对比超声内镜
Contrast Harmonic Echo–Endoscopic Ultrasound Improves Accuracy in Diagnosis of Solid Pancreatic Masses
PIETRO FUSAROLI,*ALESSIA SPADA,?MARIA GRAZIA MANCINO,*and GIANCARLO CALETTI*
*Department of Clinical Medicine,GI Unit,University of Bologna/Aziendo Sanitaria Locale of Imola,Imola,Italy;and?Department of Economical,Mathematical and Statistical Sciences,University of Foggia,Italy
BACKGROUND&AIMS:Contrast harmonic echo(CHE) has been developed for endoscopic ultrasound(EUS).This new
technique detects echo signals from microbubbles in vessels
with very slow?ow,without artifacts.We assessed whether
CHE–EUS increases the accuracy of diagnosis of pancreatic
solid lesions.METHODS:At a tertiary-care EUS center,we examined90patients who were suspected of having pancreatic
solid neoplasm.Radial and linear echoendoscopes were used
with dedicated software for CHE.Sonovue(Bracco Interna-
tional BV,Amsterdam,The Netherlands)uptake,pattern,and
washout were studied;data were compared for pancreatic le-
sions and adjacent parenchyma.The?nal diagnosis was ob-
tained based on results of surgical pathology and/or EUS–?ne
needle aspiration(FNA)analyses.RESULTS:The?nding of a hypoenhancing mass with an inhomogeneous pattern was a sensitive and accurate identi?er of patients with adenocarci-noma(96%and82%,respectively)(49of51patients with primary pancreatic adenocarcinoma had a hypoenhancing mass that was inhomogeneous and had fast washout).This?nding was more accurate in diagnosis than the?nding of a hypo-echoic lesion using standard EUS(P?.000).Hyperenhance-ment speci?cally excluded adenocarcinoma(98%),although sensitivity was low(39%).Of neuroendocrine tumors,11of13 were non–hypo-enhancing(9hyperenhancing,2isoenhancing). Interestingly,CHE–EUS allowed detection of small lesions in7 patients who had uncertain standard EUS?ndings because of biliary stents(n?5)or chronic pancreatitis(n?2).Targeted EUS–FNA was performed on these lesions.CONCLUSIONS: Detection of a hypoenhancing and inhomogeneous mass accurately identi?ed patients with pancreatic adenocarci-noma.CHE–EUS increased the detection of malignant le-sions in dif?cult cases(patients with chronic pancreatitis or biliary stents)and helped guide EUS–FNA.A hyperenhanc-ing pattern could be used to rule out adenocarcinoma. Keywords:Contrast Agents;Image Enhancement;Contrast Har-monic;Echo Features;Pancreatic Lesions.
I ntravenous ultrasound contrast agents are made of micro-
bubbles?lled with heavy gases that allow a better visualiza-tion of the blood supply.1Their use has become a standard of practice in transabdominal ultrasound to detect and character-ize focal lesions of the liver and the pancreas.2Ultrasound contrast agents have been shown to improve the diagnostic accuracy and overcome some technical limitations owing to meteorism and abdominal fat.3–7
On the other hand,the use of ultrasound contrast agents in endoscopic ultrasound(EUS)is not widespread yet.The major limitation is attributable to their use in combination with nondedicated techniques such as color-and power-Doppler8–15 that are hampered by several artifacts.
A dedicated contrast harmonic echo(CHE)has become avail-able for the enhancement of ultrasound contrast agents in EUS only recently.CHE–EUS is a new technique that is able to detect signals from microbubbles in vessels with very slow?ow with-out the burden of Doppler-related artifacts.
We have used CHE–EUS with Sonovue(sulfur hexa?uoride MBs;Bracco International BV,Amsterdam,The Netherlands) for the investigation of patients with pancreatic solid masses since2007.The aim of our study was to assess whether CHE–EUS increases diagnostic accuracy of pancreatic solid lesions by improving differential diagnosis.
Materials and Methods
Patients
This was a retrospective analysis of prospectively en-rolled patients between July2007and December2008.
Inclusion Criteria
Inclusion criteria for the study were as follows:echofea-tures of an undetermined,predominantly solid pancreatic le-sion seen at standard EUS(ie,the solid component was?50% of the total volume of the lesion).All the patients had been referred for EUS after detection of the lesions by transabdom-inal ultrasound and/or computerized tomography and/or mag-netic resonance imaging.
Exclusion Criteria
Exclusion criteria were a known or suspected unstable coronary disease or patients unwilling to consent.
This study was approved by our local ethics committee.
