Eur Radiol (2013) 23:730–738 DOI 10.1007/s00330-012-2641-9

GASTROINTESTINAL

Differentiation of adenomyomatosis of the gallbladder from early-stage, wall-thickening-type gallbladder cancer using high-resolution ultrasound Ijin Joo & Jae Young Lee & Jung Hoon Kim & Soo Jin Kim & Min A. Kim & Joon Koo Han & Byung Ihn Choi

Received: 2 April 2012 / Revised: 27 July 2012 / Accepted: 1 August 2012 / Published online: 18 December 2012 # European Society of Radiology 2012

Abstract Objectives To evaluate the diagnostic performance of transabdominal high-resolution ultrasound (HRUS) for differentiation of adenomyomatosis from early-stage, wallthickening-type gallbladder (GB) cancer. Methods HRUS was defined as the addition of high megahertz imaging to conventional low megahertz imaging with use of state-of-the-art imaging technology. HRUS findings were retrospectively compared in 45 patients with adenomyomatosis and 28 patients with stage T1/T2 wallthickening-type GB cancer. For evaluating HRUS performance in the differential diagnosis of adenomyomatosis from GB cancer, receiver operating characteristic curve analysis was used with a five-point confidence scale independently scored by three blinded radiologists who also analysed morphological abnormalities. I. Joo : J. Y. Lee (*) : J. H. Kim : J. K. Han : B. I. Choi Department of Radiology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, South Korea e-mail: [email protected] J. Y. Lee : J. H. Kim : J. K. Han : B. I. Choi Institute of Radiation Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, South Korea S. J. Kim Center for Gastric Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, South Korea M. A. Kim Department of Pathology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, South Korea

Results The area under the receiver operating characteristic curve (Az) values of HRUS in the diagnosis of adenomyomatosis were 0.948, 0.915 and 0.917 for reviewers 1, 2 and 3. Symmetrical wall thickening, intramural cystic spaces, intramural echogenic foci and twinkling artefacts were significantly associated with adenomyomatosis (P<0.05), whereas irregular thickening of the outer wall, focal innermost hyperechoic layer (IHL) discontinuity, IHL irregularity, IHL thickening greater than 1 mm, loss of multilayer pattern in the GB wall, and intralesional vascularity were significantly associated with cancer (P<0.05). The sensitivity, specificity and accuracy of intramural cystic spaces/echogenic foci for the diagnosis of adenomyomatosis were 80.0 %, 85.7 % and 82.2 %. Conclusions This study showed that HRUS can be helpful for distinguishing adenomyomatosis from early-stage, wallthickening-type GB cancer. Key Points • Transabdominal high-resolution ultrasound (HRUS) helps differentiate adenomyomatosis from gallbladder cancer. • HRUS can evaluate the detailed anatomy of the gallbladder wall. • Adenomyomatosis of the gallbladder shows characteristic findings on HRUS. Keywords Gallbladder . Adenomyomatosis . Gallbladder cancer . Ultrasound . High-resolution ultrasound

Introduction Generalized or localized wall thickening of the gallbladder (GB) is frequently encountered on CT performed for routine health check-ups, staging work-up of an underlying disease or follow-up after surgery. In such cases, adenomyomatosis and early-stage, wall-thickening-type

