Ignite Creation Date:
2024-05-06 @ 12:30 AM
Last Modification Date:
2024-10-26 @ 10:50 AM
Study NCT ID:
NCT01583699
Status:
COMPLETED
Last Update Posted:
2015-07-21
First Post:
2012-01-08
Brief Title:
Endomicroscopy and Gastric MALT-lymphoma
Sponsor:
Medical University of Vienna
Organization:
Medical University of Vienna
Study Overview
Official Title:
Confocal Laser Endomicroscopy as Diagnostic Tool for Gastrointestinal MALT-lymphoma
Status:
COMPLETED
Status Verified Date:
2015-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Extranodal marginal zone B-cell lymphoma MZBL of the mucosa associated lymphoid tissue MALT-lymphoma represents a distinct clinical entity and is the most common form of extranodal lymphoma with a predilection for the stomach About 90 of gastric MALT-lymphomas are associated with infection with Helicobacter pylori HP and eradication of the pathogen leads to regression of the tumor in a high percentage of patients at early tumour stages Nevertheless following complete remission after HP-eradication the risk of relapse justifies lifelong follow-up examinations Supported by recent findings at the investigators department endoscopic controls should include a close examination of the small bowel as relapses can involve different gastrointestinal sites To continue the investigators diagnostic approach as well as to further improve the detection rate of MALT-lymphoma relapses the investigators plan to introduce the novel confocal laser endomicroscope CLE into the diagnostic management of MALT-lymphoma patients In the context of a prospective clinical pilot trial the investigators aim to establish MALT-lymphoma specific CLE-markers that can be used for the in vivo diagnosis of the disease Comparing endomicroscopic findings drawn from the stomach and small bowel of 50 MALT-lymphoma patients who will undergo staging or follow up endoscopies at the investigators department to the histological evaluation of biopsy samples as present gold standard the investigators want to determine whether CLE can provide reliable data for the accurate detection of MALT-lymphoma associated changes Endomicroscopic aspects of patients with chronic gastritis gastric adenocarcinoma and healthy subjects should serve as controls In comparison to random biopsies which represent the current standard the investigators aim to prove whether endomicroscopy will find MALT-lymphoma lesions more accurately and thus help to spare patients unnecessary biopsies
Detailed Description:
Introduction
Extranodal marginal zone B-cell lymphoma MZBL of the mucosa associated lymphoid tissue MALT-lymphoma is the most common form of extranodal lymphoma 1 2 Although MALT-lymphoma may involve different organs the stomach represents the site of predilection of this malignant disease About 90 of gastric MALT-lymphomas are associated with infection with Helicobacter pylori HP 3 and eradication of the pathogen leads to tumor regression in a high percentage of patients at early tumor stages 4 5 Relapses after HP-eradication and primary advanced tumor stages require chemotherapeutic treatment radiation therapy and in some cases surgery 6 Following complete remission lifelong follow-up examinations should be performed in order to detect relapses 7
Histologically MALT-lymphoma is characterized by an infiltration of the lamina propria by lymphomatous centrocyte-like cells that spread into the surrounding mucosal layers 8 In immunohistochemistry they show CD 20 positive staining properties When they spread to lymph nodes or spleen they accumulate typically within the marginal zone for this reason they are classified as marginal zone lymphoma 2 Dissemination to other organs especially to other mucosal sites may occur frequently wherefore detailed diagnostics are required during MALT-lymphoma staging and follow-up Spreading within the gastrointestinal tract GI-tract to the small bowel for example is rare but can be assessed very easily with standard endoscopic procedures as recently reported at our department 9
For gastric MALT-lymphoma gastroscopy with biopsy assessment is the current follow-up examination of choice Multiple biopsies should be taken randomly from all gastric sites and specifically from all suspicious lesions Recent developments for the enhancement of the tissue contrast during the endoscopic examinations chromoendoscopy or Narrow Band Imaging for example helped to detect MALT-lymphoma lesions Nevertheless detection rates hardly changed since all these techniques rely on the presence of superficial features10
An endoscopic technique that allows an evaluation of deeper wall layers is endoscopic ultrasonography During the last years it has become an important amending tool in the diagnostic management of gastric MALT-lymphoma Although it provides essential information about tumor infiltration depth and lymph node involvement in the context of staging procedures it cannot replace histological assessment during follow-up since endosonographic findings do not show a good correlation to histological results over time 11 12