Gold Standard of Diagnosis
The?nal diagnosis was achieved either by surgical pa-thology(n?65)or by aspiration cytology/histology with EUS–?ne-needle aspiration(FNA)(n?78).Some patients had both techniques performed(n?60).Patients with EUS–FNA–nega-Abbreviations used in this paper:AUC,area under the curve;CHE, contrast harmonic echo;EUS,endoscopic ultrasound;FNA,?ne-needle aspiration;NET,neuroendocrine tumors;ROC,receiver operator char-acteristic.
?2010by the AGA Institute
1542-3565/$36.00
doi:10.1016/j.cgh.2010.04.012
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY2010;8:629–634
tive results for malignancy were always followed up with clinical and instrumental examinations to rule out false-negative re-sults(minimum follow-up period,12months).
Echoendoscopes and Standard Endoscopic
Ultrasound Technique
We used radial and linear echoendoscopes for this study.Both echoendoscopes were equipped with a pink ultra-sound transducer purposely developed for CHE–EUS.
A commercially available radial echoendoscope(GFUE160; Olympus,Tokyo,Japan)was used for the pure diagnostic im-aging.A prototype linear echoendoscope(XGF-UCT180;Olym-pus)was used both for diagnostic imaging and for EUS–FNA. The ultrasound processor was the Aloka Alfa-10(Aloka,Tokyo, Japan),which incorporates dedicated software for the CHE.
The EUS examinations were performed under conscious sedation using meperidine and midazolam with patients lying on the left lateral decubitus.
All the EUS examinations were performed by experienced endosonographers(G.C.and P.F.).The techniques of EUS ex-amination and of EUS–FNA were described in detail else-where.16
Technique of Contrast Harmonic
Echo–Endoscopic Ultrasound
Sonovue was used as the contrast agent in all the cases.
The extended pure harmonic detection mode,which com-bines receiving frequencies of?ltered fundamental and second harmonic components with a transmitting frequency of3.4 MHz,was used for CHE–EUS.17
For an optimal visualization of the microbubbles a mechan-ical index of0.36was required with the radial echoendoscope and of0.28with the linear echoendoscope.
The standard dose of Sonovue was2.5mL.Notably,no difference in image quality was obtained by using a full vial or a half vial of Sonovue(5vs2.5mL)in our experience before this study(data not shown).
After having performed a complete EUS examination of the pancreas in B-mode,the echoendoscope was placed in front of the pancreatic area of interest and switched to the CHE mode. The intermittent modality of the monitor was activated to keep a reference B-mode imaging beside the CHE image.For each examination,2.5mL of Sonovue rapidly was injected intrave-nously followed by a5-mL?ush of saline.Then,Sonovue uptake and washout were evaluated for at least150seconds in each lesion.
The CHE screen is almost black at baseline.A few seconds after infusion the microbubbles of Sonovue are seen as strong white echo-signals depicting large and small vessels.Arterioles and venules,both within the parenchyma and into the tumor, are visualized,too.
Perfusion of the pancreatic lesions was continuous with dynamic observation of the shift from the unenhanced phase to the contrast-enhanced phase.The enhancement pattern of the lesions was compared with that of the adjacent normal paren-chyma and was the result of the internal vascular architecture of the lesion(hypovascular or hypervascular,regular or disrupted vessels).A few seconds after infusion of Sonovue the arterial phase was observed as hyperechogenicity of the aorta and other major perilesional arteries.Approximately40seconds after in-fusion the venous phase began as recognized by the hyperecho-genicity of the splenomesenteric-portal vessels.
Similarly to transabdominal ultrasound,the Sonovue uptake was differentiated into3patterns(hyperenhancement,isoen-hancement,and hypoenhancement).We also de?ned2distri-bution patterns(homogeneous,inhomogeneous),and2types of washout(slow,fast).
Each examination was recorded on DVD.The videos were reviewed carefully by the endosonographers after each exami-nation and a de?nition of Sonovue uptake,pattern,and wash-out was reached by consensus in all cases.
Statistical Analysis
The sensitivity,speci?city,positive predictive value,neg-ative predictive value,and accuracy in the characterization of adenocarcinoma were calculated for standard EUS and CHE–EUS,and in the characterization of lesions other than adeno-carcinoma for CHE–EUS.
In addition to evaluation of adenocarcinoma,receiver oper-ator characteristic(ROC)analysis was performed for a compar-ison between standard EUS and CHE–EUS to examine the interaction between sensitivity and speci?city,and to quantify test performance using the area under the curve(AUC)and P value.18,19
Statistical data analysis was performed with the statistical software SPSS15.0for Windows(SPSS Inc,Chicago,IL).
