EUS-guided Through-the-needle Microforceps Biopsy Outcomes

Pancreatic Cyst Clinical Trial

Official title:

How Does the EUS-guided Through-the-needle Microforceps Biopsy Improve Diagnosis of Pancreatic Cystic Lesions: A Multicenter Prospective Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04140435
• Other study ID #: IGEA07-2019
• Status: Recruiting
• Start date: October 22, 2019
• Est. completion date: November 1, 2022

Study information

• Verified date: May 2022
• Source: Institute of Gastroenterology and Advance Endoscopy
• Contact: Manuel Valero, MD
• Phone: (+54) 2914429990
• Email: valero.manuel[@]hotmail.com
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

INTRODUCTION: The diagnosis of pancreatic cystic lesions (PCLs) is increasing due to improvements of cross-sectional imaging. It is mandatory, for appropriate management, to make an accurate diagnosis and risk stratification, since some of these lesions may harbor malignancy or have potential for malignant transformation and hence surgical resection is required. Diagnostic evaluation of PCLs can be challenging, requiring a combination of different methods. Usually PCLs are been initially detected by cross-sectional imaging. However, imaging alone has not been shown to reliably identify the underlying pathology in PCLs with a high degree of accuracy. Hence, Endoscopic ultrasound with fine-needle aspiration (EUS-FNA) is routinely performed. EUS-FNA plays an important role in cyst characterization since allows morphological examination (EUS-B mode), aspiration for cytology and cyst fluid analysis for carcinoembryonic antigen (CEA), amylase and glucose levels; and allows to tissue sample in case of mural nodules o wall thickness. Even though EUS-FNA has been shown to be the test of choice for select lesions with high-risk features, has its limitations related to low sensitivity and specificity. The morphological characterization by EUS of PCL, as well as with the cross-sectional images, depends most of the time, on the subjective interpretation of the operator, which can be very difficult sometimes and depend on experience. A cyst fluid CEA cutoff of 192 ng/mL has been commonly accepted for differentiating mucinous from non-mucinous cysts. However, has the limitation of requiring at least 0.5 mL of cyst fluid for CEA analysis, has a relatively low sensitivity (75%) and specificity (84%), cannot differentiate cyst histotypes, and controversial results have been reported. Finally targeted cyst wall with the tip of the FNA needle can increase the diagnostic accuracy, yet the cytological yield with EUS-FNA remains low due to the relatively small tissue sample. Hence, diagnostic accuracy of currently available tools for evaluation of PCLs including cross-sectional imaging, EUS morphologic features, EUS-FNA for cyst fluid analysis and cytology is not perfect, leading to possible misdiagnosis.

Description:

Recently, a EUS-guided through-the-needle microforceps device (Moray Micro Forceps, US Endoscopy, Mentor, Ohio, United States), witch can be passed through the lumen of a 19-gauge FNA needle, has been introduced as a novel approach for PCLs tissue acquisition. It has been shown that this device can drastically changed the diagnosis, providing diagnoses otherwise not suggested by cytology or cyst fluid CEA levels. The possibility of obtaining histological specimens from the cyst wall with this microforceps may change the management os PCLs, by obtening enough material for supplementary immunohistochemical analysis, allowing for even more accurate histological diagnosis, and in the case of IPMNs, possibly histological subtyping. The aims of this study is to assess: 1) the increment in diagnostic yield, by using this device, when compared to standard evaluation with cross-sectional imaging, EUS-FNA with cyst fluid analysis, 2) to evaluate the technical success, clinical success and safety, 3) Finally inter-observer accuracy in the assessment of PCLs using the different methods will be mesure, by the participation of all the endosonographers of Argentina, in the context of the annual EUS meeting.