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GB cancer are often included together in the differentials owing to their similarity in appearance on CT with a recommendation for further work-up [1, 2]. For the differentiation between adenomyomatosis and GB cancer, MR imaging is known to be useful because it can sensitively depict the pearl necklace sign, which is pathognomonic of adenomyomatosis and directly indicates the presence of Rokitansky–Aschoff sinuses in the thickened wall [3, 4]. However, MR imaging is expensive and requires patients to hold still for long periods of time. Since 1981, there have been many reports regarding the appearance of adenomyomatosis on ultrasound (US). The typical findings of adenomyomatosis on US and endoscopic US (EUS) are diffuse or localized wall thickening with intramural cysts and echogenic areas with comet tail artefacts [5–9]. According to a report published in 2001, US had an accuracy of only 66 % for the diagnosis of adenomyomatosis [10]. However, the results came from the use of only conventional transabdominal US prior to the emergence of harmonics, compounding techniques and speckle reduction imaging. Since 2001, there have been significant advances in US technology that offer the ability to overcome the drawbacks of conventional US. These technological advances include harmonics, compounding techniques, and speckle reduction imaging as stated above. These techniques have been proven to enhance the contrast/ spatial resolution and to reduce artefacts and noise, which are beneficial to the investigation of cystic organs or cystic lesions [11–13]. Therefore, the advantages of these techniques can be used effectively for the diagnosis of adenomyomatosis of the gallbladder by increasing the image quality and lesion conspicuity of intramural cysts and echogenic areas. These techniques are available in both high and low megahertz transducers. The addition of a high megahertz transducer enables smaller intramural cysts or echogenic areas of adenomyomatosis to be depicted better than by a low megahertz transducer alone. Reportedly, a combination of these advanced techniques with low megahertz and high megahertz transducers for the evaluation of gallbladder diseases, named high-resolution ultrasound (HRUS), allows for a clearer and more accurate evaluation of the GB wall compared with conventional US [14, 15]. To our knowledge, there are no published reports on the usefulness of HRUS for differentiating adenomyomatosis of the GB from early-stage, wall-thickeningtype GB cancer, which may mimic adenomyomatosis. Therefore, the objective of this study was to evaluate the diagnostic performance of HRUS for differentiating between adenomyomatosis and early-stage, wallthickening-type GB cancer.

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Materials and methods Patients This retrospective study was approved by our institutional review board, and the requirement for informed consent was waived. Using a computerized search of our pathology and radiology information systems between January 2006 and October 2009, we identified 130 consecutive patients who had undergone preoperative HRUS of the GB and were pathologically confirmed to have either adenomyomatosis (n049) or cancer (n081) by subsequent cholecystectomy. Among the 49 patients with adenomyomatosis, we excluded two patients who had undergone percutaneous cholecystostomy before the HRUS examination, resulting in inadequate images for evaluation. We also excluded another two patients who had no significant GB wall thickening (less than 3 mm) on the review of the HRUS images. Among the 81 patients with GB cancer, 53 patients were excluded because of the presence of papillary or massive-type cancers on the gross examination and/or adjacent organ invasion on the histopatholgy (stage T3 or T4 cancer). No patient had both adenomyomatosis and cancer. Therefore, 73 consecutive patients, 45 with adenomyomatosis and 28 with wall-thickening-type stage T1-T2GB cancer, were included in this study. The adenomyomatosis group (n045) consisted of 28 males and 17 females with a mean age of 53.4±14.4 years (range 17-80 years). In this group, the mean BMI was 23.6 ± 4.0 kg/m2 (range 14.6–33.3 kg/m2). The adenomyomatosis group included 13 patients with generalized involvement of the GB wall, 16 with segmental involvement, and 16 with focal involvement. Laparoscopic cholecystectomy was performed because of gallstone-related symptoms in 17 patients, wall thickening of the gallbladder in 24 patients, and gallbladder polyps in 4 patients. The GB cancer group (n028) consisted of 12 male and 16 female patients with a mean age of 65.7 ± 9.5 years (range 42– 80 years). In this group, the mean BMI was 23.2 ± 3.0 kg/m2 (range 15.9–28.4 kg/m2). The histopathological analysis of the GB cancer group showed 13 patients with flat wall thickening and 15 with nodular wall thickening. In terms of staging, two patients had T1a tumours, another two had T1b tumours, and the remaining 24 had T2 tumours. The tumour was located at the fundus in 6 patients, in the fundus and body in 5 patients, in the body in 10 patients, in the body and neck in 2 patients, in the neck in 3 patients, and in the entire GB in 2 patients. A flow chart of our study based on the recommended standards for reporting diagnostic accuracy is presented in Fig. 1. HRUS image acquisition The preoperative transabdominal HRUS was performed using a LOGIQ 9 ultrasound machine (GE Healthcare, Milwaukee,

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Fig. 1 Flow chart of patient selection. HRUS highresolution ultrasound, GB gallbladder