Results
In the study period,114patients were referred to our gastrointestinal unit for suspected pancreatic solid neoplasms. Among these,24patients were excluded because no solid tu-mors were found at standard EUS(cystic lesions,17;bile duct stones,5;inability to image the entire pancreas because of previous gastric surgery,2).
CHE–EUS was performed on90patients who constituted our study group.Their echofeatures at standard EUS were as follows:hypoechoic lesions either with regular or irregular margins(n?76),isoechoic lesions(n?5),hyperechoic lesions (n?1),and ill-de?ned lesions owing to concomitant chronic pancreatitis and/or biliary stents(n?8).The?nal diagnosis for Table1.Population Characteristics
Median age,y(range)67(34–86)
Sex44M,46F
Median size of the lesions,mm
(range)
25.0(9–100) Location of the lesions Head,57;body,30;tail,3 Final diagnosis
Adenocarcinoma51
NET13
Focal pancreatitis13
No pathologic?nding5 Metastasis,renal2 Metastasis,melanoma1 Metastasis,sarcoma1
Abscess1 Schwannoma1
Juxta-ampullary carcinoma1 Intrapancreatic lymph node1
630FUSAROLI ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol.8,No.7
each case according to either surgical pathology or EUS–FNA combined with follow-up evaluation is reported in Table 1.The classi?cation of ?nal diagnosis according to the Sonovue patterns of uptake,distribution,and washout is shown in Table 2.The analysis of Sonovue patterns in relation to the ?nal diagnosis also is shown in Table 2.
Primary pancreatic adenocarcinoma was the most frequent lesion in our population.Of note,of 51adenocarcinomas,49turned out to be hypoenhancing,inhomogeneous,and with fast washout (Figure 1).Sensitivity,speci?city,and overall accuracy were 96%,64%,and 82%,respectively.In comparison,the ?nd-ing of a hypoechoic lesion on standard EUS showed lower sensitivity,speci?city,and overall accuracy (86%,18%,and 57%,respectively)(Table 3).
The AUC of the ROC analysis for standard EUS was 0.521(standard error,0.062)(P ?NS),whereas for CHE–EUS the AUC was 0.801(standard error,0.051),(extremely signi?cant:P ?.001)(Supplementary Figure 1).The ROC curve calculated for CHE–EUS showed an AUC greater than standard EUS (difference between areas,0.280).
Interestingly,CHE–EUS allowed detection of small hypoen-hancing lesions in 7of 8patients with uncertain standard EUS ?ndings owing to biliary stents (n ?5)or diffuse chronic pancreatitis (n ?2)(Figure 1).Targeted EUS–FNA of these hypoenhancing lesions detected malignant cells.The mean size of these lesions was 18.8mm (range,15–30mm).
Hyperenhancement was a very speci?c sign (98%)for exclu-sion of adenocarcinoma although its sensitivity was low (39%).Moreover,11of 13neuroendocrine tumors (NET)were non–hypoenhancing (9hyperenhancing,2isoenhancing)(Table 3and Figure 2).
No complications occurred related to the use of Sonovue.
Discussion
Higher sensitivity and speci?city have been reported for
EUS in the diagnosis of pancreatic malignancies in comparison with transabdominal ultrasound,computed tomography,and magnetic resonance imaging.20–25
However,EUS presents some limitations.It is operator-depen-dent and biliary stents and chronic pancreatitis are well-known confounding factors.26,27EUS–FNA often is required for tissue con?rmation but it may be hampered by the same factors.28–31
Table 2.Correlation Between Final Diagnosis and Sonovue Pattern
Final diagnosis according to Sonovue pattern
Hypoenhancing (n ?63)
Hyperenhancing (n ?16)
Isoenhancing (n ?11)Adenocarcinoma 49NET
9NET
2Focal pancreatitis 9Metastasis (renal)
2No pathologic ?nding 4NET
2Juxta-ampullary carcinoma 1Focal pancreatitis 4Intrapancreatic lymph node 1Metastasis,melanoma 1Adenocarcinoma
1
Metastasis,sarcoma 1No pathologic ?nding 1Schwannoma
1
Abscess
1Adenocarcinoma
1
Sonovue pattern according to ?nal diagnosis
Adenocarcinoma (n ?51)NET (n ?13)
Focal pancreatitis (n ?13)Hypoenhancing 49Hypoenhancing 2Hypoenhancing 9Hyperenhancing 1Hyperenhancing 9Hyperenhancing 0Isoenhancing 1Isoenhancing 2Isoenhancing 4Homogeneous 1Homogeneous 9Homogeneous 4Inhomogeneous 50Inhomogeneous 4Inhomogeneous 9Fast 50Fast 4Fast 10Slow
1
Slow
9
Slow
3
Figure 1.(A )Left panel :standard EUS shows a hypoechoic mass with irregular margins.Right panel :CHE–EUS shows a hypoenhancing le-sion with small and large intratumoral vessels (arrows )with inhomoge-neous pattern predicting an adenocarcinoma.(B )Another case in which a biliary stent (arrow )is creating artifacts (arrowheads ),hampering the exploration of the pancreatic head.(C )After Sonovue injection a small hypoenhanced area (arrowheads )is detected with disrupted internal vessel (arrows ).Targeted EUS–FNA revealed adenocarcinoma.