• MATERIALS AND METHODS Study design and Setting: It is multicenter, prospective, interventional, non-controlled or randomized and double blind study, performed at the Institute of Gastroenterology and Advanced Endoscopy - IGEA (Bahía Blanca, Argentina), in conjunction with five high volume centers of all over Argentina (La Plata, Buenos Aires x 2, Neuquen and Mendoza), with patients included from July 2019 to July 2020. The study protocol and consent form has been approved by the institutional review board, will be registered at ClinicalTrials.gov and will be conducted according to the declaration of Helsinki. Written informed consent will be obtained from all subjects. No financial support will be received from the manufacturer of the microforceps, and none of the authors have any conflicts of interest. Data collection: Patient demographics, clinical history, cross-sectional imaging and EUS cyst findings like number of cysts, location, size and features (unilocular/septated, mural nodules, thickened wall, communication with pancreatic duct, dilated pancreatic duct and solid component) will be review. Fluid characteristics (viscosity, color, volume), amylase, glucose, CEA level and citology will be analyzed. The CEA level will be classified as <5, 6-192, >192 ng/mL and glucose level as > 50 and ≤ 50 mg/dl. ( ) EUS-FNA type of needle used, biopsy route (stomach/duodenum) and number of passes will be recorded as well as TTNB number of biopsies. Adverse events, technical and clinical success of EUS-FNA and TTNB will be recorded. Results of both procedures will be expressed in terms of cyst histotype, grade of dysplasia and mucinous vs. nonmucinous. Finally surgery result and follow up (12 month) will be used as gold standards. Follow-up data will be obtained from clinical encounters and/or telephone calls. Adverse events will be recorded per published American Society for Gastrointestinal Endoscopy criteria. Intervention: EUS-TTNB procedure technique. All procedures will be performed in a hospital-based interventional endoscopy suite, under intravenous sedation in a standardized manner and under antibiotics prophylactic. In cases of intracystic bleeding or impossibility of emptying the cyst, antibiotic therapy will be prolonged for 5 days. An endosonographer of each institution will perform the EUS procedures, but all the endosonographers of Argentina will analyze the results. EUS procedures will be performed with a linear echo-endoscope (EG-3870 UTK - Pentax, Tokyo, Japan; Hitachi Medical Systems, Tokyo, Japan). Cysts morphology will be recorded as was previously described and then punctured under Doppler guidance by using a 19-gauge EUS-FNA needle (Expect needle; Boston Scientific, Marlborough, Mass or EchoTip Ultra needle; Cook Medical, Bloomington, Ind). The stylet will be removed and the through-the-needle microbiopsy forceps (Moray; US Endoscopy, Mentor, Ohio, USA), with a sheath diameter of 0.8 mm and a jaw opening width of 4.3 mm, will be inserted through the needle into the cystic lumen. Microbiopsies will be obtained from the cyst wall randomly and from mural nodules or septae when observed. The open jaws of the forceps will be pushed gently onto the cyst wall, closed and pulled back to cause visible tenting. Two "bites" per pass of the microforceps will be obtained. Then the forceps will be removed, leaving the needle tip inside the cyst, the specimen will be placed in formalin vials and the forceps will be generously washed with normal saline solution before repeat biopsy. In the absence of intracystic bleeding, the procedure will be repeated 2 times, based on previous information with this device, or until 2 visible specimens are obtained. After completion of biopsies, the cyst fluid will be completely aspirated and sent for biochemistry (CEA, amylase, glucose) and cytology analyses, as was previously mentioned. If the cyst fluid is scarce, analysis of CEA concentration will be preferred over cytology. If a mural nodule is visualized on EUS, it will be accessed separately by using the 19-gauge needle for EUS-FNA cytology. No on-site cytopathological examination will be performed and all specimens will be evaluated by experienced gastrointestinal cytopathologists. Microbiopsies will be fixed immediately in 10% formalin solution and send to be stained with standard hematoxylin and eosin (H and E) and supplementary immunohistochemical (IHC) staining when indicated. After the procedure, patients will be observed for 2 hours in the recovery room before being discharged.

