Endoscopic Ultrasonography

Number: 0446

Policy

1. Aetna considers endoscopic ultrasonography (EUS) medically necessary for any of the following indications:

   1. Diagnosiing common bile duct stones; or
   2. Evaluating abnormalities of the biliary tree; or
   3. Evaluating abnormalities of the gastrointestinal tract wall or adjacent structures; or
   4. Evaluating abnormalities of the pancreas, including masses, pseudocysts and chronic pancreatitis; or
   5. Evaluating adenopathy and masses of the posterior mediastinum (endoscopic ultrasonography with fine-needle aspiration); or
   6. Evaluating idiopathic acute pancreatitis; or
   7. Gallbladder drainage for acute cholecystitis; or
   8. Placement of fiducials into tumors within or adjacent to the wall of the gastrointestinal tract; or
   9. Providing endoscopic therapy under ultrasonographic guidance; or
   10. Providing endoscopic ultrasound-guided biliary drainage for palliation of malignant biliary obstruction; or
   11. Sampling tissue of lesions within, or adjacent to, the wall of the gastrointestinal tract; or
   12. Staging of lung cancer (endoscopic ultrasonography with fine-needle aspiration); or
   13. Staging tumors of the gastrointestinal tract (including the esophagus, the stomach, the rectum), pancreas and bile ducts; or 
   14. Surveillance of certain gastric subepithelial masses (asymptomatic glomus tumors or small (less than 3 cm) gastrointestinal stromal tumors); or
   15. To perform celiac plexus block for chronic pancreatitis or celiac plexus neurolysis for pancreatic cancer.

2. Aetna considers EUS experimental and investigational for all other indications (not an all-inclusive list) because of insufficient evidence in the peer-reviewed literature, including the following conditions:

   1. Diagnosis of esophageal varices; and
   2. EUS-elastography (for differentiation of benign and malignant pancreatic masses; differential diagnosis of malignant lymph nodes; for adrenal glands, hepatobiliary/gastrointestinal tract pathology (including anal canal), lung, mediastinum, and urogenital tract); and 
   3. Evaluation of common bile duct dilation in persons without signs or symptoms; and 
   4. Staging of tumors shown to be metastatic by other imaging methods (unless the results are the basis for therapeutic decisions); and  
   5. When the results will not alter care of the member.

3. Aetna considers endoscopic ultrasonography-guided ablation therapies for the treatment of pancreatic cystic neoplasms experimental and investigational because their effectiveness has not been established.

4. Aetna considers endoscopic ultrasonography-guided interstitial brachytherapy for the treatment of unresectable pancreatic cancer experimental and investigational because its effectiveness has not been established.

5. Aetna considers EchoTip Insight (an endoscopic ultrasound-guided device) experimental and investigational for direct measurement of hepatic portosystemic pressure gradient because its effectiveness has not been established.

Background

Endoscopic ultrasonography (EUS) incorporates high-frequency ultrasound into the tip of the endoscope to visualize the gastrointestinal wall and surrounding structures.  Using endoscopy, ultrasound probes can be placed in close proximity to the target anatomy, thereby enhancing resolution of the gastrointestinal wall and adjacent structures.  Tissue samples can be obtained and therapy can be performed by passing instruments under ultrasonographic guidance.

Endoscopic ultrasonography is used for staging tumors of the gastrointestinal tract, pancreas and bile ducts; the most notable application is in staging esophageal, gastric, and rectal tumors.  Studies show that EUS is the most accurate imaging modality for staging depth of tumor invasion, with pre-operative accuracy in the 80 % to 90 % range when compared with surgical pathology.  However, biopsy and histopathologic evaluation are needed to identify the specific histology.  Endoscopic ultrasonography can not reliably distinguish an inflammatory process from a neoplastic process.  In addition, EUS has proved less accurate in staging lymph node than in staging depth of tumor invasion because the node has to be located and then identified as benign or malignant.

A recent advance of EUS is high-frequency ultrasound probe sonography (HFUPS).  This has been researched as a method of providing ultrasound imaging of visible lesions without endoscope exchange as it can be performed through the biopsy channel of an endoscope.  Two commercially available probes, the Olympus UM-2R/UM-3R Ultrasonic Probes (Olympus Optical Co.) and the Fujinon Sonoprobe SP-701 (Fujinon, Inc.), have received 510(k) status from the Food and Drug Administration.  High-frequency ultrasound probe sonography has been used in the staging of esophageal, gastric, ampullary, pancreatobiliary, and colonic neoplasms; however, there is limited information on the clinical impact of HFUPS.  The American Society for Gastrointestinal Endoscopy (ASGE) reviewed the medical literature on HFUPS and concluded that HFUPS can provide detailed imaging of the gastrointestinal wall for the evaluation and staging of mucosal and submucosal lesions of the gastrointestinal tract and pancreatico-biliary tree.  It may also provide useful information that could affect therapeutic strategies in patients with superficial lesions; however, the technique should be reserved for use by centers with significant experience in EUS.  In addition, further studies on the clinical impact of HFUPS are necessary.

Endoscopic ultrasonography has been proven a reliable and accurate diagnostic tool for staging tumors of the gastrointestinal tract, pancreas and bile ducts; evaluating abnormalities of the gastrointestinal tract wall or adjacent structures; tissue sampling of lesions within, or adjacent to, the wall of the gastrointestinal tract; evaluation of abnormalities of the pancreas, including masses, pseudocysts and chronic pancreatitis; evaluation of abnormalities of the biliary tree; and providing endoscopic therapy under ultrasonographic guidance.  These indications for EUS were supported by the guidelines on the Appropriate Use of Gastrointestinal Endoscopy (1997) developed by the ASGE with the assistance and support of the American Gastroenterological Association, the American College of Gastroenterology, the Society for Surgery of the Alimentary Tract, the Society of American Gastrointestinal Endoscopic Surgeons, and the American Society for Colon and Rectal Surgery.

Sreenarasimhaiah (2005) stated that the emergence of EUS has given promise to improved staging with its ability to examine tumors from within the gastrointestinal lumen with extremely close proximity.  An additional advantage is the ability to perform fine-needle aspiration (FNA) biopsy to confirm or exclude tumor involvement.  Many studies have demonstrated superior accuracy in staging with EUS and EUS-FNA for tumors of the esophagus, stomach, pancreas, rectum, and mediastinum, including lung cancer.  This is in agreement with previous findings. 

Guidelines from the ASGE (Jacobson et al, 2003) concluded that EUS-FNA is indicated for the evaluation of adenopathy and masses of the posterior mediastinum.  The guidelijnes state that it is the procedure-of-choice for tissue sampling of such lesions in the subcarinal, subaortic (aorto-pulmonary window), and peri-esophageal stations found on cross-sectional imaging.  The guidelines state that EUS-FNA should also be considered in the pre-operative staging of patients with non-small cell lung cancer without definite adenopathy on cross-sectional imaging.

The medical position on the management of patients with gastric subepithelial masses from the American Gastroenterological Association Institute (Hwang and Kimmey, 2006) noted that patients with symptoms that can be attributed to the mass should undergo endoscopic or surgical resection of the mass.  Current evidence does not allow making a firm recommendation on the optimal management of the patient with an incidentally detected, asymptomatic gastric subepithelial mass.  Options include performing no further testing or monitoring, following the mass with periodic endoscopic or EUS surveillance, and endoscopic or surgical resection of the mass.  These management options should be discussed with the patient and whenever possible guided by EUS imaging and tissue sampling information, because the clinical significance of the mass is highly variable.  This guideline recommended EUS surveillance for asymtomatic patients with glomus tumor or gastrointestinal stromal tumor that is less than 3 cm in diameter.

In a meta-analysis and systematic review, Puli et al (2009) evaluated the accuracy of EUS in diagnosing nodal metastasis of rectal cancers.  The authors concluded that the sensitivity and specificity of EUS is moderate.  They stated that further refinement in EUS technologies and diagnostic criteria are needed to improve the diagnostic accuracy.

Shirakawa et al (2004) noted that peripheral lung lesions are increasing in numbers.  Since conventional diagnostic procedures have limitations in availability and results, endoscopic diagnosis is essential for the prevention of unnecessary operations.  The authors concluded that: when the lesion can be correctly described by endobronchial ultrasonography from inside the lesion, endobronchial ultrasonography is useful to guide transbronchial lung biopsy, can contribute to a reduction in patient discomfort and improves the accuracy of diagnosis.  Kramer and colleagues (2004) concluded that EUS-FNA can replace more than half of the surgical staging procedures in lung cancer patients with mediastinal and/or upper retroperitoneal positron emission tomography hot spots, thereby saving 40 % of staging costs.

The Canadian Agency for Drugs and Technologies in Health's report on endobronchial ultrasound (EBUS) for lung cancer diagnosis and staging (Ho et al, 2009) noted that EBUS is a new technology that involves the introduction of an ultrasound probe into the thoracic region via the bronchial airway while patients are under conscious sedation or general anesthesia.  The probe is used to generate images of pulmonary and mediastinal structures.  Its use allows minimally invasive sampling of peripheral pulmonary lesions, and mediastinal and hilar lesions.  The development of the built-in linear probe, as opposed to a radial probe, enables real time guidance during EBUS-transbronchial needle aspiration (EBUS-TBNA).  These investigators reviewed published literature by cross-searching Embase and Medline databases between 2004 and April 2009.  Parallel searches were performed on PubMed and The Cochrane Library (Issue 1, 2009) databases.  The websites of regulatory agencies, and health technology assessment and related agencies, were searched, as were specialized databases.  The Google search engine was used to search for information on the Internet.

These researchers identified 1 health technology assessment (HTA), 1 meta-analysis, 2 cost analyses, and 3 observational studies on the use of EBUS for lung cancer diagnosis and staging.  The HTA examined the safety and effectiveness of EBUS for detection and staging in patients with suspected or established lung cancer.  No meta-analysis was performed, and the conclusions that were presented came from individual trials.  The HTA found a statistically significantly increased diagnostic yield for mediastinal lymph nodes when EBUS-TBNA was compared to conventional TBNA.  In the 2009 meta-analysis, the overall diagnostic accuracy of EBUS-TBNA in detecting metastatic mediastinal lymph nodes in patients who were suspected of having lung cancer was assessed.  Endobronchial ultrasound-guided transbronchial needle aspiration had a pooled sensitivity of 0.93 (95 % confidence interval [CI]: 0.91 to 0.94) and a pooled specificity of 1.00 (95 % CI: 0.99 to 1.00) for lung cancer detection and staging.  When compared directly, EBUS-TBNA was found to be more sensitive than conventional TBNA.  The findings from recent trials were in agreement with the findings of the meta-analysis on EBUS-TBNA diagnostic accuracy.  The authors concluded that based on the existing evidence, EBUS is an accurate and safe tool for use in lung cancer diagnosis and staging.

