endoscopic ultrasound in oncology
TRANSCRIPT
Endoscopic Ultrasound inOncology
Vivek Kaul, MD*, Shivangi Kothari, MDKEYWORDS
� Endoscopic ultrasound � Oncologic imaging � Cancer staging � Fine-needle aspiration � Oncology
KEY POINTS
� Endoscopic ultrasound (EUS) has emerged as an indispensable, dynamic imaging modality inoncology.
� The ability to provide real-time imaging and acquire tissue in a minimally invasive manner is partic-ularly appealing.
� Whereas previously limited to larger centers, EUS is now widely available, even in smallercommunities.
� For the vast majority of applications, EUS is a highly accurate, safe, and complementary (tocross-sectional imaging) technology, which has significant impact on the care of patients withcancer.
� Since its inception more than 2 decades ago, EUS technology has made rapid strides in terms ofechoendoscope sophistication and processor design and quality.
� In coming years, newer techniques such as elastography and contrast-enhanced EUS will furtheradvance oncologic imaging and continue to benefit patients.
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INTRODUCTION
Endoscopic ultrasound (EUS) has emerged as amajor technological advance in the realmof endoscopic imaging, particularly in gastroin-testinal (GI) oncology. Not only is EUS comple-mentary to cross-sectional imaging (computedtomography [CT], magnetic resonance [MR] imag-ing) for staging purposes, it also provides a safe,minimally invasive and highly effective portal foraccurate tissue diagnosis via fine-needle aspira-tion (FNA) and core-biopsy techniques.1
With ever increasing availability even in smallercenters, EUS has become the standard of carefor staging and tissue acquisition in several GI ma-lignancies, including esophageal, gastric, pancre-atic, and rectal neoplasms. In addition, EUS hasbeen used for staging and tissue diagnosis ofseveral non-GI tumors (lung, renal, adrenal, andlymphoma).
Division of Gastroenterology & Hepatology, Center for AdvMedical Center/Strong Memorial Hospital, 601 Elmwood* Corresponding author.E-mail address: [email protected]
Ultrasound Clin 9 (2014) 43–52http://dx.doi.org/10.1016/j.cult.2013.08.0041556-858X/14/$ – see front matter Published by Elsevier I
This article reviews the current role and impactof EUS in oncology along with a review of therecent literature and a brief description of the tech-nical aspects of EUS imaging. EUS in GI oncologyis discussed first, followed by a review of non-GIoncologic applications of EUS.
EUS EQUIPMENT
The EUS platform combines the advantages ofmodern flexible videoendoscopes with those ofa high-resolution ultrasound probe/processor, re-sulting in a powerful dynamic, transluminal imagingmodality with real-time tissue-acquisition capabil-ities. Two types of echoendoscopes are available:the 360� electronic radial echoendoscope(Fig. 1A) with imaging perpendicular to the endo-scope axis, and the linear-array echoendoscope(see Fig. 1B) with imaging along the axis of theendoscope and the ability to perform FNA. These
anced Therapeutic Endoscopy, University of RochesterAvenue, Box 646, Rochester, NY 14642, USA
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Fig. 1. (A) Radial echoendoscope. (B) Linear echoendoscope.