Definitions: Technical success will be defined as successful puncture of the pancreatic cyst with the 19-gauge needle under EUS guidance, advance the microforceps into the cyst, and successful tissue acquisition, that will be confirmed by gross visualization of the specimen from the jaws of the forceps. Clinical success will be defined as the ability to obtain a histopathological diagnosis of the PCL, by cytological or histological evaluation, using the microforceps biopsies. TTNB specimen diagnostic accuracy will be calculated at 3 different diagnostic levels: 1) Provide a specific diagnosis of the cyst histotype based on the characteristics of the epithelium and/or the cells composing the cyst wall. 2) Define the grade of dysplasia. 3) Differentiate mucinous versus nonmucinous cysts based on: The presence of a mucinous epithelium with cytoplasmic mucin and the presence of colloid-like extracellular mucin. The TTNB sampling diagnostic reliability (sensitivity and specificity) will be assessed by the evaluation of the correlation between the TTNB sampling results and surgical specimens (Gold Standard) in patients who underwent surgery or 12 months follow up in case of non-surgical PCL. Cysts with characteristics consistent with mucinous pancreatic cystic (mucinous epithelium with cytoplasmic mucin and/or colloid-like extracellular mucin) on FNA cytology, microforceps histology and/or surgical histology (when available) will be determined as mucinous pancreatic cystic. Otherwise, a final diagnosis will be determined, based on available cross-section imaging, EUS characterization, cyst fluid markers (CEA≥ 192 ng/mL and glucose ≤ 50) and stable appearance on 12 months follow-up. Cyst fluid CEA will be used to initially categorize the lesion as likely non-mucinous (CEA< 192 ng/mL), likely mucinous (CEA≥ 192 ng/mL) or inconclusive (between 6 and 191 ng/mL). Adverse events (AEs) will be defined and classified according to American Society for Gastrointestinal Endoscopy guidelines. Interobserver Agreement: It was mentioned before that diagnostic evaluation of PCLs can be challenging, requiring a combination of different methods, that many of them may have a low sensitivity and specificity, being dependent most of the time, on the subjective interpretation of the operator, which can be very difficult sometimes and experience dependent. The increment in diagnostic yield of a new method is appreciated as the result of the comparison of the new and previous methods accuracy. It is rational to understand that, if the method accuracy is experience dependent, this difference between methods accuracy will be less in more experience work groups. So when the increment in diagnostic yield of a new procedure is been analyzed it is important to ensure that the results can be apply to most of the practitioners (external validity/inter-observer agreement) and not only one group of work since it will only reflect the experience of that group (internal validity/ intra-observer agreement). For that outcome is that inter-observer agreement will be evaluated in the context of the Argentinian annual EUS meeting, where different cases will be presented to all the endosonographers of Argentina. Cases will be presented in 3 stages where a diagnostic assessment will have to be made in each stage. Initially (1st stage) patient's demographic data (sex, age), clinical history and images (CT, MRI, ultrasound) will be shown. Then (2nd stage) EUS images and videos will be presented and finally (3rd stage) the cyst fluid analysis results biochemistry (CEA, glucose, amylase) and cytology will be reviewed. Only 10 cases will be analyzed, during the meeting, due to time limitation, and agreement will be continue beeing evaluated using an online platform where cases will be presented using the same methodology. An external assistant to the protocol will analyze all the result and the different institutes will provide the cases, in a double blind manner, where neither the participating physician nor the operators will know the final results (TTNB or surgery).

Statistical analysis: Summary data will be expressed as mean +/- standard deviation (SD), or median and range for continuous variables and as number with percentage for categorical variables. Fisher o Chi-square test for categorical variables and the t test for continuous variables will be performed when indicated. The sensitivity, specificity, predictive values and accuracy of TTNB will be calculated with the 95% Confidence Interval (95% CI). To examine inter-observer agreement, kappa values will be calculated. Kappa coefficients below 0.4 indicate "poor agreement," values between 0.4 and 0.8 represent "moderate to good agreement," and values greater than 0.8 indicate "excellent agreement." A P value < 0.05 will be considered to be statistically significant. All the statistical analysis will be performed using SPSS software suite v.22.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: November 1, 2022
• Est. primary completion date: October 1, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• Aged = 18 years old patients.

• Patints that agree to participate in the study.

• PCLs = 10mm, large enough to accommodate the microforceps.

• Patients with PCLs and high-risk features (cyst > 3 cm, thickened wall, dilated pancreatic duct, mural nodules and solid component).

• New diagnosis of a PCL or interval changes in morphology on surveillance (cyst growth or high-risk features).

• Patients with PCLs and symptoms (e. g. pancreatitis, abdominal pain, obstructive jaundice).

