NCCT the largest measured diameter was 6.9 mm (SD = 3.5 mm). Ultrasound overestimated stone size by an average of 2.2 mm (p < 0.001). Stones were further categorized by size measured on NCCT: 5 mm (n=28), 5.1-10 mm (n=38), and > 10 mm (n=13). For the smaller stones measuring 5 mm on NCCT, ultrasound overestimated the size in 82.1% of the cases by an average of 3.3 mm (84.6%). For stones 5.1-10 mm, ultrasound overestimated size in 52.6% of the cases by an average of 1.9 mm (27.1%). In the largest group of stones measuring > 10 mm, ultrasound overestimated size in 38.5% of the cases by an average of 0.4 mm (3.0%). Therefore, as stone size increased, ultrasound overestimated stone size less frequently and by a smaller amount (Table 1). Of the 79 patients available for size comparisons, 71 (89.9%) of the ultrasound images reported the presence of a stone ≥ 5 mm. Of these clinically significant stones on ultrasound, 19 (26.8%) were found to be ˂ 5 mm on NCCT.

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In 66 patients, the number of stones was recorded for both ultrasound and NCCT and available for comparison. The average number of stones reported on ultrasound was 1.7 (SD = 3.1) and on NCCT was 3.3 (SD = 0.98) . Of these patients, NCCT identified on average 1.6 more stones (p < 0.001).

COMMENT There has been increasing interest in the ideal imaging modality to diagnose and monitor nephrolithiasis. NCCT has become the gold standard imaging modality for the evaluation of flank pain. The sensitivity and specificities of NCCT approach 98-100% 15. Additional advantages include the accurate detection of ureteral calculi and the ability to identify alternative diagnoses that may require more immediate intervention. Equally important is the ability of NCCT to accurately measure stone size and quantify stone burden. Stone size is the main factor used in clinical decision making for the management of urolithiasis. Smaller calculi < 5 mm have been shown to have a high likelihood of spontaneous passage. Coll et al. 6 showed that CT measurements of ureteral stone size have a nearly inverse linear relationship with the frequency of spontaneous passage. Expectant management is therefore dependent on accurate stone measurement. Our findings demonstrate that in ˃ 25% of the cases, US reports a 5 mm stone that on NCCT is found to be smaller than 5 mm. This highlights a major limitation of relying on US alone to guide patients on the likelihood of spontaneous stone passage. For the management of renal calculi, stone burden is the most significant factor used to determine the type of endourologic intervention. Small, non-obstructing stones are often

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observed as these have a high likelihood of spontaneous passage. As stone size increases, the efficacy of shock wave lithotripsy and ureteroscopy decrease. Patients choosing these methods for larger stones should be counseled on the need for multiple sessions or staged approaches. Percutaneous Nephrolithotomy is often recommended for larger stone burdens to offer the best results with the fewest interventions 16. Evaluating the efficacy of renal US for the diagnostic evaluation of nephrolithiasis has been previously studied with varying conclusions. Fowler et al. 9 in 2002 reported that US had limited value in the detection of renal calculi, demonstrating a sensitivity of only 24% when compared with CT. Size however was concordant in 79% of the cases. In 2010, Ray et al. 5 compared CT and US for the identification and measurement of renal calculi. They concluded that ultrasound overestimated stone size by a mean of 1.9 ± 1.2 mm for stones ≤ 5 mm when compared with CT. More recently, Kanno et al. 17 found that US was effective at both detecting and accurately measuring renal calculi. In their comparison, US had a sensitivity of 70% and a specificity of 94%. The concordance rate for size measurement was 72%. The importance of revisiting this topic is evident due to the recent heightened focus on avoiding patient exposure to ionizing radiation. In 2006, the National Academies BEIR VII committee concluded that “current scientific evidence is consistent with the hypothesis that there is a linear dose-response relationship between exposure to ionizing radiation and the development of radiation-induced solid cancers in humans” 18. While this risk is small and no threshold doses have been established, it has become a primary consideration for patients with kidney stones, many of whom are young, who will likely have recurrent episodes requiring repeated imaging.