Kaul & Kothari44
endoscopes typically have “oblique viewing” op-tics, can have a water-filled balloon attached forbetter acoustic coupling, and can image at fre-quencies of 5 to 12 MHz, depending on the makeand model. Catheter-based “mini-probes” arealso available (2–2.6 mm diameter, 20 MHz and30 MHz); these are mechanical radial ultrasoundprobes that can be passed into the standardvideoendoscope working channel for imagingsmaller lesions and those lesions outside thereach of currently available echoendoscopes (eg,imaging in the proximal colon). The newer ultra-sound processors combined with the electronicechoendoscopes and ultrasound probes providehigh-resolution imaging, especially given the trans-luminal proximity to the target organs. A wide arrayof FNA needles is available, ranging from the verythin caliber 25-gauge to the larger 19-gauge“core” needles.Most EUS procedures can be performed using
moderate sedation and on an outpatient basis,with very low overall complication rates.2,3
EUS IN GI ONCOLOGY
Esophageal Cancer
EUS has become an integral part of preoperativestaging of esophageal cancer. In many aspects,it is complementary to CT and positron emissiontomography (PET) imaging, particularly in thosepatients suspected to have locally advanced dis-ease. Given the survival advantage offered by neo-adjuvant therapy, EUS plays an important role inhelping identify this subset of patients (ie, thosewith bulky, locally advanced disease). EUS allowsevaluation of the primary tumor (T staging) as wellassessment of both regional and distant lymphnode status (N staging).4,5 Invasion of the aorta
and other great vessels, lung, and pleura canalso be determined with EUS (Fig. 2).The ability to perform dynamic imaging and
obtain tissue in both the mediastinum andabdomen is particularly useful. In the mediastinum,the paraesophageal and para-aortic regions, aorto-pulmonary window, subcarinal space, and inferiormediastinum are easily accessible for examinationand tissue sampling. Below the diaphragm, theceliac axis, gastrohepatic ligament, and left lobeof the liver are imaged easily, and the ability toaccurately document metastases in these areashas a significant impact on the management ofesophageal cancer. EUS has limited utility inpatients with established metastatic disease.For esophageal cancer T staging, typically a
radial echoendoscope is used to assess theesophageal-wall layers and depth of infiltration oftumor. The standard criteria used for T stagingat EUS are listed in Table 1. Bulky and stenotic tu-mors may not allow passage of echoendoscopes,thus limiting the examination. Many of these pa-tients will require neoadjuvant therapy anyway,given the high probability of locally advanced(T3) and/or nodal disease (N1). Dilation of the ste-notic esophageal lumen to 14 to 16 mm may facil-itate EUS in these patients; more aggressivedilation is not recommended given the increasedrisk of perforation, which will then delay cancermanagement.6,7 Probe-based and wire-guidedsonographic imaging can be performed in thissetting, although this is likely of limited benefitfrom a clinical management perspective. Medias-tinal and intra-abdominal lymph nodes can beeasily examined and targeted for FNA using thelinear-array echoendoscope. The FNA needlepath should not cross the primary tumor, to pre-vent seeding of uninvolved tissue with neoplasticcells.
Fig. 2. (A–D) Esophageal cancer, EUS staging. MM, muscularis mucosae; SM, submucosa; T, tumor.
Endoscopic Ultrasound in Oncology 45
EUS has been shown to be highly accurate inthe staging of esophageal cancer, particularly forearly lesions, when performed by experienced en-doscopists. Although some earlier data suggestedlower accuracy, a more recent, large meta-analysis reported very high sensitivity, specificity,and accuracy rates.8,9 An earlier meta-analysis re-viewed accuracy of EUS, PET, and CT in the stag-ing of esophageal cancer.4 For EUS, the sensitivityand specificity for detecting celiac lymph nodemetastases were 85% and 96%, respectively.Sensitivity and specificity for other regional lymphnode metastases were 80% and 70%, respec-tively. For CT, sensitivity and specificity forregional lymph node metastases were 50% and
Table 1EUS Tstaging for esophageal and other luminaltumors
EUS Imaging T Stage
Tumor invades into submucosa T1
Tumor invades into muscularispropria
T2
Tumor invades through muscularispropria
T3
Tumor invades adjacentorgans/vessels
T4
83%, respectively. For abdominal lymph nodemetastases, these values were 42% and 93%,respectively, and for distant metastases 52%and 91%, respectively. For Fluorine-18-fluoro-deoxyglucose PET scanning, sensitivity and spec-ificity for regional lymph node metastases were57% and 85%, respectively. For distant metasta-ses these values were 71% and 93%, respectively.
Restaging with EUS in patients after neoadju-vant treatment can be difficult, especially in termsof T staging (owing to local inflammation, fibrosis,necrosis, and radiation changes). However, recur-rent nodal disease (regional or distant) can be eval-uated and targeted for FNA.