WI) by two abdominal radiologists (J.Y.L. and S.J.K) with more than 10 years of experience in abdominal US between January 2006 and October 2009. The following protocol was used in our institution. The GB was first examined by the intercostal and/or subcostal approach using a convex probe (4C, bandwidth 1.5–4.5 MHz), always with real-time spatial compound imaging techniques (3 compound beams per frame) and speckle reduction techniques of a mild degree as well as with and without harmonic imaging. The GB was then evaluated using a linear probe (7L, bandwidth 2.5–7.0 MHz). To optimize the evaluation of the GB with the linear probe, realtime spatial compound imaging techniques (3 and 5 compound beams per frame) and speckle reduction techniques of a mild degree were always used. Because of the issue of penetration and spatial resolution, harmonic imaging techniques were usually, but not always, used. Switching between the convex probe and the linear probe was occasionally performed during an HRUS study depending on the operators’ need. Colour Doppler studies were selectively performed in 53 patients (29 with adenomyomatosis and 24 with cancer) to demonstrate colour Doppler twinkling artefacts or to evaluate the vascularity of the suspected lesion depending on the operators’ decision.

(probable presence of intramural cysts or intramural echogenic foci); 3, indeterminate (thickened GB wall without evidence favouring adenomyomatosis or cancer); 2, probably cancer (thickened GB wall with the probable presence of a mucosal lesion and the absence of intramural cysts or intramural echogenic foci); and 1, definitely cancer (thickened GB wall with the definite presence of a mucosal lesion and the absence of intramural cysts or intramural echogenic foci). In addition, two of the three reviewers (J.Y.L. and S.J.K.) independently interpreted the presence or absence of predefined abnormal findings. In cases of discrepancy, the remaining reviewer (J.H.K.) made the final decision. The predefined HRUS findings included the following: abnormal findings in the GB wall on the greyscale US, including symmetrical wall thickening, irregular thickening of the outer wall, focal innermost hyperechoic layer (IHL) discontinuity, IHL irregularity, IHL thickening greater than 1 mm, loss of the multilayer pattern in the GB wall, intramural cystic spaces and intramural echogenic foci, which are depicted in Fig. 2; abnormal findings on the colour Doppler US, including colour Doppler twinkling artefacts and intralesional vascularity; and ancillary findings, including GB stones, sludge or polyps.

Image analysis

Statistical analysis

The clinical information and identifying numbers of each patient were removed from all images, and research numbers were assigned by the study coordinator (I.J.). The US images were independently reviewed on a PACS workstation monitor (M-View; Marotech, Seoul, Korea) by three experienced abdominal radiologists (J.Y.L., J.H.K., and S.J.K. with 17, 16, and 10 years of experience in abdominal US, respectively) in March 2011. The radiologists were blinded to the radiology report and histopathological diagnosis but were aware of the study objective of differentiating between adenomyomatosis and wall-thickening-type GB cancer. The three reviewers scored each study on a five-point confidence scale based on the following criteria: 5, definitely adenomyomatosis (definite presence of intramural cysts or intramural echogenic foci signifying intramural calcification or cholesterol deposits); 4, probably adenomyomatosis

The diagnostic performance of each reviewer in terms of differentiating adenomyomatosis from early-stage, wall-thickening-type GB cancer was assessed using a receiver operating characteristic (ROC) curve analysis. The area under the ROC curve (Az) value was considered indicative of diagnostic accuracy. Interobserver agreement was evaluated using weighted κ statistics with linear weights and was interpreted as follows: poor, less than 0.20; fair, 0.20–0.39; moderate, 0.40– 0.59; good, 0.60–0.79; and excellent, 0.80 or greater. Fisher’s exact test was used to assess the association between each HRUS finding (based on the consensus interpretation) and the histopathological diagnosis of adenomyomatosis or cancer. For the statistically significant HRUS findings, the sensitivity, specificity, accuracy, positive predictive value (PPV) and negative