In a systematic review on the safety and effectiveness of EBUS-TBNA, Varela-Lema et al (2009) reviewed a total of 20 publications.  Of these, 14 were original studies that examined the clinical usefulness of the technique in visualizing and staging lymph nodes in patients with suspected or established lung cancer.  Sensitivity ranged 85 % to 100 % and negative predictive value ranged 11 % to 97.4 %.  Three studies evaluated the clinical usefulness of the technique in the diagnosis of sarcoidosis.  EBUS-TBNA was diagnostic in 88 % to 93 % of patients.  One retrospective study evaluated the use of EBUS-TBNA in the diagnosis of lymphoma.  None of the studies included in the present review reported important complications.  Endobronchial ultrasound-guided transbronchial needle aspiration is a safe and highly accurate procedure for the examination and staging of mediastinal and hilar lymph nodes in patients with known or suspected lung malignancy.  The evidence is promising for sarcoidosis but is insufficient for lymphoma.

Adams et al (2009) carried out a systematic review of published studies evaluating EBUS-TBNA for mediastinal lymph node staging to ascertain the pooled sensitivity and specificity of this investigation.  A literature search was constructed and performed by a professional medical librarian to identify the literature from 1960 to February 2008.  Pooled specificity and sensitivity was estimated from the extracted data with an exact binomial rendition of the bivariate mixed-effects regression model.  Of 365 publications, 25 were identified in which EBUS-TBNA was specifically focused on mediastinal node staging.  Of these, only 10 had data suitable for extraction and analysis.  The overall test performance was excellent with an area under the summary receiver operating characteristics curve of 0.99 (95 % CI: 0.96 to 1.00); similarly, EBUS-TBNA had excellent pooled specificity of 1.00 (95 % CI: 0.92 to 1.00) and good pooled sensitivity of 0.88 (95 % CI: 0.79 to 0.94).  The authors concluded that EBUS-TBNA has excellent overall test performance and specificity for mediastinal lymph node staging in patients with lung cancer.  The results compare favorably with published results for computed tomography (CT) and positron emission tomography.

Cameron and colleagues (2010) stated that EBUS-TBNA is a recently developed, accurate, safe and cost-effective technique that allows sampling of mediastinal lymph nodes and peri-bronchial lesions including pulmonary and mediastinal lesions.  Its major indications are the nodal staging of non-small cell carcinomas of the lung, their re-staging following chemotherapy and/or radiation, the diagnosis of sarcoidosis and of metastases from extra-thoracic malignancies, and the diagnosis of mediastinal lymphadenopathy and masses of unknown etiology.

In a pilot study, Aumiller et al (2009) examined the feasibility of detecting pulmonary embolism (PE) in the central airways by EBUS.  Consecutive patients underwent flexible bronchoscopy with a convex EBUS probe under local anesthesia and moderate sedation within 24 hrs after angio-CT had documented a central PE.  The EBUS images were compared to the CT findings.  Among 32 patients (mean age of 69 years, 20 men), angio-CT documented 101 PE, of which 97 (96 %) were also detected with EBUS.  The 4 emboli not detected consisted of 1 in a middle lobe and 3 in a left upper lobe artery.  At least 1 embolus was detected with EBUS in every patient, which is sufficient to confirm a diagnosis of central PE.  No bronchoscopic complications were observed.  Mean procedure time was reduced from 5 mins in the first 16 patients to 3 mins in the last 16.  The authors concluded that EBUS was a feasible and safe approach to detecting central pulmonary emboli.  Moreover, they stated that blinded, comparative trials are needed to evaluate its use as a primary tool for diagnosing these emboli.

Soja et al (2009) examined the use of EBUS for the assessment of bronchial wall remodeling in patients with asthma.  In 35 patients with asthma and 23 control subjects, high-resolution CT (HRCT) scanning and EBUS were used to measure bronchial wall thickness in the 10th segment of the right lung.  With a radial 20-MHz probe, EBUS identified the 5-laminar structure of the bronchial wall.  Layer 1 (L(1)) and layer 2 (L(2)) were analyzed separately, and layers 3 through 5 (L(3-5)), which corresponded to cartilage, were analyzed jointly.  Digitalized EBUS images were used for the quantitative assessment of bronchial wall thickness and the wall area (WA) of the layers.  Finally, bronchial biopsy specimens were taken for measuring the thickness of the reticular basement membrane (RBM).  The thickness and WA of the bronchial wall layers, which were assessed using EBUS, were correlated with FEV(1) and RBM.  There was no significant difference in the measurements of total bronchial wall thickness using EBUS and HRCT scanning.  The thickness and WA of the bronchial wall and its layers were significantly greater in patients with asthma than in the control subjects.  A negative correlation among the thicknesses of L(1), L(2), and L(3-5) and FEV(1), and a positive correlation with RBM were observed only in the patients with asthma.  The authors concluded that EBUS allows precise measurement of the thickness and WA of bronchial wall layers.  The correlation of these parameters with asthma severity suggested implementation of EBUS in the assessment of bronchial wall remodeling in patients with asthma.

In a meta-analysis, Wu et al (2011) evaluated the accuracy of EUS elastography by pooling data of existing trials.  A total of 7 studies involving 368 patients with 431 lymph nodes (LNs) were included.  Pooling was conducted in a fixed-effect model or a random-effect model.  The pooled sensitivity of EUS elastography for the differential diagnosis of benign and malignant LNs was 88 % (95 % CI: 0.83 to 0.92), and the specificity was 85 % (95 % CI: 0.79 to 0.89).  The area under the curve under summary receiver operating characteristic (SROC) was 0.9456.  The pooled positive likelihood ratio was 5.68 (95 % CI: 2.86 to 11.28), and the negative likelihood ratio was 0.15 (95 % CI: 0.10 to 0.21).  The subgroup analysis by excluding the outliers provided a sensitivity of 85 % (95 % CI: 0.79 to 0.90) and a specificity of 91 % (95 % CI: 0.85 to 0.95) for the differential diagnosis of benign and malignant LNs.  The area under the curve under SROC was 0.9421.  The authors concluded that EUS elastography is a promising, non-invasive method for differential diagnosis of malignant LNs and may prove to be a valuable supplemental method to EUS-guided FNA.

Will and Meyer (2012) stated that endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC) are considered the gold standard in the interventional treatment of biliary obstruction, in particular, with palliative intention.  If ERCP and PTC are not possible, an alternative drainage procedure such as the endoscopic ultrasound-guided cholangiodrainage (EUCD) can be used.  Endoscopic US-guided cholangiodrainage is an endoscopic/sonografic procedure, which is used in case of post-operatively changed anatomy of the upper gastro-intestinal tract (BII gastric resection, pylorus-preserving pancreas head resection, Whipple procedure, [sub-]total gastrectomy, Roux-en-Y reconstruction) and, thus, if papilla of Vater (papilla) can not be reached or catheterized or if the patient denies PTC; and in subjects with recurrent, advanced or metastasized tumor lesion(s) of the upper abdomen, hepatobiliary system as well as pancreas and associated obstruction of the biliary tree/jaundice.  The authors stated that with regard to the limited diffusion process, EUCD can not be considered a standard procedure yet.  The advantages comprise low tissue trauma, primary internal drainage and the possible endoscopic re-intervention in case of complications.  The high technical challenge in performing EUCD is an unfavorable aspect for broader use in clinical practice.  However, the disclosed treatment results demonstrating an acceptable complication rate show that EUCD can be competitively considered to ERCP und PTC with a great chance for primary success.  These investigatros concluded that EUCD is an elegant, not yet fully established, but rather still experimental procedure of interventional endoscopy/EUS, which needs great expertise of the endoscopist in an inter-disciplinary center of visceral medicine as one of the main predictions.  In experienced hands, a safe procedure can be provided, for which a systematic follow-up and a multi-center evaluation of peri-interventional management are still needed in order to achieve a final assessment of EUCD for guideline approval.

Cardoso et al (2012) stated that accurate pre-operative staging is important in determining the appropriate treatment of gastric cancer.  Recently, EUS has been introduced as a staging modality.  However, reported test characteristics for EUS in gastric cancer vary.  These investigators identified, synthesized, and evaluated findings from all articles on the performance of EUS in the pre-operative staging of gastric cancer.  Electronic literature searches were conducted using Medline, Embase, and the Cochrane Central Register of Controlled Trials from January 1, 1998 to December 1, 2009.  All search titles and abstracts were independently rated for relevance by a minimum of 2 reviewers.  Meta-analysis for the performance of EUS was analyzed by calculating agreement (Kappa statistic), and pooled estimates of accuracy, sensitivity, and specificity for all EUS examinations, using histopathology as the reference standard. Subgroup analyses were also performed.  A total of 22 articles met inclusion criteria and were included in the review.  Endoscopic ultrasonography pooled accuracy for T staging was 75 % with a moderate Kappa (0.52); EUS was most accurate for T3 disease, followed by T4, T1, and T2.  Endoscopic ultrasonography pooled accuracy for N staging was 64 %, sensitivity was 74 %, and specificity was 80 %.  There was significant heterogeneity between the included studies.  Subgroup analyses found that annual EUS volume was not associated with EUS T and N staging accuracy (p = 0.836, 0.99, respectively).  The authors concluded that EUS is a moderately accurate technique that seems to describe advanced T stage (T3 and T4) better than N or less advanced T stage.  Stratifying by EUS annual volume did not affect EUS performance in staging gastric cancer.

The National Comprehensive Cancer Network’s clinical practice guideline on gastric cancers (including cancer in the proximal 5 cm of the stomach) (NCCN, 2013) states that “clinical staging has greatly improved with the availability of diagnostic modalities such as endoscopic ultrasound (EUS) …. EUS performed prior to any treatment is important in the initial clinical staging of gastric cancer …. This is especially important in patients who are being considered for EMR [endoscopic mucosal resection]”.

Xu and associates (2013) stated that EUS elastography is a novel method for visualization of tissue elasticity modulus during a conventional EUS examination.  The reported yield of EUS elastography for the differentiation of benign and malignant pancreatic masses has shown variable results.  In a systemic review and meta-analysis, these investigators examined the accuracy of EUS elastography by pooling data of available trials.  The Medline, PubMed, Embase, and Cochrane Central Trials databases were used to retrieve all the studies that assessed the diagnostic accuracy of EUS elastography for the differentiation of benign and malignant pancreatic masses.  Pooling was carried out using a fixed-effect model when significant heterogeneity was not present; otherwise, the random-effect model was used.  If there were less than 4 studies using the same diagnostic standard, forest plots were constructed without pooling.  In 6 studies using the qualitative color pattern as the diagnostic standard, the sensitivity was 99 % (95 % CI: 98 to 100 %) and the specificity was 74 % (95 % CI: 65 to 82 %).  The area under the curve under the summary receiver-operating characteristic was 0.9624.  In 3 studies using the quantitative hue histogram value as the diagnostic standard, the sensitivity was 85 to 93 % and the specificity was 64 to 76 %.  The authors concluded that EUS elastography is a promising non-invasive technique for the differentiation of pancreatic masses with a high sensitivity, and may prove to be a valuable complementary method to EUS-FNA.