The newest development that has been introduced in the endoscopic management of the gastrointestinal tract is the so called confocal laser endomicroscope CLE Confocal microscopy was developed by Marvin Minsky in the late 1950s Its principle is the microscopic scanning of focal points below the surface of an object In comparison to conventional light microscopy it uses a special filter system to avoid image overlapping by surrounding tissue In detail a light source normally a laser is focused by a microscope objective lens to a diffraction limited spot on or inside the object Light that is scattered or fluorescence excited achieved through fluorescein staining for example and emitted at the focus in the sample will partially return back through the optics along the path from which it arrived A beam-splitter placed into the path reflects the return light towards a detector The optics will focus the light from the focal point in the specimen to its conjugate focus near the detector hence the technology is termed con-focal Here a spatial filter pinhole is used to extinguish all light deriving from areas outside the focal point Light reflections from the focal point itself will be forwarded to the detector which is connected to a computer system that digitalises the optical signal and creates the in vivo histological image 13
Focusing on its clinical impact confocal microscopy is the first technique to allow in vivo evaluation of tissue structures beneath their surface Because of many breakthroughs in miniaturisation mostly in the 1990s this technology could be applied for intraluminal use in gastroenterology integrated into an otherwise standard endoscope It allows the in vivo histological visualisation of the upper 250 micrometers of all walls within the gastrointestinal tract additionally to the normal function of white light endoscopy provided by two separate screens on top of the workstation 13
The in vivo visualisation of different GI-pathologies led to the first publications on the clinical use of CLE Kiesslich et al as one of the pioneers of the technique published a case on live imaging of Helicobacter pylori by CLE in the stomach 14 At our department we recently reported the endomicroscopic findings of a patient with Whipples disease Detecting foamy macrophages within the lamina propria which were clearly distinguishable from goblet cells in the surrounding CLE could provide in vivo histology at the single cell level 15
Assessing GI-pathologies more systematically there have been many publications dealing with the use of CLE in the context of follow-up examinations of conditions that predispose to the development of malignancies For Barretts oesophagus for example Kiesslich et al found high sensitivity and specificity rates for the detection of Barretts metaplasia as well as for the prediction of Barretts associated neoplastic changes - for both results CLE derived pictures were compared to conventional histology 16 In a first prospective randomized double-blind controlled crossover trial Dunbar et al proved these findings as CLE-targeted biopsies had a higher diagnostic yield for Barretts oesophagus associated neoplasia than standard endoscopy with 4-quadrant random biopsy 17 Similar results have already been published for patients with ulcerative colitis that were routinely screened for colon cancer It could be shown that CLE is a useful tool to improve the diagnostic yield At the same time it helped to take conventional biopsies more accurately which can spare patients unnecessary biopsies 18
Combining the potential of CLE to improve the diagnostic yield during surveillance with its properties of scanning the upper 250µm of the GI-wall which equates nearly the whole depth of the mucosa makes it the ideal tool for the diagnostic management of gastric MALT-lymphoma where pathologies typically arise from the lamina propria a deeper layer of the mucosa 8
Study Aims
In this clinical pilot study the investigators aim to examine patients with gastric MALT-lymphoma by confocal laser endomicroscopy CLE in the context of staging or follow-up endoscopies To our knowledge no systematic study on the use of CLE in MALT-lymphoma patients has yet been performed
The investigators aim to determine whether the diagnosis of MALT-lymphoma can be achieved by evaluating endomicroscopic features of suspicious lesions of both the stomach and the small bowel as these GI-parts are easily accessible by upper endoscopy Conventional biopsies from the GI-parts observed should serve as comparable gold standard
Including endomicroscopic results of patients with chronic gastritis gastric adenocarcinoma and healthy subjects as controls the investigators aim to establish MALT-lymphoma specific markers that can be used for a biopsy-free in vivo diagnosis of the disease
Study Design
Prospective clinical trial without randomisation or blinding
Study Population
Patients referred to our department for upper endoscopy in the context of staging or follow-up of gastric MALT-lymphoma
Exclusion criteria
patients allergic to one of the drug components including drugs used for conscious sedation like propofol or midazolam as well as fluorescein the fluorescent dye used for CLE
refusal to participate in the study
patients age below 18 years
Methods
This investigation will be performed at the Division of Gastroenterology and Hepatology Department of Internal Medicine III in close cooperation with the Division of Oncology Department of Internal Medicine I and the Clinical Institute of Pathology at the Medical University of Vienna
As this study has been planned as a pilot trial it mainly focuses on the qualitative endomicroscopic features drawn from our examinations to yield reference pathologies for accurate diagnosis in the future Nevertheless a quantitative analysis will be performed by comparing CLE-derived diagnoses with histological results to calculate sensitivity and specificity of CLE based MALT-lymphoma diagnosis Based on current incidence and relapse rates of the disease the investigators estimated to include 50 patients in order to get a meaningful patient sample for qualitative and quantitative analysis Given the current number of MALT-lymphoma patients who undergo staging or follow-up endoscopies at the investigational site this patient sample can be included within a period of two years