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Fig. 2 Schematic drawings showing the HRUS findings in the gallbladder wall. a Normal gallbladder wall on HRUS. The inner hyperechoic layer indicates the mucosa, the middle hypoechoic layer indicates the muscle and the outer hyperechoic layer indicates the perimuscular connective tissue. b Symmetrical wall thickening. c Irregular thickening of the outer wall. d Focal innermost hyperechoic layer (IHL) discontinuity. e IHL irregularity. f Loss of the multilayer pattern. g Intramural cystic spaces. h Intramural echogenic foci

predictive value (NPV) of the differentiation between adenomyomatosis and cancer were estimated. A multivariate stepwise logistic regression model was used to identify the best diagnostic predictors. Variables with a P value less than 0.10 in the univariate analysis were included in the logistic regression model. All statistical analyses were performed with commercially available statistical software (Medcalc, version 11.5.1, Mariakerke, Belgium). A P value of less than 0.05 was considered to indicate a statistically significant difference.

Table 1 Diagnostic performance (Az) and interobserver agreement of the reviewers for distinguishing adenomyomatosis of the gallbladder from early-stage, wall-thickening-type GB cancer κ value

Az value Reviewer 1 2 3

Az value 0.948 0.915 0.917

Reviewer 1 vs. 2 1 vs. 3 2 vs. 3

κ value 0.765 0.638 0.581

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Table 2 Consensus review of the presence of the HRUS findings in patients with adenomyomatosis and in patients with cancer HRUS findings

Adenomyomatosis (n045)

Cancer (n028)

P value

Symmetrical wall thickening Irregular thickening of the outer wall Focal IHL discontinuity IHL irregularity IHL thickening greater than 1 mm Loss of multilayer pattern in the wall Intramural cystic spaces Intramural echogenic foci

32 5 2 5 29 4 23 33

(71.1) (11.1) (4.4) (11.1) (64.4) (8.9) (51.1) (73.3)

5 (17.9) 16 (57.1) 11 (39.3) 24 (85.7) 27 (96.4) 18 (64.3) 0 (0) 4 (14.3)

<0.001 <0.001 <0.001 <0.001 0.001 <0.001 <0.001 <0.001

Twinkling artefact on colour Doppler studya Intralesional vascularity on colour Doppler studya Gallbladder stones or sludge Polyps

10 4 17 6

(34.5) (13.8) (37.8) (13.3)

2 (8.3) 15 (62.5) 5 (17.9) 8 (28.6)

0.045 <0.001 0.115 0.133

Data are the numbers of patients with percentages in parentheses IHL innermost hyperechoic layer, representing mucosa a

Included 53 patients (29 with adenomyomatosis and 24 with cancer) who had undergone colour Doppler studies

Results Diagnostic performance and interobserver agreement The Az value of HRUS in the differential diagnosis of adenomyomatosis from early-stage, wall-thickening-type GB cancer and the interobserver agreement data are shown in Table 1. There was good agreement (κ00.60–0.79) between reviewers 1 and 2 and reviewers 1 and 3. There was moderate agreement (κ00.40–0.59) between reviewers 2 and 3. HRUS features for the differentiation of adenomyomatosis from cancer: univariate analysis The qualitative HRUS findings in adenomyomatosis of the GB and early-stage, wall-thickening-type GB cancer

Fig. 3 Segmental adenomyomatosis of the gallbladder in a 30-yearold man. a Short axis view of the thickened wall in the body portion of the gallbladder demonstrates several intramural echogenic foci (arrows). b Long-axis view of the gallbladder using colour Doppler

are summarized in Table 2. Symmetrical wall thickening (P<0.001; Figs. 3 and 4), intramural cystic spaces (P< 0.001; Fig. 4), intramural echogenic foci (P < 0.001; Figs. 3 and 5) and colour Doppler twinkling artefacts (P 00.045; Fig. 3) were significantly associated with adenomyomatosis. Irregular thickening of the outer wall (P<0.001), focal IHL discontinuity (P<0.001), IHL irregularity (P < 0.001; Fig. 6), IHL thickening greater than 1 mm (P00.001; Fig. 6), loss of the multilayer pattern in the GB wall (P<0.001; Fig. 7) and intralesional vascularity on colour Doppler (P<0.001) were significantly associated with GB cancer and were therefore considered to be negative predictors of adenomyomatosis. The values of sensitivity, specificity, accuracy, PPV and NPV for each HRUS finding that was statistically significant are shown in Table 3.