In a meta-analysis, Mei and colleagues (2013) evaluated the accuracy of EUS elastography for diagnosis of solid pancreatic masses.  A total of 13 articles for EUS elastography diagnosing solid pancreatic masses were selected.  The Mantel-Haenszel and DerSimonian Laird methods were used to analyze pooled results.  This study involved 1,044 patients.  Main outcome measures included the pooled sensitivity, specificity, likelihood ratios, diagnostic odds ratio, and summary receiver operating characteristic (sROC) curve.  The pooled sensitivity, specificity, and diagnostic odds ratio of EUS elastography distinguishing benign from malignant solid pancreatic masses were 0.95 (95 % CI: 0.94 to 0.97), 0.67 (95 % CI: 0.61 to 0.73), and 42.28 (95 % CI: 26.90 to 66.46), respectively.  The sROC area under the curve was 0.9046.  The subgroup analysis based on excluding the outliers showed that the heterogeneity was eliminated, and the pooled sensitivity and specificity were 0.95 (95 % CI: 0.93 to 0.97) and 0.7 (95 % CI: 0.63 to 0.76), respectively.  The sROC area under the curve was 0.8872.  The authors concluded that EUS elastography is a reliable technique for the characterization of solid pancreatic masses and may be a useful complementary tool for EUS-guided FNA.  However, they stated that a more accurate computer-aided diagnosis method for EUS elastography is in demand to reduce various biases and improve the accuracy of EUS elastography for diagnosis of solid pancreatic masses.

Furthermore, the NCCN’s clinical practice guideline on “Pancreatic adenocarcinoma” (Version 1.2014) does not mention the use of EUS elastography as a management tool.

The World Gastroenterology Organization’s clinical practice guideline on “Esophageal varices” (WGO, 2014) stated that “Esophagogastroduodenoscopy (EGD) is the gold standard for the diagnosis of esophageal varices.  If the gold standard is not available, other possible diagnostic steps would be Doppler ultrasonography of the blood circulation (not endoscopic ultrasonography)”.

Dietrich et al (2014) stated that real-time elastography (RTE) performed during EUS is a relatively new technique that allows the evaluation of tissue stiffness, with the intent of better characterizing lesions during EUS examinations.  These investigators described the technique of RTE-EUS, as well as the clinical applications, including the study of pancreatic lesions, but also hepatobiliary, gastro-intestinal (GI) tract pathology (including anal canal), lymph nodes, adrenal glands, lung and mediastinum, as well as urogenital applications.  The authors stated that one of the advantages of the RTE-EUS technique is the possibility to be used in various locations accessible from the GI tract; they also discussed future developments of elastography -- a technique that will certainly not replace biopsy, but will rather be an adjunct during EUS examinations.

Diagnosis of Common Bile Duct Stones

Giljaca et al (2015) stated that there has been no systematic review of the accuracy of EUS and magnetic resonance cholangio-pancreatography (MRCP) in the diagnosis of common bile duct stones using appropriate reference standards. In a Cochrane review, these researchers compared the accuracy of EUS and MRCP for the diagnosis of common bile duct stones.  They searched MEDLINE, EMBASE, Science Citation Index Expanded, BIOSIS, and Clinicaltrials.gov until September 2012.  They searched the references of included studies to identify further studies and of systematic reviews identified from various databases (Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA), Medion, and ARIF (Aggressive Research Intelligence Facility)).  These investigators did not restrict studies based on language or publication status, or whether data were collected prospectively or retrospectively.  They included studies that provided the number of true positives, false positives, false negatives, and true negatives for EUS or MRCP.  They only accepted studies that confirmed the presence of common bile duct stones by extraction of the stones (irrespective of whether this was done by surgical or endoscopic methods) for a positive test, and absence of common bile duct stones by surgical or endoscopic negative exploration of the common bile duct or symptom free follow-up for at least 6 months for a negative test, as the reference standard in people suspected of having common bile duct stones.  They included participants with or without prior diagnosis of cholelithiasis; with or without symptoms and complications of common bile duct stones, with or without prior treatment for common bile duct stones; and before or after cholecystectomy.  At least 2 authors independently screened abstracts and selected studies for inclusion.  Two authors independently collected the data from each study.  They used the bi-variate model to obtain pooled estimates of sensitivity and specificity.  These researchers included a total of 18 studies involving 2,366 participants (976 participants with common bile duct stones and 1,390 participants without common bile duct stones); 11 studies evaluated EUS alone, and 5 studies evaluated MRCP alone; 2 studies evaluated both tests.  Most studies included patients who were suspected of having common bile duct stones based on abnormal liver function tests; abnormal trans-abdominal US; symptoms such as obstructive jaundice, cholangitis, or pancreatitis; or a combination of the above.  The proportion of participants who had undergone cholecystectomy varied across studies; not 1 of the studies was of high methodological quality.  For EUS, the sensitivities ranged between 0.75 and 1.00 and the specificities ranged between 0.85 and 1.00.  The summary sensitivity (95 % CI) and specificity (95 % CI) of the 13 studies that evaluated EUS (1,537 participants; 686 cases and 851 participants without common bile duct stones) were 0.95 (95 % CI: 0.91 to 0.97) and 0.97 (95 % CI: 0.94 to 0.99).  For MRCP, the sensitivities ranged between 0.77 and 1.00 and the specificities ranged between 0.73 and 0.99.  The summary sensitivity and specificity of the 7 studies that evaluated MRCP (996 participants; 361 cases and 635 participants without common bile duct stones) were 0.93 (95 % CI: 0.87 to 0.96) and 0.96 (95 % CI: 0.90 to 0.98).  There was no evidence of a difference in sensitivity or specificity between EUS and MRCP (p = 0.5).  From the included studies, at the median pre-test probability of common bile duct stones of 41 % the post-test probabilities (with 95 % CI) associated with positive and negative EUS test results were 0.96 (95 % CI: 0.92 to 0.98) and 0.03 (95 % CI: 0.02 to 0.06).  At the same pre-test probability, the post-test probabilities associated with positive and negative MRCP test results were 0.94 (95 % CI: 0.87 to 0.97) and 0.05 (95 % CI: 0.03 to 0.09).  The authors concluded that both EUS and MRCP have high diagnostic accuracy for detection of common bile duct stones.  People with positive EUS or MRCP should undergo endoscopic or surgical extraction of common bile duct stones and those with negative EUS or MRCP do not need further invasive tests.  However, if the symptoms persist, further investigations will be indicated.  The 2 tests were similar in terms of diagnostic accuracy and the choice of which test to use would be determined by the availability and contra-indications to each test.  Moreover, they stated that it should be noted that the results were based on studies of poor methodological quality and so the results should be interpreted with caution; further studies that are of high methodological quality are needed to determine the diagnostic accuracy of EUS and MRCP for the diagnosis of common bile duct stones.

British Society of Gastroenterology guidelines on the management of common bile duct stones (Williams, et al., 2008) states: "EUS appears comparable to ERCP as a diagnostic test for CBDS, and performs better than either USS or CT. Unlike ERCP, EUS does not require instrumentationof the sphincter of Oddi and does not subject patients to the associated risk of pancreatitis. With regards to MR, systematic reviewof prospective studies has failed to show a statistically significant difference in performance when the two modalities are compared, though for small CBD stones EUS may still be more sensitive. However, it should be noted that, unlike MR, EUS has yet to become widely available. In addition, it requires the patient to undergo endoscopy, does not provide images of the intra-hepatic ducts and may be difficult to perform on patients with altered gastric or duodenal anatomy."

Diagnosis of Pelvic Lesions

Han and colleagues (2015) stated that pre-operative diagnosis of pelvic lesions remains challenging despite advances in imaging technologies. Endoscopic ultrasonography-guided biopsy is an effective diagnostic modality for sampling the digestive tract and surrounding areas.  However, a meta-analysis summarizing the diagnostic effectiveness of EUS-guided biopsy for pelvic lesions has not been published.  In a systematic review and meta-analysis, these investigators evaluated the utility of EUS-guided biopsy in the diagnosis of pelvic lesions.  Articles were identified via structured database search; only studies where pelvic lesions were confirmed by surgery or clinical follow-up were included.  Data extracted were selected with strict criteria.  A fixed-effects model was used to estimate the sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR).  A summary receiver operating characteristic curve (SROC) was also constructed.  A total of 10 studies containing a total of 246 patients were included.  The pooled sensitivity of EUS-guided biopsy for differential diagnosis of pelvic masses was 0.89 (95 % CI: 0.83 to 0.94), and the specificity was 0.93 (95 % CI: 0.86 to 0.97).  The area under the SROC was 0.9631.  The combined PLR, NLR, and DOR were 11.75 (95 % CI: 5.90 to 23.43), 0.12 (95 % CI: 0.07 to 0.20), and 100.06 (95 % CI: 37.48 to 267.10), respectively.  There is potential presence of publication bias in this meta-analysis.  The authors concluded that the finding of this meta-analysis showed that EUS-guided biopsy is a powerful tool for differentiating pelvic masses with a high sensitivity and specificity.  Moreover, they stated that EUS-guided biopsy is a safe procedure with low rate of complication, although more high-quality prospective studies are needed to be done.

Nisenblat et al (2016) noted that approximately 10 % of women of reproductive age suffer from endometriosis. Endometriosis is a costly chronic disease that causes pelvic pain and subfertility.  Laparoscopy, the gold standard diagnostic test for endometriosis, is expensive and carries surgical risks.  Currently, no non-invasive tests that can be used to accurately diagnose endometriosis are available in clinical practice.  In a Cochrane review, these investigators provided estimates of the diagnostic accuracy of imaging modalities for the diagnosis of pelvic endometriosis, ovarian endometriosis and deeply infiltrating endometriosis (DIE) versus surgical diagnosis as a reference standard.  They described performance of imaging tests for mapping of deep endometriotic lesions in the pelvis at specific anatomical sites.  Imaging tests were evaluated as replacement tests for diagnostic surgery and as triage tests that would assist decision-making regarding diagnostic surgery for endometriosis.  The authors concluded that none of the evaluated imaging modalities was able to detect overall pelvic endometriosis with enough accuracy that they would be suggested to replace surgery.  Specifically for endometrioma, TVUS qualified as a SpPin triage test; MRI displayed sufficient accuracy to suggest utility as a replacement test, but the data were too scant to permit meaningful conclusions.  Trans-vaginal ultrasound (TVUS) could be used clinically to identify additional anatomical sites of DIE compared with MRI, thus facilitating pre-operative planning.  Recto-sigmoid endometriosis was the only site that could be accurately mapped by using TVUS, trans-rectal ultrasonography (TRUS), MRI or multi-detector computerized tomography enema (MDCT-e).  Studies evaluating recent advances in imaging modalities such as TVUS with bowel preparation (TVUS-BP), rectal water contrast during trans-vaginal ultrasonography (RWC-TVS,), 3.0T MRI and MDCT-e were observed to have high diagnostic accuracies, but were too few to allow prudent evaluation of their diagnostic role.  They stated that in view of the low quality of most of the included studies, the findings of this review should be interpreted with caution; future well-designed diagnostic studies undertaken to compare imaging tests for diagnostic test accuracy and costs are recommended.