All patients who fulfill the listed inclusion criteria will receive the patient information form of this study together with the usual informed consent form of the respective endoscopic examination they are about to undergo Patient information will be done at least 24 hours before the intervention as practised at our unit If the patient agrees to participate in the study he will be prepared for endoscopy with our confocal laser endomicroscope Pentax EC3870K with the ISC-1000 confocal endomicroscopy processor - Pentax Tokyo Japan and Optiscan Pty Ltd Notting Hill Victoria Australia by administration of intravenous propofol andor midazolam as routinely used for conscious sedation during endoscopic procedures at our department Additionally 5-10 ml of a 10 solution of fluorescein sodium will be administered intravenously to enhance tissue fluorescence during endomicroscopy
All drugs will be administered by medical specialists assistant doctors or registered nurses as routinely practiced at our institution
CLE picture capturing will start at the deepest point reachable in the small bowel During withdrawal of the scope CLE pictures will be taken every 10 centimetres in the small bowel then from the antrum and body of the stomach and from the esophagus Furthermore CLE will be applied for distinct looking areas suspicious of pathologic origin Wherever CLE pictures are obtained a conventional biopsy will be taken from the same localisation
CLE pictures will be captured and stored routinely using our standard data management system They will be evaluated immediately during the endoscopic procedure together with a board certified GI-pathologist who will establish an initial diagnosis
Conventional biopsies will be processed and evaluated according to the criteria as outlined in the recent WHO-classification for MALT-lymphoma In all patients immunologic phenotyping on paraffin sections will be done for demonstration of light chain restriction and for the phenotype CD20CD5-CD10-cyclinD1- which in context with the microscopic appearance is consistent with MALT-lymphoma In addition all patients will be assessed for MALT-lymphoma specific translocations especially t1118q21q21
Endomicroscopic controls patients with chronic gastritis gastric adenocarcinoma and healthy subjects will be collected from present data of endomicroscopic procedures already performed within routine examinations
At the end of the study all CLE pictures and histological cuts will be evaluated separately by two blinded board certified pathologists In case of discordant diagnoses they will analyse the respective cases together to reach an agreement on the final diagnosis All cases where the initial and the final diagnosis are deviating from each other will be re-evaluated together by all specialists involved
Ethical implications
Confocal laser endomicroscopy is a safe new technique that has already been studied in clinical trials 16 17 Its safety is being guaranteed by the use of low intensity laser light that can at worst cause local bleaching of fluorescein containing cells which is harmless reversible and even used as diagnostic sign in experimental conditions 13
This study protocol had been already approved by the ethics commission of the Medical University of Vienna All procedures in the context of this study will be performed in accordance to the Declaration of Helsinki as well as to the guidelines for Good Scientific Practice GSP of the Medical University of Vienna
Expected impact and Outlook
If the investigators find MALT-lymphoma specific markers that can be used for a biopsy-free in vivo diagnosis this could lead to another reduction of invasive procedures for the affected patients which may have an important clinical impact as biopsy assessment is often limited by the rather bad coagulation status of oncologic patients
In case the study aims will be supported by the results of this pilot trial a randomized controlled trial comparing in vivo diagnosis to conventional histological assessment in matters of diagnostic yield will be performed
Extranodal marginal zone B-cell lymphoma MZBL of the mucosa associated lymphoid tissue MALT-lymphoma is the most common form of extranodal lymphoma 1 2 Although MALT-lymphoma may involve different organs the stomach represents the site of predilection of this malignant disease About 90 of gastric MALT-lymphomas are associated with infection with Helicobacter pylori HP 3 and eradication of the pathogen leads to tumor regression in a high percentage of patients at early tumor stages 4 5 Relapses after HP-eradication and primary advanced tumor stages require chemotherapeutic treatment radiation therapy and in some cases surgery 6 Following complete remission lifelong follow-up examinations should be performed in order to detect relapses 7
Histologically MALT-lymphoma is characterized by an infiltration of the lamina propria by lymphomatous centrocyte-like cells that spread into the surrounding mucosal layers 8 In immunohistochemistry they show CD 20 positive staining properties When they spread to lymph nodes or spleen they accumulate typically within the marginal zone for this reason they are classified as marginal zone lymphoma 2 Dissemination to other organs especially to other mucosal sites may occur frequently wherefore detailed diagnostics are required during MALT-lymphoma staging and follow-up Spreading within the gastrointestinal tract GI-tract to the small bowel for example is rare but can be assessed very easily with standard endoscopic procedures as recently reported at our department 9