July 2010CHE–EUS IN PANCREATIC TUMORS 631
We have shown that CHE–EUS may overcome some of these limitations and improve the diagnostic accuracy.Interestingly,in 7patients whose pancreas was visualized inadequately owing to biliary stents or diffuse chronic pancreatitis,a small hypoen-hancing lesion clearly was seen only by CHE–EUS,allowing targeting of EUS–FNA.The ?nal diagnosis was adenocarci-noma in all these patients.After a careful review of these videos,it was the common opinion of the investigators that these lesions were visualized inadequately with standard EUS and that CHE–EUS was fundamental for targeting EUS–FNA.In this respect,CHE–EUS provided an increase in diagnostic yield of pancreatic adenocarcinoma of almost 8%.
Until now,contrast-enhanced EUS has been performed with power-or color-Doppler.Dietrich et al 8used contrast-enhanced color-Doppler EUS to investigate patients with an undeter-mined pancreatic tumor.Ductal adenocarcinoma of the pan-creas showed a hypovascularity in 57of 62cases whereas all other pancreatic lesions showed isovascularity or hypervascu-larity (20neuroendocrine tumors,10serous microcystic adeno-mas,and 1teratoma).In their experience,hypovascularity as a sign of malignancy in contrast-enhanced EUS obtained 92%sensitivity and 100%speci?city.
We used Sonovue in combination with the dedicated CHE–EUS technique.Unlike contrast-enhanced color-and power-Doppler EUS that are limited by movement artifacts (known as ballooning and overpainting),CHE–EUS allowed a clear depic-tion of small intrapancreatic and intratumoral vessels.
The ?rst description of CHE–EUS with a preliminary proto-type was given by Dietrich et al.32The technique subsequently was improved and validated by a Japanese study 17reporting the experience with a dedicated CHE and a prototype linear ech-oendoscope in mixed clinical conditions such as pancreatobili-ary carcinomas,gastrointestinal stromal tumors,and lymph node metastases.In this feasibility study it was shown that a mechanical index of 0.4allowed a successful visualization of parenchymal perfusion and microvasculature in the pancreas.On the other hand,contrast-enhanced power-Doppler EUS did not depict the parenchymal perfusion images and branching vessels,whereas blooming artifacts of large vessels were ob-served.
Our ?nding of a hypoenhancing mass with an inhomoge-neous pattern was very sensitive and accurate for the prediction of adenocarcinoma (96%and 82%,respectively).The AUC was extremely signi?cant (AUC,0.801;P ?.001),re?ecting a higher diagnostic accuracy for CHE–EUS compared with standard EUS (AUC,0.521;P ?NS).
Besides,the ROC curves showed a greater AUC for CHE–EUS than for standard EUS,con?rming a better performance of CHE–EUS for evaluation of adenocarcinoma.
However,the speci?city of this CHE–EUS ?nding for the prediction of adenocarcinoma was lower than in the study by Dietrich et al.8We believe that this difference was owing to the inclusion of focal pancreatitis in our study.We think that the real clinical conditions are better represented this way rather than restricting the analysis only to neoplastic lesions.However,the differentiation between adenocarcinoma and focal mass-forming pancreatitis was not possible by the sole means of CHE–EUS in 9of 13focal pancreatitis cases.Recently accom-plished improvements of the settings of the CHE in the ultra-sound processor are currently under evaluation for differential diagnosis in this respect.