Management of Acute Cholecystitis

An UpToDate reviewof acute cholecystitis (Vollmer, et al., 2016) states that transmural drainage utilizes endoscopic ultrasound guidance to access the inflamed gallbladder with a needle puncture, followed by dilation and stent placement over a guidewire. The review stated that the transmural drainage technique is technically successful in most cases (97 percent) and resolves acute cholecystitis in over 95 percent of patients The review states that, in high risk patients, endoscopic transmural drainage is used as a bridge to definitive gallbladder surgery. 

Choi and Lee (2015) noted that w the evolution of the linear echo-endoscope and the improved ability to direct a needle within the field of interest, the therapeutic potential of EUS has greatly expanded. Endoscopic ultrasonography-guided trans-mural gallbladder drainage (EUS-GBD) may be the next frontier for therapeutic EUS.  Since EUS-GBD was first described in 2007, recent reports have suggested it as an alternative to external gallbladder drainage for acute cholecystitis;  EUS-GBD includes EUS-guided trans-mural nasogallbladder drainage, EUS-guided gallbladder aspiration, and EUS-guided trans-mural gallbladder stenting.

Penas-Herrero et al (2015) stated that EUS-GBD has been introduced as an alternative to percutaneous trans-hepatic GBD for the treatment of acute cholecystitis in non-surgical candidates. These investigators performed a systematic review of the English language literature through PubMed search until June 2014.  A total of 155 patients with acute cholecystitis treated with EUS-GBD in 8 studies and 12 case reports, and 2 patients with EUS-GBD for other causes were identified.  Overall, technical success was obtained in 153 patients (97.45 %) and clinical success in 150 (99.34 %) patients with acute cholecystitis.  Adverse events developed in less than 8 % of patients, all of them managed conservatively.  Endoscopic ultrasound-GBD has been performed with plastic stents, nasobiliary drainage tubes, standard or modified tubular self-expandable metal stents (SEMS) and lumen-apposing metal stents (LAMS) by different authors with apparently similar outcomes.  No comparison studies between stent types for EUS-GBD have been reported.  The authors concluded that EUS-GBD is a promising novel alternative intervention for the treatment of acute cholecystitis in high surgical risk patients.  Feasibility, safety and effectiveness in published studies from expert centers were very high compared to currently available alternativess.  Moreover, they stated that further studies are needed to establish the safety and long-term outcomes of this procedure in other practice settings before EUS-GBD can be widely disseminated.

Re-Staging of Locally Advanced Rectal Cancer

Zhao et al (2014) stated that endorectal EUS can provide accurate and reliable information for initial staging of locally advanced rectal cancer (LARC) in both the depth of rectal cancer penetration (T-stage) and regional lymph node involvement (N-stage). However, there is still no consensus about its accuracy in re-staging LARC after neoadjuvant chemoradiotherapy (NAT).  These investigators retrieved previous studies and performed a meta-analysis for evaluating the accuracy of EUS for re-staging of LARC after NAT.  It was found the accuracy of EUS for T re-staging of LARC was relatively low and over-staging was common, although the accuracy for assessing T3/4 was significantly higher than T0 to T2 stage.  The specificity of EUS for assessing N stage was relatively high, but the sensitivity was relatively low.  The authors concluded that data obtained in this study confirmed the overall accuracy of EUS is insufficient to serve as a basis for decisions on re-staging; exploring the possible application of new techniques is needed for better re-staging.

NCCN guidelines on rectal cancer (2016) state that "MRI, CT and EUS are the most commonly used modalities for restaging after neoadjuvant treatment, but the accuracy of these techniques for determining T stage and lymph node involvement is limited".

Pre-Operative Staging of Esophageal Cancer

Lee and associates (2014) noted that predicting the invasion depth of superficial esophageal squamous cell carcinoma (SESCC) is important when selecting among therapeutic strategies.  These researchers compared magnified endoscopy with narrow-band imaging (ME-NBI) with EUS for predicting the depth of tumor invasion in patients with SESCC.  This study enrolled 51 patients with SESCC (52 SESCC lesions) who underwent both ME-NBI and EUS at Pusan National University Hospital during 2010 to 2013.  These investigators reviewed the patients' medical records and compared ME-NBI and EUS findings with histopathological results according to clinicopathological factors.  A total of 46 lesions in 45 patients were included in the final analysis; ME-NBI and EUS had overall accuracies of 76.1 % and 84.8 %, respectively, in distinguishing mucosal from non-mucosal cancers.  There were no differences between ME-NBI and EUS in terms of sensitivities and specificities in distinguishing mucosal from non-mucosal cancers (p = 0.500, and p = 0.688, respectively).  When both ME-NBI and EUS suggested a mucosal depth of lesion invasion, the frequency of mucosal cancer in the final histopathology was 94 %.  However, if either ME-NBI or EUS suggested a non-mucosal depth of invasion, the frequency of mucosal cancer was only 21 %.  The authors concluded that ME-NBI and EUS were accurate predictors of SESCC invasion depth.  If both methods suggested a mucosal depth of lesion invasion, the accuracy of the prediction was increased. They stated that, when possible, it would be better to evaluate the invasion depth of SESCC using both ME-NBI and EUS before deciding to perform endoscopic resection.

Ishihara and colleagues (2017) stated that diagnosis of cancer invasion depth is crucial for selecting the optimal treatment strategy in patients with GI cancers.  These investigators conducted a meta-analysis to determine the utilities of different endoscopic modalities for diagnosing invasion depth of ESCC.  They carried out a comprehensive search of Medline, Cochrane Central, and Ichushi databases to identify studies evaluating the use of endoscopic modalities for diagnosing invasion depth of superficial ESCC.  They excluded case reports, review articles, and studies in which the total number of patients or lesions was less than 10.  A total of 14 studies fulfilled selection criteria; SROC curves showed that ME and EUS performed better than non-ME.  Magnified endoscopy was associated with high sensitivity and a very low (0.08) negative likelihood ratio (NLR), while EUS had high specificity and a very high (17.6) positive likelihood ratio (PLR) for the diagnosis of epithelial or lamina propria cancers; NLR less than 0.1 provided strong evidence to rule out disease, and PLR greater than 10 provided strong evidence of a positive diagnosis.  The authors concluded that EUS and ME performed better than non-ME for diagnosing invasion depth in ESCC; ME has a low NLR and is a reliable modality for confirming deep invasion of cancer, while EUS has a high PLR and can reliably confirm that the cancer is limited to the surface.  They stated that effective use of these 2 modalities should be considered in patients with ESCC.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on ”Esophageal and esophagogastric junction cancers” (Version 2.2016) stated that “Prior to surgery, clinical staging should be performed to assess resectability with CT scan of the chest and abdomen, whole body PET (integrated PET/CT is preferred), and endoscopic ultrasound (EUS)”.

Endoscopic Ultrasonography-Guided Ablation Therapies for Neuroendocrine Tumors and Pancreatic Cystic Neoplasms

Zilli and colleagues (2018) stated that EUS with fine-needle infusion (EUS-FNI) of alcohol is one of the most reported methods of EUS-guided tumor ablation as it works by inducing cell membrane lysis, protein denaturation and vascular occlusion all leading to cell death.  The possible candidates for EUS-FNI are patients who are not candidates for surgery, with G1 or G2 pancreatic neuroendocrine neoplasms (PNENs) of less than or equal to 2 cm.  Another available EUS-guided therapy is the EUS-guided radiofrequency ablation (EUS-RFA), adverse events (AEs) such as acute pancreatitis, pancreatic leaks, infection of necrotic pancreatic tissue post treatment and bleeding) are possible because the pancreas is thermo-sensitive.  Finally, a new flexible bipolar hybrid ablation system (ERBE Elektromedizin GmbH, Tübingen, Germany) has been developed: it combines bipolar RFA with cryo-technology and is believed to perform ablation with less collateral thermal damage than monopolar systems.  EUS-guided cryotherm ablation has been initially tested on patients with unresectable locally advanced pancreatic adenocarcinoma and appeared to induce tumor reduction with a low complication rate (damage along the probe track, persistence of neoplastic tissue, particularly within the border zones).  This technology will be used in the future also for the treatment gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs), but further studies are needed to confirm the role and efficacy of these therapies in this setting of patients.  The authors concluded that the advancement of the EUS techniques has had an impact also on the therapeutic field because of their limited AEs, with the introduction of several EUS-guided ablation therapies, which are particularly indicated for patients unsuitable for surgery, as they can achieve both tumor reduction and symptoms control.  Moreover, they stated that the feasibility and safety of interventional EUS for the treatment of small neuroendocrine tumors needs still proving in both animal and human trials.

Feng and associates (2018) noted that pancreatic cystic neoplasms (PCNs) are being increasingly detected because of rapid advances in radiologic technology and an increased imaging demand.  The management of PCNs is challenging as most of these neoplasms are asymptomatic, but have malignant potential, and surgical resection has substantial perioperative morbidity and mortality.  Endoscopic ultrasonography-guided ablation, as a minimally invasive treatment, has received increasing attention in the past few years.  However, the resolution after EUS-guided ablative therapy still needs to be improved.  In this case report, EUS-guided RFA combined with lauromacrogol ablation was applied for the first time in the treatment of PCN, and it showed complete resolution at a 3-month follow-up.  Moreover, they stated that the safety, efficacy, and optimum indications still remain to be investigated in a large and long-term follow-up study with different PCNs types and sizes.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Neuroendocrine tumors” (Version 3.2017) does not mention endoscopic ultrasonography as a management tool.