US shows symmetrical wall thickening of the fundus and body of the gallbladder and the colour Doppler twinkling artefacts behind the intramural echogenic foci

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Fig. 4 Fundal adenomyomatosis of the gallbladder in a 47-year-old woman. a HRUS image reveals symmetrical wall thickening of the fundus of the gallbladder. The intramural cystic spaces appeared as anechoic structures (arrows). b Gross specimen obtained by cholecystectomy matched the HRUS findings well

HRUS features for differentiation of adenomyomatosis from cancer: multivariate analysis In the multivariate stepwise logistic regression analysis, only three findings on greyscale HRUS (intramural echogenic foci, IHL irregularity and loss of the multilayer pattern in the GB wall) were included in the regression model. Findings of the colour Doppler study were not included because 20 patients did not undergo colour Doppler studies during the HRUS examinations. Presence of intramural echogenic foci was an independent positive predictor of adenomyomatosis (odds ratio of 16.748, 95 % confidence interval (CI) of 1.152–243.595), whereas IHL irregularity (odds ratio of 0.086, 95 % CI of 0.016–0.473) and loss of the multilayer pattern in the GB wall (odds ratio of 0.052, 95 % CI of 0.005–0.511) were independent negative predictors of adenomyomatosis of the GB.

Discussion In our ROC curve analysis, HRUS had high Az values (greater than 0.90) for all reviewers in terms of differentiating adenomyomatosis from early-stage, wall-thickeningtype GB cancer. HRUS also had good or moderate interobserver agreement in the differential diagnosis between adenomyomatosis of the GB and early-stage, wall-thickening-type GB Fig. 5 Adenomyomatosis of the gallbladder in a 74-year-old man. a HRUS image shows segmental thickening of the gallbladder wall with a preserved multilayer pattern and a smooth innermost hyperechoic layer lining that is observed as a thin, uniform inner hyperechoic layer (arrows). b Oblique longaxis view of the gallbladder shows an intramural echogenic focus (arrow)

cancer. Compared with a previous study that evaluated the diagnostic performance of conventional US, CT and MR imaging in the diagnosis of adenomyomatosis, the HRUS in our study had higher Az values than conventional US (mean Az value00.76) or helical CT (mean Az value00.86) but slightly lower Az values than MR imaging (mean Az value00.98) [10]. Considering that the previous study included adenocarcinomas without consideration of the tumour stage as a control group whereas we included only patients with early-stage, wallthickening-type GB cancers as a control group, the diagnostic performance of HRUS for differentiating adenomyomatosis from early-stage, wall-thickening-type GB cancer seems to be encouraging. Haradome et al. evaluated the usefulness of MR cholangiopancreatography (MRCP) in differentiating between adenomyomatosis and early-stage, wall-thickening- and polypoid-type cancers [4]. The study reported Az values of 0.91 for MRCP and 0.93 for a combination of MRCP and arterial phase MR images, which seems to be similar to our results with respect to the Az values. In a prior study to determine the differential diagnostic and staging accuracies of EUS, HRUS and CT for GB polypoid lesions including adenomyomatosis and GB cancer, HRUS showed higher diagnostic accuracy than EUS or CT for the differential diagnosis of cancer from benign lesions—90 % in HRUS, 86 % in EUS and 72 % in CT—and for the prediction of depth of invasion of GB cancer—62.9 % in HRUS, 55.5 %