The ?nding of a hyperenhancing lesion on CHE–EUS,both with homogeneous and inhomogeneous patterns,was a strong predictor of histology different than adenocarcinoma (94%pos-itive predictive value),that is,NET and metastases (from renal cancer and from melanoma).NET were the most common hyperenhancing lesions overall.Based on these ?ndings,we believe that a hyperenhancing lesion in a patient with clinical suspicion of NET mandates surgical resection without the need of EUS–FNA.Metastases from renal cancer showed the same behavior of NET (hyperenhanced,homogeneous pattern,slow washout).In theses cases a good knowledge of the patient’s
Table 3.Sensitivity,Speci?city,Positive Predictive Value,Negative Predictive Value,and Accuracy of Standard EUS and CHE–EUS
Sensitivity
Speci?city Positive predictive value Negative predictive value Accuracy Hypoechoic lesion on standard EUS as a predictor of adenocarcinoma
86%(73%–94%)18%(8%–34%)58%(47%–69%)59%(24%–76%)57%(50%–64%)Hypoenhancing lesion on CHE–EUS as a predictor of adenocarcinoma
96%(85%–99%)64%(47%–78%)78%(65%–87%)93%(74%–99%)82%(74%–85%)Hyperenhancing lesion on CHE–EUS as an exclusion sign of adenocarcinoma 39%(30%–41%)98%(92%–100%)94%(74%–99%)68%(63%–69%)72%(65%–74%)Hyperenhancing lesion on CHE–EUS as a predictor of NET
69%(46%–86%)
90%(87%–94%)
56%(33%–76%)
95%(87%–98%)
88%(81%–93%)
NOTE.Data in parentheses are 95%con?dence
intervals.
Figure 2.(A )Before injection of the contrast a hypoechoic lesion is visible in the pancreatic head (arrows ).(B )In the arterial phase,approx-imately 23seconds after Sonovue injection,the lesion becomes mark-edly hyperenhanced with a homogeneous pattern predicting a neu-roendocrine tumor (arrow ).
632FUSAROLI ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol.8,No.7
medical history was fundamental to make a distinction between the2entities.
CHE–EUS was also helpful in ruling out neoplastic lesions in patients whose?nal outcome was the absence of pathologic ?ndings.Of5cases presenting with mild focal echostructural changes of uncertain interpretation on standard EUS,4were isoenhancing on CHE–EUS(ie,the uncertain areas showed an identical uptake of Sonovue compared with the normal sur-rounding parenchyma).The absence of disease was con?rmed by negative EUS–FNA and follow-up evaluation.
As far as costs are concerned,we believe that CHE–EUS did not weigh signi?cantly on the whole expenses of the procedure (the cost of half a Sonovue vial is about10%of the cost of a EUS–FNA needle in our country).Our proposal of a clinical algorithm incorporating CHE–EUS is shown in Supplementary Figure2.
Lastly,it deserves mentioning another technique of image enhancement.EUS-elastography is used to differentiate poten-tially neoplastic tissue from in?ammation.It is based on the measurement of tissue stiffness performed with the ultrasound processor:this parameter appears to correlate with the malig-nant potential of the lesions.EUS-elastography is a software-based analysis and no contrast injection is needed.33No sys-tematic comparison between CHE–EUS and EUS-elastography has been published.A preliminary experience on21patients presented at Digestive Diseases Week reported that CHE–EUS was superior to EUS-elastography for the differentiation be-tween benign and malignant pancreatic lesions.34However, larger studies are warranted on this issue.
In summary,CHE–EUS was shown to be feasible and safe for the study of solid lesions of the pancreas.It was able to depict the small vessels by Sonovue enhancement without the com-mon artifacts encountered with contrast-enhanced color-and power-Doppler EUS.The?nding of a hypoenhanced lesion with inhomogeneous uptake was a sensitive and accurate pre-dictor of pancreatic adenocarcinoma.Moreover,CHE–EUS al-lowed overcoming artifacts induced by biliary stents and chronic pancreatitis and performance of targeted EUS–FNA,to improve the diagnosis of pancreatic adenocarcinoma.On the other hand,the?nding of a hyperenhanced lesion was highly predictive of a lesion different from adenocarcinoma.
Supplementary Material
Note:To access the supplementary material accompa-nying this article,visit the online version of Clinical Gastroenter-ology and Hepatology at https://www.wendangku.net/doc/df14964072.html,,and at doi:10.1016/ j.cgh.2010.04.012.
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Reprint requests
Address requests for reprints to:Pietro Fusaroli,MD,University of Bologna,Viale Oriani1,40024Castel S.Pietro Terme,Italy.e-mail: p.fusaroli@ausl.imola.bo.it;fax:(39)051-6955206. Acknowledgments
The authors thank the Olympus Company for loaning our center the dedicated linear echoendoscope and for providing the Sonovue vials used in this study.
Con?icts of interest
The authors disclose no con?icts.
of0.500.
Supplementary Figure 2.A clinical algorithm incorporating the use of CHE–EUS.
July 2010CHE–EUS IN PANCREATIC TUMORS 634.e2