Jiang and Chai (2018) noted that EUS-guided laser ablation (LA) is potentially applicable to tumors in the left lobe of the liver and pancreas.  These researchers introduced the novel use of EUS-guided LA for left adrenal metastases from pancreatic adenocarcinoma.  A 70-year old woman was referred to the authors hospital for dull abdominal pain and tiredness for 1 month; CT discovered a 1.0 × 1.7 cm mass in the area of the left adrenal gland.  The lesion was highly suspicious for metastasis due to her history of pancreatic adenocarcinoma 1 year ago, which was removed through radical surgery.  Intra-operative frozen-section pathology revealed a tumor invading the left adrenal gland.  The left adrenal mass was clearly visualized on EUS and exhibited irregular hyper-enhancement during contrast.  The tumor was successfully treated by 4 sessions of EUS-guided LA.  After the procedure, symptomatic relief was achieved and remained.  At the 4-month follow-up, contrast-enhanced CT revealed that the volume of the target was significantly decreased.  The authors introduced a new method for left adrenal metastasis using thermal ablation through EUS.  They stated that as a potential alternative access to the percutaneous approach, EUS-guided LA may provide a minimally invasive treatment to relieve the tumor burdens and symptoms when applied accurately.

Endoscopic Ultrasonography-Guided Interstitial Brachytherapy for the Treatment of Unresectable Pancreatic Cancer

Oh and co-workers (2016) noted that pancreatic adenocarcinoma is the 4rth leading cause of cancer-related death in the United States.  Due to the aggressive tumor biology and late manifestations of the disease, long-term survival is extremely uncommon and the current 5-year survival rate is 7 %.  Over the last 20 years, EUS has evolved from a diagnostic modality to a minimally invasive therapeutic alternative to radiologic procedures and surgery for pancreatic diseases.  Endoscopic ultrasonography-guided celiac plexus intervention is a useful adjunct to conventional analgesia for patients with pancreatic cancer; EUS-guided biliary drainage has emerged as a viable option in patients who have failed endoscopic retrograde cholangiopancreatography.  Recently, the use of lumen-apposing metal stent to create gastro-jejunal anastomosis under EUS and fluoroscopic guidance in patients with malignant gastric outlet obstruction has been reported.  On the other hand, anti-tumor therapies delivered by EUS, such as the injection of anti-tumor agents, brachytherapy and ablations are still in the experimental stage without clear survival benefit.

Sun and colleagues (2017) stated that EUS-guided interstitial brachytherapy is promising in the treatment of unresectable malignant carcinoma adjacent to the digestive tract.  The feasible treatment plan is not established.  These investigators developed a novel treatment plan and evaluated the feasibility in patients with unresectable pancreatic cancer.  A total of 42 patients with unresectable pancreatic cancer (stage III: n = 18; stage IV: n = 24) were retrospectively included.  A special treatment-planning system (TPS) for EUS was designed and evaluated by comparing with the traditional TPS.  The patients underwent EUS-guided interstitial brachytherapy based on the new software.  In the test model, there was no obvious difference of irradiation doses calculated by the 2 software (EUS TPS versus traditional TPS) (p > 0.05).  Under the support of EUS TPS, a novel treatment plan for EUS-guided interstitial brachytherapy was successfully established, which contained 7 principles.  All patients tolerated the treatment well without any serious complications.  In 15 patients (stage III) whose minimal peripheral dose was larger than 90 Gy, partial remission rate was 80 % (12/15); 12 patients (12/18) in stage III were alive for over 12 months with a median peripheral dose of 107.5 Gy.  The expected median survival time of the 42 patients was 9.0 months (95 % CI: 7.6 to 10.4 months).  The authors concluded that these findings suggested that the new TPS based on EUS images can calculate the dose distribution in EUS section with an interactive interface.  This software will play an important role in EUS-guided interstitial brachytherapy in patients with unresectable pancreatic malignant carcinoma.  Moreover, they noted that the present study had several drawbacks, including its non-case-controlled nature and the small number of patients recruited (n =42); thus, further prospective studies of an appropriate design and adequate sample size are needed to evaluate the new software.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Pancreatic adenocarcinoma” (Version 3.2017) does not mention endoscopic ultrasonography-guided interstitial brachytherapy as a therapeutic option.

Evaluation of Idiopathic Acute Pancreatitis

In the absence of alcohol or gallstones, caution must be exercised when attributing a possible etiology for AP to another agent or condition. Medications, infectious agents, and metabolic causes such as hypercalcemia and hyperparathyroidism are rare causes, often falsely identified as causing AP (35,36,37). Although some drugs such as 6-mercaptopurine, azathioprine, and DDI (2′,3′-dideoxyinosine) can clearly cause AP, there are limited data supporting most medications as causative agents (35). Primary and secondary hypertriglyceridemia can cause AP; however, these account for only 1–4% of cases (36). Serum triglycerides should rise above 1,000 mg/dl to be considered the cause of AP (38,39). A lactescent (milky) serum has been observed in as many as 20% of patients with AP, and therefore a fasting triglyceride level should be re-evaluated 1 month after discharge when hypertriglyceridemia is suspected (40). Although most do not, any benign or malignant mass that obstructs the main pancreatic can result in AP. It has been estimated that 5–14% of patients with benign or malignant pancreato-biliary tumors present with apparent IAP (41,42,43). Historically, adenocarcinoma of the pancreas was considered a disease of old age. However, increasingly patients in their 40s—and occasionally younger—are presenting with pancreatic cancer. This entity should be suspected in any patient >40 years of age with idiopathic pancreatitis, especially those with a prolonged or recurrent course (27,44,45). Thus, a contrast-enhanced CT scan or MRI is needed in these patients. A more extensive evaluation including endoscopic ultrasound (EUS) and/or MRCP may be needed initially or after a recurrent episode of IAP.

Wilcox and co-workers (2016) stated that although idiopathic pancreatitis is common, the natural history is not well studied, and the best diagnostic approach to both single and multiple attacks remains undefined.  These investigators prospectively evaluated patients with idiopathic pancreatitis over a 10-year period, and clinical information for each episode was reviewed; EUS was performed in all patients.  Patients with microlithiasis or bile duct stones were referred for cholecystectomy and ERCP, respectively.  For those with a single attack, if EUS was normal or chronic pancreatitis or pancreas divisum (PD) was diagnosed, the patient was followed-up for recurrence.  For those with multiple attacks and a negative EUS, ERCP and sphincter of Oddi (SOD) manometry with endoscopic therapy as appropriate were recommended.  All patients were followed-up in the long-term to evaluate for recurrent pancreatitis, the primary study end-point.  A total of 201 patients were identified (80 single attack, 121 multiple attacks; mean age of 53 years, range of 17 to 95 years; standard deviation [SD] of 16.3 years; and 53 % women).  After EUS, 54 % of patients with a single attack were categorized as idiopathic, and for multiple attacks SOD dysfunction was the most common diagnosis (41 %).  Long-term follow-up (median of 37 months; interquartile range [IQR] of 19 to 70 months) documented recurrence of pancreatitis in 15 (24 %; 95 % CI: 15 % to 38 %) patients with a single attack and in 48 (49 %; 95 % CI: 38 % to 62 %) patients with multiple attacks.  Despite endoscopic therapy, patients with PD and SOD dysfunction had relapse rates of 50 % (95 % CI: 35 % to 68 %) and 55 % (95 % CI: 31 % to 82 %), respectively.  The authors concluded that following a single idiopathic attack of pancreatitis and a negative EUS examination, relapse was infrequent.  Despite endoscopic therapy, patients with multiple attacks, especially those attributed to PD and SOD dysfunction, had high rates of recurrence.  These investigators stated that EUS may be a useful, minimally invasive tool for the diagnostic evaluation of idiopathic pancreatitis.

Somani and colleagues (2017) noted that recurrent acute pancreatitis (RAP) is defined based on the occurrence of 2 or more episodes of acute pancreatitis.  The initial evaluation fails to detect the cause of RAP in 10 % to 30 % of patients, whose condition is classified as idiopathic RAP (IRAP).  Idiopathic acute pancreatitis (IAP) is a diagnostic challenge for gastroenterologists.  In view of associated morbidity and mortality, it is important to determine the etiology of pancreatitis to provide early treatment and prevent recurrence; EUS is an investigation of choice for imaging of pancreas and biliary tract.  In view of high diagnostic accuracy and safety of EUS, a EUS-based management strategy appeared to be a reasonable approach for evaluation of patients with a single/recurrent idiopathic pancreatitis.  The most common diagnoses by EUS in IAP is biliary tract disease.  These investigators discussed the role of EUS in the clinical management and diagnosis of patients with IAP.  It elaborated the diagnostic approach to IAP in relation to EUS and other different modalities.  The authors concluded that considering all the prior studies, the diagnostic yield of EUS was not influenced by whether the episode is 1st or recurrent.  Thus, these investigators stated that EUS should be performed after the 1st episode of IAP if possible; MRCP preferably secretin-enhanced MRCP (MRCP-S) could be performed if EUS expertise is not available.  MRCP can be complimentary to EUS in identifying controversial etiologies like PD, and SOD dysfunction.  Endoscopic retrograde cholangiopancreatography (ERCP) could be then be performed to treat biliary stones and PD.  However, in view of high risk of post ERCP pancreatitis, ERCP with SOM should be reserved in those patients in whom MRCP and EUS has found to be negative for diagnostic and therapeutic evaluation especially with post cholecystectomy cases.  The authors recommended an EUS as the 1st-line examination in the evaluation of patients with idiopathic pancreatitis, because it is minimally invasive, low risk and accurately identifies most occult causes of pancreatitis.

Wan and associates (2018) noted that IAP poses a diagnostic challenge for gastroenterologists, because confirmation of the disease etiology has important implications for the selection of the best possible treatment and the prevention of possible recurrence or the development of chronic pancreatitis (CP); ERCP, EUS, and MRCP typically are used to diagnose IAP when conventional radiologic methods fail.  However, their exact role in the diagnosis of IAP has not yet been determined.  These investigators searched the PubMed, Embase, OVID, Cochrane Library (including CENTRAL), China National Knowledge Infrastructure (CNKI), and Wanfang databases from inception to April 2017.  Studies involving the use of EUS and/or MRCP for the etiologic diagnosis of IAP were included.  A meta-analysis was performed by using Review Manager Version 5.2 for comparative studies and R software 3.3.3 to determine diagnostic yield of the studies.  Among the 34 studies that met the inclusion criteria (n = 2,338), 7 studies used a combination of EUS and MRCP and totaled 249 patients.  The results comparing EUS with MRCP showed a diagnostic yield of 153 of the 239 patients (64 %) in the EUS group, which was higher than the yield of 82 of 238 patients (34 %) in the MRCP group (p < 0.001) in the 7 studies, and the diagnostic yield was 60 % in the EUS group, 24 % in the MRCP group, and 43 % in the MRCP-S group.  In subgroup analysis of CP and biliary disease, EUS was superior to MRCP (p < 0.001), but when comparing the efficacy of the modalities in the diagnosis of PD, MRCP-S was obviously superior to MRCP and EUS (12 % versus 2 % versus 2 %).  The authors concluded that EUS and MRCP should both be used in the diagnostic work-up of IAP as complementary techniques; EUS had a higher diagnostic accuracy than MRCP (64 % versus 34 %) in the etiologic diagnosis of IAP and should be preferred for establishing a possible biliary disease and CP diagnosis, whereas MRCP-S was superior to EUS and MRCP in diagnosing a possible anatomic alteration in the bilio-pancreatic duct system, such as PD.