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Fig. 6 T2 stage, nodular-type cancer involving the body of the gallbladder in a 66-year-old man. Long-axis view of the gallbladder on HRUS shows an asymmetrical thickening of the gallbladder wall with irregular thickening of the inner hyperechoic layer (mucosa layer, open arrow) and the middle hypoechoic layer (muscle layer, solid arrow)

in EUS and 44.4 % in CT, respectively [14]. Our study and the previous study both show that HRUS has the potential to become an important diagnostic technique for the differential diagnosis and staging of GB lesions. To exactly determine the relative diagnostic performance of HRUS compared with CT and MR imaging in the differential diagnosis of adenomyomatosis from early-stage, wallthickening-type GB cancer, further studies with HRUS, CT and MR imaging in the same population are needed. Our univariate analysis showed that symmetrical wall thickening, intramural cystic spaces, intramural echogenic foci and colour Doppler twinkling artefacts were significantly associated with adenomyomatosis of the GB. All of these findings have been described to be characteristic of adenomyomatosis of the GB [5, 6, 16, 17]. Our results show that symmetrical GB wall thickening favours adenomyomatosis,

Fig. 7 T2 stage, flat-type cancer involving the fundus and body of the gallbladder in a 62-year-old woman. One of the reviewers considered this lesion to be a definite adenomyomatosis. a Long-axis view demonstrates symmetrical wall thickening in the fundus and body of the gallbladder without intramural cystic spaces or echogenic foci. b Magnification of the posterior wall of the gallbladder on HRUS image

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although wall thickening itself is a non-specific finding and is also found in wall-thickening-type GB cancer, which accounts for 18 % of patients with GB cancer [18]. The symmetry of adenomyomatosis can be explained by the observations that the diffuse type of adenomyomatosis involves the whole GB wall symmetrically and the segmental or annular type narrows the lumen symmetrically. The focal or localized type usually involves the fundus in a crescent-moon or round shape and is symmetrical with respect to the apex [5]. In our study, the presence of either intramural echogenic foci or cystic spaces, which indicate cholesterol crystals/ stones or bile within the pathognomonic Rokitansky–Aschoff sinuses, respectively [19], had a sensitivity of 80.0 %, specificity of 85.7 % and accuracy of 82.2 % for the diagnosis of adenomyomatosis of the gallbladder on HRUS. Compared with a previous study using a conventional US technique that reported an accuracy of 66 % for the diagnosis of adenomyomatosis [10], our study showed a much higher accuracy. The enhancement of accuracy can be attributed to more detailed visualization of these pathognomonic findings by the application of advanced US technology and high megahertz imaging. Even compared with a previous MR imaging study with a sensitivity, specificity and accuracy of the pearl necklace sign on MRCP images of 62 %, 93 % and 74 %, respectively [4], the diagnostic performance of HRUS in our study seems to be competitive. HRUS has an advantage over MR imaging in depicting Rokitansky–Aschoff sinuses when they are filled with cholesterol crystals and stones because intramural echogenic foci can be easily detected on US despite their small size owing to their bright echogenicity and the frequent coexistence of comet tail artefacts or colour Doppler twinkling artefacts on US. In addition, the

reveals the thickening of the mucosa and muscle layer, shown as a single layer of intermediate echogenicity (asterisk) that lacks the normal multilayered pattern of the gallbladder wall. (star lumen, asterisk mucosa and muscle layer, plus sign perimuscular connective tissue layer)

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Table 3 Sensitivity, specificity, accuracy, positive predictive value and negative predictive value of the significant HRUS findings for the diagnosis of adenomyomatosis or cancer HRUS findings Diagnosis of gallbladder adenomyomatosis Symmetrical wall thickening Intramural cystic spaces Intramural echogenic foci Intramural cystic spaces or echogenic foci Colour Doppler twinkling artefacts Diagnosis of gallbladder cancer Irregular thickening of the outer wall Focal IHL discontinuity IHL irregularity IHL thickening greater than 1 mm Loss of multilayer pattern of the wall Intralesional vascularity on colour Doppler study

Sensitivity (%)

Specificity (%)

Accuracy (%)

PPV (%)

NPV (%)

71.1 51.1 73.3 80.0 34.5

(32/45) (23/45) (33/45) (36/45) (10/29)

82.1 (23/28) 100 (28/28) 85.7 (24/28) 85.7 (24/28) 91.7 (22/24)

75.3 (55/73) 69.9 (51/73) 78.1 (57/73) 82.2 (60/73) 60.4 (32/53)

86.5 (32/37) 100 (23/23) 89.2 (33/37) 90.0 (36/40) 83.3 (10/12)