For gastric MALT-lymphoma gastroscopy with biopsy assessment is the current follow-up examination of choice Multiple biopsies should be taken randomly from all gastric sites and specifically from all suspicious lesions Recent developments for the enhancement of the tissue contrast during the endoscopic examinations chromoendoscopy or Narrow Band Imaging for example helped to detect MALT-lymphoma lesions Nevertheless detection rates hardly changed since all these techniques rely on the presence of superficial features10
An endoscopic technique that allows an evaluation of deeper wall layers is endoscopic ultrasonography During the last years it has become an important amending tool in the diagnostic management of gastric MALT-lymphoma Although it provides essential information about tumor infiltration depth and lymph node involvement in the context of staging procedures it cannot replace histological assessment during follow-up since endosonographic findings do not show a good correlation to histological results over time 11 12
The newest development that has been introduced in the endoscopic management of the gastrointestinal tract is the so called confocal laser endomicroscope CLE Confocal microscopy was developed by Marvin Minsky in the late 1950s Its principle is the microscopic scanning of focal points below the surface of an object In comparison to conventional light microscopy it uses a special filter system to avoid image overlapping by surrounding tissue In detail a light source normally a laser is focused by a microscope objective lens to a diffraction limited spot on or inside the object Light that is scattered or fluorescence excited achieved through fluorescein staining for example and emitted at the focus in the sample will partially return back through the optics along the path from which it arrived A beam-splitter placed into the path reflects the return light towards a detector The optics will focus the light from the focal point in the specimen to its conjugate focus near the detector hence the technology is termed con-focal Here a spatial filter pinhole is used to extinguish all light deriving from areas outside the focal point Light reflections from the focal point itself will be forwarded to the detector which is connected to a computer system that digitalises the optical signal and creates the in vivo histological image 13
Focusing on its clinical impact confocal microscopy is the first technique to allow in vivo evaluation of tissue structures beneath their surface Because of many breakthroughs in miniaturisation mostly in the 1990s this technology could be applied for intraluminal use in gastroenterology integrated into an otherwise standard endoscope It allows the in vivo histological visualisation of the upper 250 micrometers of all walls within the gastrointestinal tract additionally to the normal function of white light endoscopy provided by two separate screens on top of the workstation 13
The in vivo visualisation of different GI-pathologies led to the first publications on the clinical use of CLE Kiesslich et al as one of the pioneers of the technique published a case on live imaging of Helicobacter pylori by CLE in the stomach 14 At our department we recently reported the endomicroscopic findings of a patient with Whipples disease Detecting foamy macrophages within the lamina propria which were clearly distinguishable from goblet cells in the surrounding CLE could provide in vivo histology at the single cell level 15
Assessing GI-pathologies more systematically there have been many publications dealing with the use of CLE in the context of follow-up examinations of conditions that predispose to the development of malignancies For Barretts oesophagus for example Kiesslich et al found high sensitivity and specificity rates for the detection of Barretts metaplasia as well as for the prediction of Barretts associated neoplastic changes - for both results CLE derived pictures were compared to conventional histology 16 In a first prospective randomized double-blind controlled crossover trial Dunbar et al proved these findings as CLE-targeted biopsies had a higher diagnostic yield for Barretts oesophagus associated neoplasia than standard endoscopy with 4-quadrant random biopsy 17 Similar results have already been published for patients with ulcerative colitis that were routinely screened for colon cancer It could be shown that CLE is a useful tool to improve the diagnostic yield At the same time it helped to take conventional biopsies more accurately which can spare patients unnecessary biopsies 18
Combining the potential of CLE to improve the diagnostic yield during surveillance with its properties of scanning the upper 250µm of the GI-wall which equates nearly the whole depth of the mucosa makes it the ideal tool for the diagnostic management of gastric MALT-lymphoma where pathologies typically arise from the lamina propria a deeper layer of the mucosa 8
Study Aims
In this clinical pilot study the investigators aim to examine patients with gastric MALT-lymphoma by confocal laser endomicroscopy CLE in the context of staging or follow-up endoscopies To our knowledge no systematic study on the use of CLE in MALT-lymphoma patients has yet been performed
The investigators aim to determine whether the diagnosis of MALT-lymphoma can be achieved by evaluating endomicroscopic features of suspicious lesions of both the stomach and the small bowel as these GI-parts are easily accessible by upper endoscopy Conventional biopsies from the GI-parts observed should serve as comparable gold standard
Including endomicroscopic results of patients with chronic gastritis gastric adenocarcinoma and healthy subjects as controls the investigators aim to establish MALT-lymphoma specific markers that can be used for a biopsy-free in vivo diagnosis of the disease