Furthermore, an UpToDate review on “Etiology of acute pancreatitis” (Vege, 2019) states that “In patients with an isolated episode of acute pancreatitis, if the initial evaluation does not yield an etiology, we perform an endoscopic ultrasonography (EUS).  In patients with a negative EUS or if EUS is unavailable, we perform magnetic resonance cholangiopancreatography (MRCP) following secretin administration.  Endoscopic retrograde cholangiopancreatography (ERCP) is not routinely recommended as a diagnostic test for idiopathic acute pancreatitis because of its complications.  It is reserved for endotherapy in patients with abnormal MRCP/EUS findings (e.g., choledocholithiasis, and pancreatic ductal stricture), to diagnose a small tumor in the terminal bile duct or pancreatic duct in patients with a suspected pancreatic neoplasm, or to perform intraductal endoscopy in patients with a main duct intraductal papillary mucinous neoplasm.  In patients with recurrent episodes of pancreatitis (irrespective of age), EUS is the preferred initial test.  We collect bile for microscopic evaluation for cholesterol or bilirubinate crystals if EUS imaging is negative.  We perform MRCP following secretin administration in patients with a negative EUS and bile microscopy.  We do not routinely perform ERCP unless indicated for additional evaluation of abnormal MRCP/EUS findings or endotherapy.  There is significant controversy about whether sphincter of Oddi dysfunction is an underlying cause of idiopathic recurrent acute pancreatitis and both ERCP and sphincter of Oddi manometry are associated with procedure-related complications”.

Contrast-Enhanced Harmonic Endoscopic Ultrasonography in Differentiating Between Gastro-Intestinal Stromal Tumors (GIST) and Benign Subepithelial Lesions

Tang and colleagues (2019) noted that contrast-enhanced harmonic endoscopic US (CH-EUS) is a valuable device to diagnose and determine the malignant potential of gastro-intestinal stromal tumors (GIST) as early as possible when making clinical therapeutic decisions.  These researchers examined the ability of CH-EUS to discriminate between GIST and benign submucosal lesions (SML) and to predict their malignant potential.  PubMed, Medline, Embase, the Web of Science, and Cochrane Central Register of Controlled Trials databases were screened.  Using the data provided in the literatures, 2 × 2 tables were constructed to obtain the pooled sensitivity, specificity, PLR, and NLR.  A ROC curve was generated and the area under the ROC curve (AUROC) was calculated.  A total of 4 studies with 187 patients were identified to evaluate the value of CH-EUS in discriminating between GIST and benign SML.  The pooled sensitivity, specificity, and AUROC were 89 % (95 % CI: 0.82 to 0.93), 82 % (95 % CI: 0.66 to 0.92), and 0.89, respectively; 5 studies including 143 patients were analyzed to evaluate the accuracy of CH-EUS in determining the malignant potential of GIST.  The pooled sensitivity, specificity, and AUROC curve of CH-EUS were 96 % (95 % CI: 0.90 to 0.99), 53 % (95 % CI: 0.40 to 0.66), and 0.92, respectively.  The authors concluded that CH-EUS was a safe, non-invasive method that could distinguish between GIST and benign subepithelial lesions and to predict their malignant potential to a certain extent.  Moreover, these researchers stated that large, prospective, multi-center studies are needed in the future.

Endoscopic Ultrasonography-Guided Biliary Drainage for Malignant Biliary Obstruction

Park and colleagues (2018) stated that ERCP-guided biliary drainage (ERCP-BD) is a criterion standard treatment for malignant biliary obstruction (MBO) when curative surgery is not an option.  Alternative methods such as percutaneous transhepatic biliary drainage would significantly lower the quality of life (QOL).  EUS-guided biliary drainage (EUS-BD) has been developed and performed by experienced endoscopists.  In a prospective RCT, these researchers examined the safety and efficacy of EUS-BD compared with ERCP in the treatment of MBO.  A total of 30 patients were enrolled: 15 for each EUS-BD and ERCP-BD arms.  The technical success, procedural time, clinical success, and AEs were evaluated.  A total of 30 patients had extra-hepatic MBO (19 men, 11 women); 27 patients had unresectable pancreatic ductal adenocarcinomas, 1 patient had distal common bile duct cancer, and 2 patients had metastatic malignant lymphadenopathy.  There were no significant differences both in terms of technical success rate and clinical success rate (100 % versus 93 % and 93 % versus 100 % in ERCP-BD versus EUS-BD, respectively; p = 1.00, p = 1.00); 4 patients (31 %) had tumor ingrowth-caused stent dysfunction in the ERCP-BD group, whereas 2 patients had food impaction and 2 patients had stent migration in the EUS-BD group.  No significant procedure-related AEs occurred in either group.  The authors concluded that the findings of this prospective RCT suggested that EUS-BD had similar safety to ERCP-BD; EUS-BD was not superior to ERCP-BD in terms of relief of MBO.  These researchers stated that EUS-BD may have fewer cases of tumor ingrowth but may also have more cases of food impaction or stent migration.

Paik and co-workers (2018) stated that although ERCP for the palliation of MBO is the standard of care, post-procedure pancreatitis and stent dysfunctions are not uncommon.  While EUS-BD has garnered interest as a viable alternative when ERCP is impossible, its role as a primary palliation of distal MBO is yet to be proven.  In a multi-center, randomized, clinical trial, these researchers (2018) examined if EUS-BD is comparable to conventional trans-papillary stenting with ERCP in palliation of distal MBO.  They performed random allocation to EUS-BD or ERCP in 125 patients with unresectable distal MBO at 4 tertiary academic referral centers in South Korea.  Technical success rates were 93.8 % (60/64) for EUS-BD and 90.2 % (55/61) for ERCP (difference 3.6 %, 95 % 1-sided CI lower limit -4.4 %, p = 0.003 for non-inferiority margin of 10 %).  Clinical success rates were 90.0 % (54/60) in EUS-BD and 94.5 % (52/55) in ERCP (p = 0.49).  Lower rates of overall AEs (6.3 % versus 19.7 %, p = 0.03) including post-procedure pancreatitis (0 versus 14.8 %), re-intervention (15.6 % versus 42.6 %), and higher rate of stent patency (85.1 % versus 48.9 %) were observed with EUS-BD.  EUS-BD was also associated with more preserved QOL than trans-papillary stenting after 12 weeks of the procedure.  The authors concluded that this study demonstrated comparable technical and clinical success rates between EUS-BD and ERCP in relief of distal MBO.  Substantially longer duration of patency coupled with lower rates of AEs and re-intervention, and more preserved QOL were observed with EUS-BD.

Miller and colleagues (2019) EUS-BD is increasingly used for distal MBO, yet its safety and efficacy compared to ERCP or percutaneous transhepatic biliary drainage (PTBD) remain unclear.  These investigators carried out a meta-analysis to improve the understanding of the role of EUS-BD in this patient population.  They searched Embase, Medline, CENTRAL, and ISI Web of Knowledge through September 2018 for RCTs comparing EUS-BD to ERCP-BD or PTBD as treatment of distal MBO; RRs with 95 % CIs were combined using random effects models.  The primary outcome was risk of stent/catheter dysfunction requiring re-intervention.  Of 6 trials identified, 3 (n = 222) compared EUS-BD to ERCP-BD for 1st-line therapy; 3 others (n = 132) evaluated EUS-BD versus PTBD after failed ERCP-BD.  EUS-BD was associated with a decreased risk of stent/catheter dysfunction overall (RR, 0.39; 95 % CI: 0.27 - to 0.57) and in planned subgroup analysis when compared to ERCP (RR, 0.41; 95 % CI: 0.23 - to 0.74) or PTBD (RR, 0.37, 95 % CI: 0.22 - to 0.61).  Compared to ERCP, EUS was associated with a decreased risk of post-procedure pancreatitis (RR, 0.12; 95 % CI: 0.01 - to 0.97).  No differences were noted in technical or clinical success.  The authors concluded that in this meta-analysis of randomized trials comparing EUS-BD to conventional biliary drainage modalities, no difference in technical or clinical success was observed.  More importantly, EUS-BD was associated with decreased risks of stent/catheter dysfunction when compared to both PTBD and ERCP, and decreased post-procedure pancreatitis when compared to ERCP, suggesting the potential role for EUS-BD as an alternative 1st-line therapy in distal MBO. Moreover, these researchers stated that their findings should be validated with the emergence of dedicated EUS therapeutic devices and as more randomized data become available.

The authors stated that this study had several drawbacks.  The first is the relatively small number of reported RCTs and included patients.  To that end, the more conservative random effects model was used to estimate effect sizes.  The fact that differences in outcomes were no longer observed with removal of the largest study in a sensitivity analysis of the ERCP comparison subgroup reflected a lack of robustness and this study should be repeated once more randomized data are available.  The small number of studies also limited the use of a prediction interval to further ascertain heterogeneity in a random effects model, given that such statistical methods have been shown to be inaccurate and potentially misleading in small meta-analyses.  Second, the use of different devices in the individual studies created clinical heterogeneity.  Again, sensitivity analysis was performed removing the study with a dedicated device only available in Korea.  Third, the per-patient event rate was frequently not reported in studies; thus, an overall event rate was used.  Finally, the performance of EUS-BD only within expert centers limited generalizability to other settings.

Jin and associates (2020) noted that current evidence supporting the utility of EUS-BD as primary treatment for distal MBO is limited.  These investigators conducted a meta-analysis to compare the performance of EUS-BD and ERCP-guided biliary drainage (ERCP-BD) as primary palliation of distal MBO.  They searched several data-bases for comparative studies evaluating EUS-BD versus ERCP-BD in primary drainage of distal MBO up to February 28,  2019.  Primary outcomes were technical success and clinical success.  Secondary outcomes included AEs, stent patency, stent dysfunction, tumor in-/over-growth, re-interventions, procedure duration, and overall survival (OS).  A total of 4 studies involving 302 patients were qualified for the final analysis.  There was no difference in technical success (risk ratio [RR] 1.00; 95 % CI: 0.93 to 1.08), clinical success (RR 1.00; 95 % CI: 0.94 to 1.06) and total AEs (RR 0.68; 95 % CI: 0.31 to 1.48) between the 2 procedures.  EUS-BD was associated with lower rates of post-procedure pancreatitis (RR 0.12; 95 % CI: 0.02 to 0.62), stent dysfunction (RR 0.54; 95 % CI: 0.32 to 0.91), and tumor in-/over-growth (RR 0.22; 95 % CI: 0.07 to 0.76).  No differences were noted in re-interventions (RR 0.59; 95 % CI: 0.21 to 1.69), procedure duration (weighted mean difference [WMD] -2.11; 95 % CI: -9.51 to 5.29), stent patency (hazard ratio [HR] 0.61; 95 % CI: 0.34 to 1.11), and OS (HR 1.00; 95 % CI: 0.66 to 1.51).  The authors concluded that with adequate endoscopy expertise, EUS-BD could show similar safety and efficacy when compared with ERCP-BD for primary palliation of distal MBO and exhibited several clinical advantages.  Moreover, these researchers stated that further RCTs with large sample sizes are needed.