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Our multicenter data supports previous findings of poor sensitivity and size overestimation of urinary calculi with the use of ultrasound compared to NCCT. In particular, smaller stones measuring 5mm on NCCT were frequently overestimated and by a significant margin. Also importantly, this finding holds true when comparing low-dose CT with ultrasound. The inability to accurately assess stone size makes patient counseling, regarding the need for and method of intervention, difficult. Additionally, ultrasound was less sensitive for the detection of urolithiasis and importantly, the average size of those missed stones (4.5 mm) could affect patient counseling on the likelihood of spontaneous stone passage. While retrospective in nature, we feel the large number of cases across multiple patient settings and indications make our findings relevant and thought provoking. The observed differences between imaging modalities were found consistently across 3 academic medical centers and this further strengthens and distinguishes our findings from previous studies. There are several limitations to the current study in addition to the retrospective nature. First, one evaluator from each institution reviewed their own CT images instead of having a central review process with a few evaluators to account for intra-observer variability. Second, the two imaging modalities were reviewed by different individuals (a radiologist reviewed the ultrasound while an investigator reviewed the CT) which may have introduced bias. Third, we acknowledge that stone measurements are most accurately made using magnified bone windows and that our use of soft tissue windows may slightly overestimate NCCT-measured stone size 19. This however would strengthen the effect of our findings showing that US significantly overestimates stone size compared with NCCT. Lastly, we used radiologic reports instead of independently reviewing the US images. US imaging is time and user

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dependent with potential intra-observer variability particularly when documenting stone size. While in our clinical practice, radiology reports are relied upon to guide management, we understand the potential bias introduced by only independently reviewing the CT scans. The future evaluation of this common patient presentation needs to take into account the goals of the ED providers, urologists, and most importantly the patient. The safety of US, as at least an initial imaging strategy, cannot be disputed. Most stones pass without urologic intervention and very few serious alternative diagnoses are missed using US. While most of these patients can be safely discharged from the ED, those presenting for urologic follow-up with US alone are difficult to counsel as the presence, number, and overall stone burden may be inaccurate. Often further clarification requires obtaining the very imaging that was avoided in the ED and may delay necessary care. Size overestimation can also lead to patient anxiety, especially for recurrent stone formers who may be unnecessarily anticipating surgical intervention. Recently, alternative approaches to using US have been demonstrated to improve stone measurement. Using an in vitro model, Dunmire et al. found that stone size accuracy was significantly improved by measuring the acoustic shadow width instead of the width of the stone itself. The use of the stone shadow was also shown to reduce the misclassification of stones as larger than 5 mm 20. If validated in human stone formers, US may be able to be used more confidently to guide urologic management decisions.

CONCLUSION

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The current ability of US to identify and accurately measure urinary stones is inferior compared to NCCT. Ultrasonography however is safe, avoids exposure to ionizing radiation, and may be a useful initial screening modality. Future algorithms need to be developed to decide which patients require additional NCCT imaging to facilitate their urologic care.