Study Design
Prospective clinical trial without randomisation or blinding
Study Population
Patients referred to our department for upper endoscopy in the context of staging or follow-up of gastric MALT-lymphoma
Exclusion criteria
patients allergic to one of the drug components including drugs used for conscious sedation like propofol or midazolam as well as fluorescein the fluorescent dye used for CLE
refusal to participate in the study
patients age below 18 years
Methods
This investigation will be performed at the Division of Gastroenterology and Hepatology Department of Internal Medicine III in close cooperation with the Division of Oncology Department of Internal Medicine I and the Clinical Institute of Pathology at the Medical University of Vienna
As this study has been planned as a pilot trial it mainly focuses on the qualitative endomicroscopic features drawn from our examinations to yield reference pathologies for accurate diagnosis in the future Nevertheless a quantitative analysis will be performed by comparing CLE-derived diagnoses with histological results to calculate sensitivity and specificity of CLE based MALT-lymphoma diagnosis Based on current incidence and relapse rates of the disease the investigators estimated to include 50 patients in order to get a meaningful patient sample for qualitative and quantitative analysis Given the current number of MALT-lymphoma patients who undergo staging or follow-up endoscopies at the investigational site this patient sample can be included within a period of two years
All patients who fulfill the listed inclusion criteria will receive the patient information form of this study together with the usual informed consent form of the respective endoscopic examination they are about to undergo Patient information will be done at least 24 hours before the intervention as practised at our unit If the patient agrees to participate in the study he will be prepared for endoscopy with our confocal laser endomicroscope Pentax EC3870K with the ISC-1000 confocal endomicroscopy processor - Pentax Tokyo Japan and Optiscan Pty Ltd Notting Hill Victoria Australia by administration of intravenous propofol andor midazolam as routinely used for conscious sedation during endoscopic procedures at our department Additionally 5-10 ml of a 10 solution of fluorescein sodium will be administered intravenously to enhance tissue fluorescence during endomicroscopy
All drugs will be administered by medical specialists assistant doctors or registered nurses as routinely practiced at our institution
CLE picture capturing will start at the deepest point reachable in the small bowel During withdrawal of the scope CLE pictures will be taken every 10 centimetres in the small bowel then from the antrum and body of the stomach and from the esophagus Furthermore CLE will be applied for distinct looking areas suspicious of pathologic origin Wherever CLE pictures are obtained a conventional biopsy will be taken from the same localisation
CLE pictures will be captured and stored routinely using our standard data management system They will be evaluated immediately during the endoscopic procedure together with a board certified GI-pathologist who will establish an initial diagnosis
Conventional biopsies will be processed and evaluated according to the criteria as outlined in the recent WHO-classification for MALT-lymphoma In all patients immunologic phenotyping on paraffin sections will be done for demonstration of light chain restriction and for the phenotype CD20CD5-CD10-cyclinD1- which in context with the microscopic appearance is consistent with MALT-lymphoma In addition all patients will be assessed for MALT-lymphoma specific translocations especially t1118q21q21
Endomicroscopic controls patients with chronic gastritis gastric adenocarcinoma and healthy subjects will be collected from present data of endomicroscopic procedures already performed within routine examinations
At the end of the study all CLE pictures and histological cuts will be evaluated separately by two blinded board certified pathologists In case of discordant diagnoses they will analyse the respective cases together to reach an agreement on the final diagnosis All cases where the initial and the final diagnosis are deviating from each other will be re-evaluated together by all specialists involved
Ethical implications
Confocal laser endomicroscopy is a safe new technique that has already been studied in clinical trials 16 17 Its safety is being guaranteed by the use of low intensity laser light that can at worst cause local bleaching of fluorescein containing cells which is harmless reversible and even used as diagnostic sign in experimental conditions 13
This study protocol had been already approved by the ethics commission of the Medical University of Vienna All procedures in the context of this study will be performed in accordance to the Declaration of Helsinki as well as to the guidelines for Good Scientific Practice GSP of the Medical University of Vienna
Expected impact and Outlook
If the investigators find MALT-lymphoma specific markers that can be used for a biopsy-free in vivo diagnosis this could lead to another reduction of invasive procedures for the affected patients which may have an important clinical impact as biopsy assessment is often limited by the rather bad coagulation status of oncologic patients
In case the study aims will be supported by the results of this pilot trial a randomized controlled trial comparing in vivo diagnosis to conventional histological assessment in matters of diagnostic yield will be performed
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None