• Patients with PCLs but without high-risk features and anxiety about the diagnosis.

Exclusion Criteria:

• Inability to provide informed consent for the procedure.

• Pregnancy.

• Platelet count less than 50,000/ml or International Normalized Rate (INR) >2.

• Esophageal stricture or any pathology that does noy allows performing EUS.

Related Conditions & MeSH terms

• Pancreatic Cyst

Intervention

Device:
• EUS-guided through-the-needle microbiopsy forceps (Moray)
EUS-TTNB procedure technique. An endosonographer of each institution will perform the EUS procedures. Cysts morphology will be recorded and then punctured by using a 19-gauge EUS-FNA needle. Then the through-the-needle microbiopsy forceps (Moray) will be inserted through the needle into the cystic lumen. Microbiopsies will be obtained from the cyst wall randomly and from mural nodules or septae when observed. The open jaws of the forceps will be pushed onto the cyst wall, closed and pulled back to cause visible tenting. Two "bites" per pass will be obtained. Then the forceps will be removed and the specimen placed in formalin vials. The procedure will be repeated 2 times, or until 2 visible specimens are obtained. After completion of biopsies, the cyst fluid will be completely aspirated and sent for CEA, amylase, glucose and cytology analyses. If a mural nodule is visualized on EUS, it will be accessed separately by using the 19-gauge needle for EUS-FNA cytology.

Locations

Country	Name	City	State
Argentina	Institute of Gastroenterology and Advanced Endoscopy (IGEA)	Bahía Blanca	Buenos Aires

Sponsors (1)

Lead Sponsor	Collaborator
Institute of Gastroenterology and Advance Endoscopy

Country where clinical trial is conducted

Argentina, 

References & Publications (16)

Alkaade S, Chahla E, Levy M. Role of endoscopic ultrasound-guided fine-needle aspiration cytology, viscosity, and carcinoembryonic antigen in pancreatic cyst fluid. Endosc Ultrasound. 2015 Oct-Dec;4(4):299-303. doi: 10.4103/2303-9027.170417. — View Citation

Brugge WR, Lewandrowski K, Lee-Lewandrowski E, Centeno BA, Szydlo T, Regan S, del Castillo CF, Warshaw AL. Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study. Gastroenterology. 2004 May;126(5):1330-6. — View Citation

Cho CS, Russ AJ, Loeffler AG, Rettammel RJ, Oudheusden G, Winslow ER, Weber SM. Preoperative classification of pancreatic cystic neoplasms: the clinical significance of diagnostic inaccuracy. Ann Surg Oncol. 2013 Sep;20(9):3112-9. doi: 10.1245/s10434-013- — View Citation

Correa-Gallego C, Ferrone CR, Thayer SP, Wargo JA, Warshaw AL, Fernández-Del Castillo C. Incidental pancreatic cysts: do we really know what we are watching? Pancreatology. 2010;10(2-3):144-50. doi: 10.1159/000243733. Epub 2010 May 17. — View Citation

Cotton PB, Eisen GM, Aabakken L, Baron TH, Hutter MM, Jacobson BC, Mergener K, Nemcek A Jr, Petersen BT, Petrini JL, Pike IM, Rabeneck L, Romagnuolo J, Vargo JJ. A lexicon for endoscopic adverse events: report of an ASGE workshop. Gastrointest Endosc. 201 — View Citation

Crinò SF, Bernardoni L, Brozzi L, Barresi L, Malleo G, Salvia R, Frulloni L, Sina S, Parisi A, Remo A, Larghi A, Gabbrielli A, Manfrin E. Association between macroscopically visible tissue samples and diagnostic accuracy of EUS-guided through-the-needle m — View Citation

de Jong K, Poley JW, van Hooft JE, Visser M, Bruno MJ, Fockens P. Endoscopic ultrasound-guided fine-needle aspiration of pancreatic cystic lesions provides inadequate material for cytology and laboratory analysis: initial results from a prospective study. — View Citation