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Smith RC, Verga M, McCarthy S, Rosenfield AT. Diagnosis of acute flank pain: value of unenhanced helical CT. AJR. American journal of roentgenology. 1996;166:97-101. Smith RC, Rosenfield AT, Choe KA, et al. Acute flank pain: comparison of non-contrastenhanced CT and intravenous urography. Radiology. 1995;194:789-794. Brenner DJ, Hall EJ. Computed tomography--an increasing source of radiation exposure. The New England journal of medicine. 2007;357:2277-2284. Smith-Bindman R. Ultrasonography vs. CT for suspected nephrolithiasis. The New England journal of medicine. 2014;371:2531. Ray AA, Ghiculete D, Pace KT, Honey RJ. Limitations to ultrasound in the detection and measurement of urinary tract calculi. Urology. 2010;76:295-300. Coll DM, Varanelli MJ, Smith RC. Relationship of spontaneous passage of ureteral calculi to stone size and location as revealed by unenhanced helical CT. AJR. American journal of roentgenology. 2002;178:101-103. Miller OF, Kane CJ. Time to stone passage for observed ureteral calculi: a guide for patient education. The Journal of urology. 1999;162:688-690; discussion 690-681. Ulusan S, Koc Z, Tokmak N. Accuracy of sonography for detecting renal stone: comparison with CT. Journal of clinical ultrasound : JCU. 2007;35:256-261. Fowler KA, Locken JA, Duchesne JH, Williamson MR. US for detecting renal calculi with nonenhanced CT as a reference standard. Radiology. 2002;222:109-113. Sheafor DH, Hertzberg BS, Freed KS, et al. Nonenhanced helical CT and US in the emergency evaluation of patients with renal colic: prospective comparison. Radiology. 2000;217:792-797. Coursey CA, Casalino DD, Remer EM, et al. ACR Appropriateness Criteria(R) acute onset flank pain--suspicion of stone disease. Ultrasound quarterly. 2012;28:227-233. Kim BS, Hwang IK, Choi YW, et al. Low-dose and standard-dose unenhanced helical computed tomography for the assessment of acute renal colic: prospective comparative study. Acta radiologica (Stockholm, Sweden : 1987). 2005;46:756-763. Heneghan JP, McGuire KA, Leder RA, DeLong DM, Yoshizumi T, Nelson RC. Helical CT for nephrolithiasis and ureterolithiasis: comparison of conventional and reduced radiation-dose techniques. Radiology. 2003;229:575-580. Fulgham PF, Assimos DG, Pearle MS, Preminger GM. Clinical effectiveness protocols for imaging in the management of ureteral calculous disease: AUA technology assessment. The Journal of urology. 2013;189:1203-1213.

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Fielding JR, Steele G, Fox LA, Heller H, Loughlin KR. Spiral computerized tomography in the evaluation of acute flank pain: a replacement for excretory urography. The Journal of urology. 1997;157:2071-2073. 16. Turk C, Petrik A, Sarica K, et al. EAU Guidelines on Interventional Treatment for Urolithiasis. European urology. 2015. 17. Kanno T, Kubota M, Sakamoto H, et al. The efficacy of ultrasonography for the detection of renal stone. Urology. 2014;84:285-288. 18. National Research Council Committee on Health Effects of Exposure to Low Levels of Ionizing R. Health Effects of Exposure to Low Levels of Ionizing Radiations: Time for Reassessment? Washington (DC): National Academies Press (US) Copyright 1998 by the National Academy of Sciences. All rights reserved.; 1998. 19. Eisner BH, Kambadakone A, Monga M, et al. Computerized tomography magnified bone windows are superior to standard soft tissue windows for accurate measurement of stone size: an in vitro and clinical study. The Journal of urology. 2009;181:1710-1715. 20. Dunmire B, Harper JD, Cunitz BW, et al. Use of the Acoustic Shadow Width to Determine Kidney Stone Size with Ultrasound. The Journal of urology. 2016;195:171177. 15.

Figure 1. Flow diagram of patients included for each analysis in the study. Table 1. Categorical size analysis based on NCCT measurement of largest stone diameter. Average NCCT measurement was reported as the arithmetic mean of all stones within the specified size category, which was subsequently compared to the corresponding average largest stone diameter on US (standard deviation of means are reported in parentheses). The frequency and average magnitude of US overestimation was reported with respect to the NCCT measured diameter of the same stone. NCCT Measured Stone Diameter

Average Diameter on NCCT (mm)

Average Diameter on US (mm)

Frequency US overestimate

Average US size overestimate (mm)

 5 mm (n=28)

3.9 (1.0)

7.2 (2.7)

82.1% (23/28)

3.3 (84.6%)

5.1-10 mm (n=38)

7.0 (1.4)

8.9 (4.0)

52.6% (20/38)

1.9 (27.1%)

> 10 mm (n=13)

13.2 (2.7)

13.6 (2.6)

38.5% (5/13)

0.4 (3.0%)

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