The authors stated that this study had several drawbacks.  The number of included studies (n = 4) and subjects (n = 302) was relatively small.  Variation among studies was observed in study design and outcome definitions, introducing heterogeneity.  For example, in the study by Paik et al (2018) clinical success was defined as reduction of total bilirubin to less than half within 1 week.  In contrast, Kawakubo et al (2016) and Park et al.20 evaluated clinical success 4 weeks after biliary drainage.  Not all outcomes were available for each parameter of the subgroup analyses.  For example, use of chemotherapy that may affect overall survival could not be analyzed; thus, interpretations for these results need to be cautious.

Endoscopic Ultrasonography-Guided Fiducial Placement for Image-Guided Radiotherapy in GI Malignancies

Dhadham and associates (2016) noted that EUS-guided fiducial marker placement for image-guided radiation treatment (IGRT) is becoming more widespread.  Most case series reported the procedure performed using fluoroscopy for spatial geometry although the benefits of this are unclear.  In a retrospective chart review, these investigators reported the technical feasibility, safety, and migration rate of fiducial marker placement in a large cohort of patients with gastro-intestinal (GI) malignancies who underwent EUS-guided fiducial marker placement for IGRT without fluoroscopy.  They carried out a chart review on all patients referred for EUS-guided fiducial marker placement from August 1, 2007 to July 31, 2014 at Moffitt Cancer Center.  During the study period, a total of 514 patients underwent placement of 1,093 gold fiducial markers under EUS-guidance; 240 patients with esophageal/gastro-esophageal junction cancer had 405 fiducials placed.  In 188 patients with pancreatic cancer, 510 fiducials were placed.  In 54 patients with rectal cancer, 103 fiducials were placed and 32 patients had 75 fiducials placed into other GI tract lesions.  Minor bleeding, which resolved spontaneously, occurred in 2 patients.  Technical difficulty in placing fiducials was noted in 18 patients.  Intra-procedural fiducial migration was noted in 2 patients and only 2/1,093 fiducials (0.002 %) in 2 esophageal patients migrated as noted on simulation CT scan.  The authors concluded that EUS-guided fiducial marker placement without fluoroscopy was technically feasible and safe.  There were minimal intra-procedure/post-procedure complications.  These researchers stated that imaging at the time of simulation also revealed the migration rate to be extremely low; these findings may allow for more widespread adoption of EUS-guided fiducial marker placement.

The authors stated that limitations of this study included the retrospective nature.  In addition, all procedures were performed by expert interventional endoscopists with a high volume of fiducial cases.  Therefore, their success rate and low AE rate may not be reproducible in the community setting.

Coronel and colleagues (2019) stated that IGRT allows the delivery of radiation with high precision to a target lesion while minimizing toxicity to surrounding tissues.  EUS provides excellent visualization of GI tumors and consequently is being used for fiducial placement with increased frequency.  In a systematic review and meta-analysis, these investigators examined the technical aspects, safety, and efficacy of EUS fiducial placement for IGRT in GI malignancies.  They carried out a systematic literature search in the following databases: Medline, PubMed, Embase, Web of Science, and Cochrane Library, using Medical Subject Headings terms combined with text words.  A random effects model was used to determine pooled proportions of technical success, migration, and AEs rates.  Heterogeneity was assessed using the I2 statistic.  Publication bias was assessed visually using a funnel plot and by the Begg and Egger tests.  A total of 9 full articles and 5 abstracts reporting on 1,155 patients, 49 % from a single study by Dhadham et a (2016)l, were included in the meta-analysis.  The pooled rate of technical success was 98 % (95 % CI: 96 to 99).  Moderate heterogeneity (I2 = 34.18) was present, which appeared to be due to variable sample sizes.  Publication bias was present, suggesting that studies with less-substantial outcomes may have not been reported (Begg test, p = 0.87; Egger test, p < 0.01).  Pooled rates for fiducial migration and AEs were 3 % (95 % CI: 1.0 to 8.0) and 4 % (95 % CI: 3 to 7), respectively.  The authors concluded that the findings of this meta-analysis showed that EUS-guided insertion of gold fiducials for IGRT was technically feasible and safe.  Moreover, these researchers stated that further controlled studies examining its long-term effectiveness in GI malignancies are needed.

EchoTip Insight - Endoscopic Ultrasound-Guided Direct Measurement of Hepatic Portosystemic Pressure Gradient

On November 19, 2018, the Food and Drug Administration (FDA) received and granted de-novo authorization for the EchoTip Insight portosystemic pressure gradient measurement system as a Class II device.  The EchoTip Insight is indicated for direct measurement of pressures in the hepatic and portal venous vasculatures and is used in conjunction with an ultrasound (US) endoscope.  However, there is insufficient evidence to support the effectiveness of the EchoTip Insight.

Huang and colleagues (2017) noted that portal hypertension (PH) is a serious adverse event (AE) of liver cirrhosis.  The hepatic venous pressure gradient or portal pressure gradient (PPG) accurately reflects the degree of PH and is the single best prognostic indicator in liver disease.  This is usually obtained by interventional radiology (IR), although it is not routinely performed.  These researchers developed a simple novel technique for endoscopic ultrasound (EUS)-guided PPG measurement (PPGM).  Their animal studies showed excellent correlation between EUS-PPGM and IR-PPGM.  These investigators presented the first human pilot study of EUS-PPGM in patients with liver disease.  EUS-PPGM was carried out by experienced endosonographers using a linear echoendoscope, a 25-G fine-needle aspiration needle, and a novel compact manometer.  The portal vein and hepatic vein (or inferior vena cava) were targeted using a transgastric-transduodenal approach.  Clinical parameters of PH were examined in each patient.  Feasibility was defined as successful PPGM in each patient.  Safety was based on AEs captured in a post-procedural interview.  A total of 28 patients underwent EUS-PPGM with 100 % technical success and no AEs.  PPG ranged from 1.5 to 19 mm Hg and had excellent correlation with clinical parameters of portal hypertension including the presence of varices (p = 0.0002), PH gastropathy (p = 0.007), and thrombocytopenia (p = 0.036).  PPG was increased in patients with high clinical evidence of cirrhosis (p = 0.005).  The authors concluded that this novel technique of EUS-PPGM using a 25-G needle and compact manometer was feasible and appeared safe.  Given the availability of EUS and the simplicity of the manometry setup, EUS-guided PPG may represent a promising breakthrough for procuring information in the management of patients with liver disease.  These researchers stated that this work set the stage for larger clinical trials to establish the role of EUS-guided portal pressure measurement in a wider spectrum of liver disease and portal hypertension.

The authors stated that the drawbacks of this study included its retrospective study design, a single-center study with a relatively small cohort of patients (n = 28).  Patients did not have simultaneous trans-jugular hepatic venous pressure gradient measurements.  Patients with suspected cirrhosis did not have a percutaneous liver biopsy.

Samarasena and Chang (2019) stated that the number of EUS-guided interventions is rapidly growing within advanced endoscopy.  EUS offers high-resolution imaging of mediastinal and intra-abdominal vasculature, which can be targeted for various interventions, hence a growing number of studies have examined EUS-guided vascular catheterization.  Potential clinical applications of EUS-guided portal venous access include angiography, measurement of the portosystemic pressure gradient, and EUS-guided transhepatic intra-hepatic portosystemic shunt (TIPSS) creation.  These researchers stated that in animal studies, EUS-guided PPGMs were strongly correlated with values obtained through a percutaneous approach, with an excellent safety profile.  In human studies EUS-guided PPGM appeared to be safe and correlated well with clinical and endoscopic parameters such as portal hypertensive gastropathy, the presence of esophageal varices, and thrombocytopenia.  In addition, EUS-guided TIPSS was successfully performed in pigs without any reported serious post-procedural or intra-procedural complications.

Sbeit and associates (2020) noted that liver diseases are among the most common diseases worldwide and manifest as a parenchymatic and/or biliary injury due to several causes as well as focal liver lesions, ranging from benign to malignant ones.  The diagnosis of liver diseases is based mainly on biochemical and advanced imaging studies and, when required, on liver biopsy.  EUS is one of the main examination techniques used in gastroenterology as it is applied to evaluate abnormalities in the lumen of the upper and lower GI tract and to define pancreatic and hepato-biliary features, often in chronic patients.  Given its high spatial resolution and its proximity to the liver, EUS is gaining popularity in the diagnostic work-up of liver diseases.  These investigators provided a comprehensive overview of the current literature on the diagnostic indications for EUS use in patients with liver diseases.  They carried out a Medline\PubMed and Embase search, and all articles that were relevant, after reviewing abstracts, were evaluated and the full text was analyzed to extract data regarding technical success, diagnostic yield, bioptic characteristics, and complications rate.  EUS-guided imaging and biopsy techniques in liver diseases have shown consistent favorable promising results among the reports through the literature, with an excellent diagnostic yield and safety profile, especially in the context of focal lesions and portal hypertension.  The authors concluded that the application of EUS in the diagnosis of liver diseases is a promising technique and should be considered as a first-line therapeutic option in selected cases.

Zhang and co-workers (2021) stated that EUS-PPG measurement is a novel method to examine portal hypertension severity.  In a prospective study, these researchers determined the consistency between EUS-PPG and hepatic venous pressure gradient (HVPG) measurements in patients with acute or subacute portal hypertension.  A total of 12 patients were enrolled in this trial; EUS-PPG measurements were carried out using a 22-G FNA needle and a central venous pressure (CVP) measurement monitor.  The HVPG measurements were carried out by means of the trans-jugular approach.  If an HVPG measurement was not attainable and the patient underwent TIPSS treatment, a PPG was recorded as a reference standard during the procedure.  These investigators examined the safety and feasibility of EUS-PPG and calculated the correlation between the 2 measurements.  EUS-PPG measurements were successful in 11 patients (91.7 %).  Subsequent HVPG measurements failed in 2 patients with Budd-Chiari syndrome (hepatic vein occlusion subtype), 1 of whom underwent TIPSS treatment to obtain trans-jugular PPG data.  A small shunt was found during 1 HVPG measurement that introduced inaccuracy; 9 patients were included in the statistical analysis.  Mean EUS-PPG and HVPG/PPG (trans-jugular) were 18.07 ± 4.32 mm Hg and 18.82 ± 3.43 mm Hg, respectively.  Pearson's correlation coefficient between the 2 methods was 0.923 (p < 0.001).  The authors concluded that EUS-PPG measurement using a 22-G FNA needle was a safe and accurate method to evaluate portal hypertension and has the potential to supplement the measurement of HVPG in liver diseases.