Pancreatic Cancer
Pancreatic cancer is the second leading cause ofdigestive cancer–related death in the UnitedStates. Because the vast majority (w85%) of pa-tients will not be candidates for surgical resectionat the time of diagnosis, accurate diagnosis andstaging is critical to avoid unnecessary surgery inthose with unresectable disease. Again, EUS playsa critical complementary role (along with CT) inproviding accurate imaging and tissue samplingof pancreatic masses, and has now become thestandard tissue-sampling modality for patientsfound to have a pancreatic mass on CT or MRimaging (Fig. 3).
Fig. 3. (A, B) Pancreatic mass and pancreatic mass FNA.
Kaul & Kothari46
In a patient with normal (unaltered) foregut anat-omy, the entire pancreas can be examined by EUSvia the transgastric and transduodenal stations.EUS has a well-established role in the detection,tissue diagnosis, and staging of pancreaticneoplasia. It is particularly good for identifyingsmall (<2 cm) lesions in the pancreas and for ob-taining accurate cytologic information with FNA.One of the limitations of EUS in the pancreas isthe difficulty in distinguishing an inflammatory(acute or chronic) mass from a neoplastic lesion,on imaging alone; FNA may help clarify the issuein some cases.The reported accuracy of EUS for T staging of
pancreatic cancer is highly variable, ranging from63% to 94%, with reported accuracies forN staging ranging from 44% to 82%.10,11
Comparing studies for T staging is difficultbecause of changes in T-staging criteria overtime. Two of the more recent studies showedan accuracy of 63% and 67% for T staging and67% and 44% for N staging.12,13 EUS-guidedFNA (EUS-FNA) has been reported to have highsensitivity and specificity in diagnosing pancre-atic cancer (80%–90% and 100%, respec-tively).14,15 The overall complication rates arevery low, and the procedure is usually performedon an outpatient basis.EUS-FNA has been found to be valuable in diag-
nosing pancreatic cancer when other imaging andtissue-sampling modalities (CT-guided percuta-neous biopsy, tissue sampling based on endo-scopic retrograde cholangiopancreatography)have been inconclusive or negative. EUS-FNAmay aid in the diagnosis and staging of pancreaticcancer in multiple ways:
� Help identify and sample lesions that are toosmall to be characterized by CT or MRimaging
� Sample lesions that are too encased bysurrounding vascular structures to permitsafe percutaneous biopsy
� Demonstrate malignant invasion of lymphnodes located in the celiac, para-aortic, retro-duodenal, or superior mesenteric regions
� Sample suspected small metastases in theleft lobe of the liver
� Confirm peritoneal carcinomatosis via sam-pling of ascitic fluid
In terms of vascular staging, earlier data sug-gested that EUS was superior to CT in terms ofdetermining resectability. However, subsequentstudies reported lower rates of sensitivity andspecificity for vascular invasion as determined byEUS (portal imaging better than mesenteric arterialimaging).16 The current standard of care for evalu-ation of a pancreatic mass involves obtaining acontrast-enhanced “pancreatic-protocol” CTscan and, in most cases, an EUS-FNA for confir-mation of tissue diagnosis. CT provides excellentvascular staging information and assesses fordistant/metastatic tumor, while EUS enables effi-cient, minimally invasive, highly accurate tissuesampling, and an additional perspective onvascular involvement. If the CT scan suggestsdistant metastatic disease (confirmed with percu-taneous tissue sampling), EUS is typically notperformed.EUS has been found to be particularly useful in
patients with suspected pancreatic neuroendo-crine tumors (NET), with very high rates of sensi-tivity, specificity, and accuracy. The ability tolocalize pancreatic NET when prior imaging was“negative” and the ability to aspirate lesions assmall as 5 mm have made EUS-FNA an invaluabletool in this arena.17
Overall, EUS is an extremely efficient modality inpancreatic tumor imaging and tissue sampling,
Endoscopic Ultrasound in Oncology 47
and is complementary to high-quality CT in termsof the preoperative evaluation of the patient withsuspected pancreatic neoplasia.