63.9 (23/36) 56.0 (28/50) 66.7 (24/36) 72.7 (24/33) 53.7 (22/41)

57.1 39.3 85.7 96.4 64.3 62.5

(16/28) (11/28) (24/28) (27/28) (18/28) (15/24)

88.9 (40/45) 95.6 (43/45) 88.9 (40/45) 35.6 (16/45) 91.1 (41/45) 86.2 (25/29)

76.7 (56/73) 74.0 (54/73) 87.7 (64/73) 58.9 (43/73) 80.8 (59/73) 75.5 (40/53)

76.2 (16/21) 84.6 (11/13) 82.8 (24/29) 48.2 (27/56) 81.8 (18/22) 75.0 (15/20)

76.9 (40/52) 71.7 (43/60) 90.9 (40/44) 94.1 (16/17) 80.4 (41/51) 72.7 (24/33)

Numbers in parentheses were used to calculate the percentages IHL innermost hyperechoic layer, representing mucosa, PPV positive predictive value, NPV negative predictive value

visualization is further enhanced with the use of state-of-theart US techniques and high megahertz imaging (Figs. 3 and 5). Thus, MR imaging is not likely to provide as prominent a visualization as HRUS for compacted, small cholesterol crystal precipitates or calculi within the wall [4]. In terms of the depiction of intramural cystic spaces, HRUS could depict even tiny cystic lesions measuring smaller than 3 mm in diameter (Fig. 4) with a sensitivity of 51.1 %, although we still believe that MR imaging may be superior to HRUS for the depiction of intramural cystic spaces. MR imaging has superior contrast resolution and is not influenced by obesity, bowel gas or impacted gallbladder stones. Reportedly, Rokitansky–Aschoff sinuses could be more clearly visualized as background gallbladder wall enhances, whereas Rokitansky–Aschoff sinus remains anechoic on contrast-enhanced US (CEUS) [20]. Considering this advantage of CEUS, the combination of HRUS and CEUS would be more useful in the differential diagnosis between adenomyomatosis of the GB and early-stage, wallthickening-type GB cancer. Among the significant findings of HRUS for the diagnosis of early-stage, wall-thickening-type GB cancer, IHL irregularity had the highest accuracy, followed by loss of the multilayer pattern. The detailed visualization of IHL irregularity and the multilayer pattern of the gallbladder wall are mainly attributed to the compounding imaging technique and high megahertz imaging, slightly supported by speckle reduction imaging. There is a clinical concern in interpreting our data. In our study, the presence of these intramural cystic spaces had a specificity of 100 % for the diagnosis of adenomyomatosis. However, adenomyomatosis should not be diagnosed only

on the basis of the presence of several intramural cystic lesions because intramural cystic lesions can be rarely observed in GB cancer owing to the cystic dilation of cancerous glands or to the intramural spread of the cancer along pre-existing Rokitansky–Aschoff sinuses [21–23]. Our study has several limitations. Firstly, we included only patients who had surgically confirmed diagnoses that were documented in the pathological report. As adenomyomatosis of GB is likely under-reported because it is a benign condition of little concern to pathologists, our study group of patients with adenomyomatosis might include more severe cases. Secondly, the reviewers were blinded to the diagnosis of each case, but they knew the study objectives of evaluating the diagnostic performance of HRUS and discovering HRUS findings that could differentiate between adenomyomatosis and cancer. Therefore, the reviewers could exclude other diseases, such as xanthogranulomatous cholecystitis or chronic cholecystitis, that manifest as wall thickening, which is slightly different from real clinical practice. Finally, we analysed the qualitative features of HRUS (except for the finding of IHL thickening greater than 1 mm) by reviewers. Accordingly, those findings are subjective and may be influenced by individual standards. In conclusion, transabdominal HRUS, using up-todate technology with the addition of a high megahertz transducer, had a good diagnostic performance for differentiating between adenomyomatosis of the GB and early-stage, wall-thickening-type GB cancer. Understanding the HRUS features favouring adenomyomatosis of the GB versus GB cancer would be helpful in making the correct diagnosis.

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