Gaddam S, Ge PS, Keach JW, Mullady D, Fukami N, Edmundowicz SA, Azar RR, Shah RJ, Murad FM, Kushnir VM, Watson RR, Ghassemi KF, Sedarat A, Komanduri S, Jaiyeola DM, Brauer BC, Yen RD, Amateau SK, Hosford L, Hollander T, Donahue TR, Schulick RD, Edil BH, M — View Citation

Hong SK, Loren DE, Rogart JN, Siddiqui AA, Sendecki JA, Bibbo M, Coben RM, Meckes DP, Kowalski TE. Targeted cyst wall puncture and aspiration during EUS-FNA increases the diagnostic yield of premalignant and malignant pancreatic cysts. Gastrointest Endosc — View Citation

Lee KS, Sekhar A, Rofsky NM, Pedrosa I. Prevalence of incidental pancreatic cysts in the adult population on MR imaging. Am J Gastroenterol. 2010 Sep;105(9):2079-84. doi: 10.1038/ajg.2010.122. Epub 2010 Mar 30. — View Citation

Mittal C, Obuch JC, Hammad H, Edmundowicz SA, Wani S, Shah RJ, Brauer BC, Attwell AR, Kaplan JB, Wagh MS. Technical feasibility, diagnostic yield, and safety of microforceps biopsies during EUS evaluation of pancreatic cystic lesions (with video). Gastroi — View Citation

Rogart JN, Loren DE, Singu BS, Kowalski TE. Cyst wall puncture and aspiration during EUS-guided fine needle aspiration may increase the diagnostic yield of mucinous cysts of the pancreas. J Clin Gastroenterol. 2011 Feb;45(2):164-9. doi: 10.1097/MCG.0b013e — View Citation

Scheiman JM, Hwang JH, Moayyedi P. American gastroenterological association technical review on the diagnosis and management of asymptomatic neoplastic pancreatic cysts. Gastroenterology. 2015 Apr;148(4):824-48.e22. doi: 10.1053/j.gastro.2015.01.014. Revi — View Citation

Stark A, Donahue TR, Reber HA, Hines OJ. Pancreatic Cyst Disease: A Review. JAMA. 2016 May 3;315(17):1882-93. doi: 10.1001/jama.2016.4690. Review. — View Citation

Tanaka M, Fernández-del Castillo C, Adsay V, Chari S, Falconi M, Jang JY, Kimura W, Levy P, Pitman MB, Schmidt CM, Shimizu M, Wolfgang CL, Yamaguchi K, Yamao K; International Association of Pancreatology. International consensus guidelines 2012 for the ma — View Citation

Yang D, Samarasena JB, Jamil LH, Chang KJ, Lee D, Ona MA, Lo SK, Gaddam S, Liu Q, Draganov PV. Endoscopic ultrasound-guided through-the-needle microforceps biopsy in the evaluation of pancreatic cystic lesions: a multicenter study. Endosc Int Open. 2018 D — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The increment in diagnostic yield	The diagnostic performance (accuracy) of the device will be compared to standard evaluation accuracy (cross-sectional imaging and EUS-FNA with cyst fluid analysis) and finally corroborated with surgery biopsy and 12 month follow up (gold standard).	1 year
Secondary	Percentage of technical success	It will be measured the cases in witch a successful puncture of the pancreatic cyst with the 19-gauge needle under EUS guidance, advance the microforceps into the cyst, and successful tissue acquisition was performed. It will be confirmed by gross visualization of the specimen from the jaws of the forceps.	1 year
Secondary	Percentage of clinical success	It will be measured the cases in witch a histopathological diagnosis of the PCL, by cytological or histological evaluation, using the microforceps biopsies was obtained.	1 year
Secondary	Percentage of adverse events	All adverse events will recorded according to American Society for Gastrointestinal Endoscopy guidelines.	1 year
Secondary	The inter-observer agreement	It will be evaluated if the increment in diagnostic yield can be generalized. All cases will be presented to all the endosonographers of Argentina, in the context of the annual EUS meeting and then by an online platform, where they will have to asses a diagnosis in three stages: 1st stage: patient's demographic data, clinical history and images (CT, MRI, ultrasound). 2nd stage: EUS features (EUS-B mode). 3rd stage: cyst fluid analysis CEA, glucose, amylase and cytology.	1 year