Rectal Cancer
Accurate staging of rectal cancer is important,because management and prognosis are linkedto the stage of tumor. Patients with early rectalcancer (stages I and II) may proceed directly tosurgery, whereas locally advanced lesions predi-cate neoadjuvant therapy first, followed by sur-gery. EUS has been found to have high accuracyfor T and N staging in rectal cancer, and to beeven superior to CT imaging for T-stage evalua-tion. A meta-analysis of 90 articles publishedbetween 1985 and 200218 comparing the stagingaccuracy of MR imaging, EUS, and CT usingpathologic staging as the gold standard, sug-gested the following:
� For determining muscularis propria invasion(ie, T1 vs T2) EUS and MR imaging had similarsensitivity; specificity of EUS was significantlyhigher (86% vs 69%).
� For perirectal tissue invasion (T3 disease), thesensitivity of EUS was significantly higher thaneither MR imaging or CT (90% vs 82% and79%, respectively).
� For invasion of adjacent organs (T4 disease)and lymph node involvement, estimates forEUS, CT, and MR imaging were comparable.
EUS and MR imaging have been found to havecomparable accuracy for T staging, although onestudy suggested that EUS was more accurate. Interms of N staging, EUS, CT, and MR imagingseem to have similar accuracies as reported inthe literature.19–21
In general, EUS and MR imaging (with or withoutan endorectal coil) can both be used for primarytumor staging. MR imaging offers some advan-tages over EUS: it permits a larger field of viewand can visualize more proximal tumors. MRI
Fig. 4. (A, B) Gastric cancer, EUS staging. ADV, adventitia;
tends to be less operator and technique depen-dent and it allows the study of stenotic tumors.
In terms of restaging after neoadjuvant therapyfor rectal cancer, the role for EUS is limitedbecause of local inflammation, radiation changes,and necrosis. Perirectal (extraluminal) tumor recur-rence can still be identified and sampled with EUSFNA with high accuracy.
Gastric Cancer
EUS remains a valuable tool in the locoregionalstaging of gastric carcinoma (Fig. 4). Most tumorlocations are easily accessed with the dedicatedechoendoscope. Lesions high in the gastricfundus may present a technical challenge, espe-cially if they are small, given the limited retroflexioncapability of these echoendoscopes and the imag-ing artifacts created with a nonlinear endoscopeposition.
Apart from T staging of the primary tumor, EUSallows for tissue sampling of perigastric (includingceliac) lymph nodes, evaluation of any liver le-sions, and assessment of mediastinal and retro-peritoneal/periportal lymph node stations formetastases.
The role of EUS in the staging of gastric cancerhas been well studied. One meta-analysis sug-gested that T staging was superior to N stagingwhen using EUS in gastric cancer. Another meta-analysis concluded that EUS was more accuratefor T staging of advanced disease (T3/T4) thanfor staging of early cancer (T1/T2).22,23 As in theesophagus, early (superficial) gastric tumors arenow increasingly being removed and pathologi-cally staged by endoscopic resection techniques(endoscopic mucosal resection [EMR] and endo-scopic submucosal dissection [ESD]). EUS playsa critical role in helping determine which lesionsare best suited for these EMR and ESD type inter-ventions. For example, if the muscularis propria isinvolved by tumor at EUS, endoscopic resectionshould not be attempted. Equally importantly, if
MP, muscularis propria; SM, submucosa; T, tumor.
Kaul & Kothari48
real-time FNA sampling of a lymph node is positivefor malignancy during a staging EUS, endoscopicresection should not be contemplated, regardlessof T stage.
Liver Masses and Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is the sixth mostcommon cancer in the world, with an estimatedincidence of more than 650,000 cases per year.Traditionally, transabdominal ultrasonography,CT, and MR imaging have been used for thescreening, surveillance, and diagnosis of HCC.However, for some time now there has been inter-est in evaluating liver lesions by EUS because ofthe close proximity of the liver to the foregut (stom-ach and duodenum) (Fig. 5). Nguyen and col-leagues24 used EUS-FNA to detect and sampleliver lesions in 14 patients suspected to have GImalignancy, including 11 patients in whom lesionswere not seen at CT, thereby influencing patientmanagement by more accurate staging of the pri-mary malignancy. In another study, Crowe andcolleagues25 demonstrated similar yield and effi-cacy for CT-guided FNA and EUS-FNA of liver le-sions. Another study by Singh and colleagues26
found a diagnostic accuracy of 98% with EUSversus 92% with CT for the detection of liver me-tastases in 132 patients. The study revealed thatEUS found a higher number of liver lesions andwas able to more accurately characterize verysmall lesions compared to CT scan.By contrast, Dodd and colleagues27 found rela-
tively low sensitivity (58%) of EUS for detection ofHCC in a series of 34 patients. A more recent, pro-spective study compared the accuracy of EUSwith that of CT for the detection of primary liver tu-mors in 17 high-risk patients with abnormal imag-ing and increased a-fetoprotein levels.28 Thereported diagnostic accuracy of transabdominalultrasonography, CT, MR imaging, and EUS-FNAwas 38%, 69%, 92%, and 94%, respectively.
Fig. 5. Liver metastasis, gastric primary.
Current experience suggests that the diagnosisof HCC is highly dependent on the size of thelesion, with tumors smaller than 2 cm being diffi-cult to image and even more difficult to biopsy,especially if the lesion is deep in the liver or inthe right lobe. The current evidence suggeststhat EUS-FNA is a feasible and safe modality forimaging and sampling HCC and liver lesions; how-ever, larger studies and more experience isneeded to define its role in this realm.29
Subepithelial Lesions in the GastrointestinalTract
Both incidentally found and symptomatic(bleeding, obstruction, pain) subepithelial lesionsin the gastrointestinal tract can be easily imagedwith either dedicated echoendoscopes (radial orlinear) or ultrasound mini-probes, the choice of in-strument usually being dictated by lesion size andlocation.30 FNA can be performed when the exam-ination is performed using a linear echoendo-scope. Because of the submucosal/intramurallocation of these lesions, standard endoscopic for-ceps (mucosal) biopsies are typically nondiagnos-tic; hence, these patients are commonly referredfor EUS examination.Gastrointestinal stromal tumors, carcinoids,
leiomyomas, and lipomas constitute the vast ma-jority of such lesions referred for EUS evaluation(Fig. 6). While real-time EUS imaging helps deter-mine the layer of origin of the lesion, FNA cytologyand immunohistochemical staining (eg, chromog-ranin, CD-117) can help confirm the precise diag-nosis and guide management. In the case oflarger lesions, fine needle core biopsy samplescan also be obtained during real-time EUS, whichprovide tissue architecture detail and more confi-dence in the diagnosis. The EUS characteristicsof the various subepithelial lesions are shown inTable 2.
EUS IN NON-GI ONCOLOGY APPLICATIONSLung Cancer and Mediastinal Adenopathy(Lymphoma)
EUS is an excellent modality for imaging andsampling lesions in the mediastinum, and comple-ments cross-sectional imaging and bronchoscopyin the staging of lung cancer.31,32 In addition totransbronchial biopsy, PET/CT, and mediastino-scopy, EUS has emerged as an additional mini-mally invasive procedure in staging protocols forlung cancer (Fig. 7). With EUS, the aortopulmonarywindow, subcarinal space, posterior and inferiormediastinum, and paraesophageal lymph nodestations can be imaged and sampled fairlyeasily. In addition, lymphadenopathy below the
Fig. 6. (A–F) Gastrointestinal submucosal lesions, EUS imaging.
Endoscopic Ultrasound in Oncology 49
diaphragm and a significant portion of the liver canbe evaluated also. In one study, EUS, PET, and CTwere compared in assessing mediastinal adenop-athy in patients with established lung cancer.33
EUS-FNA was found to be highly sensitive (94%)and specific (100%) for predicting lymph nodestage. EUS is also able to directly image and sam-ple lung masses that are in close proximity to and/or in contiguity with the esophageal wall, withoutsignificant risk of complications. The ability ofEUS to image and sample the adrenal gland formetastatic disease is particularly useful in patientswith lung cancer, thereby significantly influencingmanagement.34
In patients with suspected lymphoma or medi-astinal adenopathy of unexplained etiology, EUScan provide effective diagnostic tissue samplingvia FNA, core biopsy, and material for flowcytometry.35
Renal Masses
Renal masses and tumors have traditionally beenimaged and sampled via a CT-guided approach.EUS is able to easily image both the left kidney(transgastric approach) and the right kidney (trans-duodenal approach), and has been recently usedto assess renal lesions. A small multicenter case
Table 2EUS features of submucosal lesions in the GItract
Lesion EUS FeaturesLayer of Origin/Location
Lipoma Hyperechoic Submucosa
Leiomyoma Hypoechoic,discrete
Muscularismucosae
Muscularis propria
GI stromaltumor
Hypoechoic,discrete
Muscularis propria
Carcinoid Hypoechoic,discrete
Submucosa
Kaul & Kothari50
series has demonstrated the feasibility and safetyof EUS-FNA for kidney lesions. In the series byDe Witt and colleagues,36 15 patients with kidneymasses (median diameter 32 mm; range 11–60 mm) located in the upper (n 5 12) and lower(n 5 3) poles of the left (n 5 10) and right (n 5 5)kidneys, respectively, underwent EUS-FNA. Initialmass detection was by previous imaging in 13(87%) patients or by EUS in 2 (13%) patients. Re-sults of EUS-FNA were diagnostic of (n 5 7) orhighly suspicious for (n 5 1) renal cell carcinoma(RCC), atypical cells (n 5 2), oncocytoma (n 5 1),benign cyst (n 5 1), and nondiagnostic (n 5 1).
Fig. 7. (A–C) Mediastinal lesions, EUS imaging. AO, aorta;
Surgical resection confirmed RCC in 7 patients inwhom preoperative EUS-FNA demonstratedRCC (n5 5) or oncocytoma (n5 1), or was not per-formed (n 5 1). No complications were reported inthis study. Although these results are encouraging,more studies are needed to further assess the roleof EUS in the realm of renal mass evaluation.
EUS-BASED THERAPEUTIC INTERVENTIONS INONCOLOGY
In addition to the imaging and tissue-acquisitioncapabilities, there are several specific EUS-based interventions that can be performed aspart of the overall management of certain malig-nancies. These procedures include celiac plexusneurolysis, EUS-guided biliary access, fiducialplacement for more targeted radiotherapy, andinjection of chemotherapeutic agents into tumor.37
A detailed discussion of these interventions isundertaken in the article Therapeutic Applicationsof Endoscopic Ultrasound by Kothari and Kaulelsewhere in this issue.
COMPLICATIONS OF EUS AND EUS-FNA
Apart from the usual complications associatedwith endoscopy (cardiovascular events, sedation-and anesthesia-related issues), some additionalEUS-specific potential adverse events merit
LN, lymph nodes; PA, pulmonary artery.
Endoscopic Ultrasound in Oncology 51
discussion. These events are primarily related tothe design and functionality of echoendoscopes(long rigid tip, oblique viewing optics) and the na-ture of transluminal interventions (FNA, fine-needle biopsy) typically performed during EUS.The risk for GI perforation and bleeding in a pro-spective study of 300 patients was 0% to0.4%.3,38 The bleeding rate was reported to beup to 6% in one study of FNA in pancreatic cysticlesions.39 Infectious complications have been re-ported in 0.3% of EUS-FNA procedures. Infectionhas been reported with FNA of cysts, in both themediastinum and the abdomen; the risk is mark-edly decreased with use of prophylactic antibi-otics. Pancreatitis after FNA of solid and cysticlesions has been reported at rates of 0.6% and2%, respectively.40 Although usually mild, severepancreatitis has also been reported. Avoidanceof normal pancreatic tissue and limiting the num-ber of needle passes may help mitigate this risk.
SUMMARY
EUS has emerged as an indispensable, dynamicimaging modality in oncology. The ability to pro-vide real-time imaging and acquire tissue in a mini-mally invasive manner is particularly appealing.Whereas previously limited to larger centers,EUS is now widely available, even in smallercommunities.
For the vast majority of applications, EUS is ahighly accurate, safe, and complementary (tocross-sectional imaging) technology that has sig-nificant potential in terms of influencing the careof patients with cancer. Since its inception morethan 2 decades ago, EUS technology has maderapid strides in terms of echoendoscope sophisti-cation, and processor design and quality. In thecoming years, newer techniques such as elastog-raphy and contrast-enhanced EUS will furtheradvance oncologic imaging and continue tobenefit patients with cancer.
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