Furthermore, an UpToDate review on “Endoscopic ultrasound-guided fine needle aspiration in the gastrointestinal tract” (Wiersema, 2021) does not mention endoscopic ultrasound-guided measurement for hepatic portosystemic pressure gradient.

Endoscopic Ultrasonography for Evaluation of Asymptomatic Common Bile Duct Dilation

Chhoda and colleagues (2021) stated that common bile duct (CBD) dilation is a frequent indication for EUS.  Among asymptomatic individuals, biliary dilation may not be clinically significant; however, EUS is often relied on for the exclusion of benign and malignant pathology that might require further intervention.  The yield of EUS evaluation for this indication is not well characterized and has significant implications for health resource utilization because asymptomatic biliary dilation is prevalent.  In a systematic review, these researchers examined the yield of EUS evaluation of asymptomatic patients with radiologic evidence of isolated CBD dilation.  They carried out a protocolled search and extracted original studies from the Cochrane Library, Ovid Embase, Google Scholar, Ovid Medline, PubMed, Scopus, and Web of Science Core Collection that described diagnostic yield of EUS among asymptomatic patients with biliary dilation.  Cumulative EUS diagnostic yield was calculated via meta-analysis of proportions using inverse variance methods and a random-effects model.  Of 2,616 studies, 8 delineated the EUS yield among 224 asymptomatic patients.  The cumulative yield of EUS for any pathology was 11.2 % (95 % CI: 3.6 % to 21.6 %).  The EUS yield for benign etiologies was 9.2 % (95 % CI: 1.1 % to 21.9 %), of which choledocholithiasis comprised 3.4 % (95 % CI: 0 % to 11.2 %) and malignant etiologies 0.5 % (9 5% CI: 0 % to 3.4 %) of cases.  The authors concluded that EUS in patients with asymptomatic CBD dilation yielded findings of choledocholithiasis and malignancy, albeit at low rates.  Moreover, these researchers stated that further descriptive studies and cost-effectiveness analysis are needed to guide clinical decision-making in this area.

These researchers stated that despite contacting authors directly because of a paucity of clear baseline data on asymptomatic patients, they were unable to perform meta regression and subgroup analyses for baseline factors to predict a significant pathology, which was a significant limitation.  In addition, a limited number of studies also prevented formal publication bias assessment of most analyses, which highlighted the issue of lack of publications on EUS characterization of asymptomatic biliary dilation.  These investigators also acknowledged a priori exclusion of studies in foreign language.  These researchers also observed heterogeneity in most of the outcome measures as indicated by the high I2 as well as prediction intervals.  Many studies had limited sample size, single-center design, and variable age and gender distribution.  Other factors such as anatomic alterations and liver enzyme alterations might also have been contributory.  As evident by the sensitivity analyses, the study by Kaspy et al (2019) contributed to some heterogeneity to both overall EUS yield among all populations and in those with normal liver chemistry.  This study included 91 individuals from a prospectively maintained database and detected no EUS abnormalities.  Overall, this meta-analysis also highlighted the need for more studies with detailed subgroup analyses to examine this clinical problem.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met:
EUS-guided fiducial placement for image-guided radiotherapy - no specific code
31652 - 31653	Bronchoscopy, rigid or flexible, including fluoroscopic guidance, when performed; with endobronchial ultrasound (EBUS) guided transtracheal and/or transbronchial sampling (eg, aspiration[s]/biopsy[ies])
31654	Bronchoscopy, rigid or flexible, including fluoroscopic guidance, when performed; with transendoscopic endobronchial ultrasound (EBUS) during bronchoscopic diagnostic or therapeutic intervention(s) for peripheral lesion(s) (List separately in addition to code for primary procedure[s])
43231	Esophagoscopy, flexible, transoral; with endoscopic ultrasound examination
43232	with transendoscopic ultrasound-guided intramural or transmural fine needle aspiration/biopsy(s)
43237	Esophagogastroduodenoscopy, flexible, transoral; with endoscopic ultrasound examination limited to the esophagus, stomach or duodenum, and adjacent structures
43238	with transendoscopic ultrasound-guided intramural or transmural fine needle aspiration/biopsy(s), (includes endoscopic ultrasound examination limited to the esophagus, stomach or duodenum, and adjacent structures)
43240	with transmural drainage of pseudocyst (includes placement of transmural drainage catheter[s]/stent[s], when performed, and endoscopic ultrasound, when performed)
43242	with transendoscopic ultrasound-guided intramural or transmural fine needle aspiration/biopsy(s) (includes endoscopic ultrasound examination of the esophagus, stomach, and either the duodenum or a surgically altered stomach where the jejunum is examined distal to the anastomosis)
43253	with transendoscopic ultrasound-guided transmural injection of diagnostic or therapeutic substance(s) (eg, anesthetic, neurolytic agent) or fiducial marker(s) (includes endoscopic ultrasound examination of the esophagus, stomach, and either the duodenum or a surgically altered stomach where the jejunum is examined distal to the anastomosis)
43259	with endoscopic ultrasound examination, including the esophagus, stomach, and either the duodenum or a surgically altered stomach where the jejunum is examined distal to the anastomosis
44406	Colonoscopy through stoma; with endoscopic ultrasound examination, limited to the sigmoid, descending, transverse, or ascending colon and cecum and adjacent structures
44407	with transendoscopic ultrasound guided intramural or transmural fine needle aspiration/biopsy(s), includes endoscopic ultrasound examination limited to the sigmoid, descending, transverse, or ascending colon and cecum and adjacent structures
45341	Sigmoidoscopy, flexible; with endoscopic ultrasound examination
45342	with transendoscopic ultrasound guided intramural or transmural fine needle aspiration/biopsy(s)
45391	Colonoscopy, flexible; with endoscopic ultrasound examination limited to the rectum, sigmoid, descending, transverse, or ascending colon and cecum, and adjacent structures
45392	with transendoscopic ultrasound guided intramural or transmural fine needle aspiration/biopsy(s), includes endoscopic ultrasound examination limited to the rectum, sigmoid, descending, transverse, or ascending colon and cecum, and adjacent structures
64530	Injection, anesthetic agent; celiac plexus, with or without radiologic monitoring
76975	Gastrointestinal endoscopic ultrasound, supervision and interpretation
CPT codes not covered for indications listed in the CPB:
76981 - 76983	Ultrasound, elastography
Other CPT codes related to the CPB:
0395T	High dose rate electronic brachytherapy, interstitial or intracavitary treatment, per fraction, includes basic dosimetry, when performed
47533	Placement of biliary drainage catheter, percutaneous, including diagnostic cholangiography when performed, imaging guidance (eg, ultrasound and/or fluoroscopy), and all associated radiological supervision and interpretation; external
47534	internal-external
77770 - 77772	Remote afterloading high dose rate radionuclide interstitial or intracavitary brachytherapy, includes basic dosimetry, when performed
77778	Interstitial radiation source application, complex, includes supervision, handling, loading of radiation source, when performed
HCPCS codes not covered for indications listed in the CPB:
C9768	Endoscopic ultrasound-guided direct measurement of hepatic portosystemic pressure gradient by any method
ICD-10 codes covered if selection criteria are met (not all inclusive):
C15.3 - C15.9	Malignant Neoplasm of the esophagus
C16.0 - C16.9	Malignant neoplasm of the stomach
C17.0 - C17.9	Malignant neoplasm of small intestine
C18.0 - C18.9	Malignant neoplasm of colon
C19 - C21.8	Malignant neoplasm of rectum, rectosigmoid junction and anus
C22.1	Intrahepatic bile duct carcinoma
C24.0 - C24.9	Malignant neoplasm of other and unspecified parts of biliary tract
C25.0 - C25.9	Malignant neoplasm of pancreas [not covered for differentiation of benign and malignant pancreatic masses] [not covered for endoscopic ultrasonography-guided interstitial brachytherapy]
C26.0 - C26.9	Malignant neoplasm of other and ill-defined digestive organs
C33 - C34.92	Malignant neoplasm of trachea, bronchus, and lung
C38.1 - C38.3	Malignant neoplasm of mediastinum
C48.0 - C48.8	Malignant neoplasm of retroperitoneum and peritoneum
C78.00 - C78.89	Secondary malignant neoplasm of respiratory and digestive systems
D00.0 - D01.9	Carcinoma in situ of digestive organs
D13.0 - D13.9	Benign neoplasm of other part and ill-defined parts of digestive system
D14.1 - D14.4 D15.2, D19.0	Benign neoplasm of larynx, trachea, bronchus and lung, pleura, and mediastinum
D37.1 - D38.6	Neoplasms of uncertain behavior of stomach, intestines, and rectum, liver and biliary passages, retroperitoneum and peritoneum, other and unspecified digestive organs, larynx, trachea, bronchus, and lung, pleura, thymus, and mediastinum
K80.30 - K80.71	Calculus of bile duct with cholangitis
K81.0	Acute cholecystitis
K85.00 - K85.02	Idiopathic acute pancreatitis
K86.0	Alcohol-induced chronic pancreatitis
K86.1	Other chronic pancreatitis
R19.00 - R19.09	Intra-abdominal and pelvic swelling, mass and lump
R22.2	Localized swelling, mass and lump, trunk
R59.0 - R59.9	Enlarged lymph nodes
ICD-10 codes not covered for indications listed in the CPB:
C7A.00 - C7A.8	Malignant neuroendocrine tumors
C77.0 - C77.9	Secondary and unspecified malignant neoplasm of lymph nodes [for differential diagnosis of malignant lymph nodes]
C78.80 - C78.89	Secondary malignant neoplasm of other digestive organs [for differentiation of benign and malignant pancreatic masses]
D13.6	Benign neoplasm of pancreas [for differentiation of benign and malignant pancreatic masses]
D13.7	Benign neoplasm of endocrine pancreas [for differentiation of benign and malignant pancreatic masses]
D36.0	Benign neoplasm of lymph nodes [for differential diagnosis of malignant lymph nodes]
D37.8 - D37.9	Neoplasm of uncertain behavior of other and unspecified digestive organs [for differentiation of benign and malignant pancreatic masses]
D49.0	Neoplasm of unspecified nature of digestive system [for differentiation of benign and malignant pancreatic masses]
E24.0 - E27.9	Disorders of the adrenal gland
I85.00 - I85.11	Esophageal Varices
N00.0 - N99.89	Diseases of the genitourinary system

The above policy is based on the following references: