Gastrointestinal Endoscopy
Volume 67, Issue 2 , Pages 304-306, February 2008

Double-EMR–derived full-thickness biopsy and functional GI disorders

GI Blood Flow Research Laboratory, Sepulveda Ambulatory Care Center, Veterans Affairs Greater Los Angeles Healthcare System, UCLA, North Hills, California, USA

Article Outline

Abbreviations: CIIP, chronic idiopathic intestinal pseudo-obstruction, FAPS, functional abdominal pain syndrome, FVN, familial visceral neuropathy, IBS, irritable bowel syndrome

 

That such full-thickness biopsy can be obtained with the aid of endoscopic devices is certainly a ground-breaking event, and will likely have historical significance if ancillary steps are perfected to make the biopsy procedure safe and the pathologic evaluation of the samples diagnostic.

In this issue of Gastrointestinal Endoscopy, a novel preclinical study by Rajan et al1 using a porcine model is reported to evaluate different endoscopic approaches for obtaining deep gastric-muscle-wall biopsy specimens and to determine whether myenteric ganglia were present in the tissue samples.

The endoscopic techniques evaluated were as follows: (1) EUS-guided Tru-Cut biopsy of the gastric wall; (2) jumbo biopsy of the post-EMR site; (3) jumbo biopsy of the gastrotomy margin; (4) serosal-side biopsy through a gastrotomy; and (5) double EMR. Seventy-two tissue samples were hence obtained: EUS-guided Tru-Cut biopsy (n = 16), jumbo biopsy of post-EMR site (n = 16), jumbo biopsy of gastrotomy (n = 16), serosal-side biopsy (n = 16), and double EMR (n = 8). Only the double-EMR tissues showed the presence of longitudinal muscle, indicating the presence of both muscle layers and the myenteric plexus (hematoxylin and eosin–stained sections). Immunoflourescence studies using PGP9.5 antibody demonstrated the presence of myenteric ganglia only in the double-EMR tissues and in none of the other gastric samples. No adjacent organs were included in the resection. The authors concluded that the double-EMR technique was the only studied technique that resulted in a deep gastric-wall sample and provided sufficient tissue to evaluate both muscle layers and the intermuscular layer containing myenteric ganglia. They suggested that further studies are needed to verify the efficacy and assess the safety of this approach.

This is an original and well-done technical study. Although the clinical relevance and applications are not clear at this time, Rajan et al point out the need to perform deep gastric-wall biopsy to the level of the myenteric ganglia to assess their role in functional dyspepsia. They postulate that a major barrier to advancing our understanding of the pathophysiology of neuromuscular GI diseases (eg, functional GI disorders) is the inability to obtain deep gastric-wall biopsy specimens that include both layers of the muscularis propria, allowing evaluation of specific cell types, including myenteric ganglia. Traditionally, a full-thickness biopsy can only be performed at autopsy or with the aid of laparotomy or laparoscopy. That such full-thickness biopsy specimens can be obtained with the aid of endoscopic devices is certainly a ground-breaking event, and will likely have historical significance if ancillary steps are perfected to make the biopsy procedure safe and the pathologic evaluation of the samples diagnostic.

What are some examples of functional GI disorders that require full-thickness biopsy to diagnose? These would include idiopathic megacolon, familial visceral neuropathy with neuronal intranuclear inclusions, and chronic idiopathic intestinal pseudo-obstruction (CIIP). Whether the full-thickness biopsy technique will play a role in the diagnosis of the common condition of irritable bowel syndrome (IBS) or the less common condition of functional abdominal pain syndrome (FAPS) is less certain at this time.

Idiopathic megacolon2 is characterized by total atrophy of the collagenous tendinous connective tissue membrane of the myenteric plexus and the tendinous collagen fiber net of the muscularis propria. Familial visceral neuropathy with neuronal intranuclear inclusions3 is an autosomal dominant condition with a variable phenotype that includes achalasia, gastroesophageal reflux, intestinal dysmotility and pseudo-obstruction, dysarthria, peripheral neuropathy and pupillary defects, and the presence of intranuclear inclusions within the neurons of the enteric nervous system. The method of full-thickness biopsy by double EMR can provide tissue for the diagnosis of both conditions.

CIIP4 is a rare disease characterized by symptoms and signs resembling mechanical obstruction in the absence of organic, systemic, or metabolic disorders, and it carries potentially life-threatening complications. The natural history of the disease in adults is not fully known. One study evaluated the clinical course of 59 consecutive patients with CIIP. These patients did not have underlying collagen vascular diseases or mitochondrial cytopathies. Full-thickness biopsy specimens were obtained in 11 cases and processed for immunohistochemical analysis of myogenic and neurogenic components of the gut wall. Patients were prospectively followed up for a median of 4.6 years (range, 1-13 years). Diagnosis was often made several years after symptom onset (median, 8 years). Thus, many patients (88%) underwent useless and potentially dangerous surgeries (mean, 2.96 per patient). Manometry showed abnormal motor patterns. Pathologic findings included neuropathies in all investigated cases, and abnormalities of interstitial cells of Cajal in 5 of 11 cases. Long-term outcome was generally poor despite surgical and medical therapies; 4 patients died of disease-related complications, 4 underwent small-bowel transplantation, almost one third required long-term home parenteral nutrition, and two thirds had some sort of nutritional limitations. The method of full-thickness biopsy by double EMR may provide a less invasive method than laparotomy or laparoscopy for an early diagnosis.

FAPS5 is less common than the other functional bowel disorders. Symptoms largely are unrelated to food intake and defecation, and it has higher comorbidity with psychiatric disorders. The etiology and pathophysiology are incompletely understood. FAPS likely represents a heterogeneous group of disorders; therefore, peripheral neuropathic pain mechanisms, alterations in endogenous pain modulation systems, or both may be involved in any one patient. The diagnosis of FAPS is made on the basis of positive symptom criteria and a longstanding history of symptoms; in the absence of alarm symptoms, an extensive diagnostic evaluation is not required. Management is based on a therapeutic physician-patient relationship and empirical treatment algorithms by using centrally acting drugs, including antidepressants and anticonvulsants. The choice, dose, and combination of drugs are influenced by psychiatric comorbidities. Psychological treatment options include psychotherapy, relaxation techniques, and hypnosis. Patients with refractory FAPS may benefit from a multidisciplinary pain-clinic approach. Whether the double-EMR full-thickness biopsy technique will impact on the diagnosis and management of these patients remains unknown.

Two articles provide justification for considering full-thickness biopsy in the common functional GI disorder of IBS. In the first article,6 10 patients (2 men, 8 women) with IBS were studied. In 9 patients, low-grade infiltration of lymphocytes in the myenteric plexus was found (proximal jejunal full-thickness biopsy specimens obtained at laparoscopy). Lymphocytes had periganglionic and intraganglionic locations. The mean number of lymphocytes per ganglion ranged from 1.9 to 7.1 per patient, with an overall mean of 3.4. No intraganglionic lymphocytes and only a few periganglionic lymphocytes (mean, 0.2) were found in the control group. Four patients had concomitant intraepithelial lymphocytosis. Neuron degeneration was evident in 6 of 9 patients with ganglionic lymphocyte infiltration and in 1 patient without. The findings indicate that inflammation and neuronal degeneration in the myenteric plexus may be involved in the pathogenesis of IBS. In the second study,7 increased stool pellet passage in animals subjected to water avoidance stress (a model of IBS) was accompanied by Fos expression in colonic myenteric ganglia. The observation potentially implicates involvement of the myenteric plexus in IBS. Whether the full-thickness biopsy by the double-EMR technique will be applicable in patients with IBS remains to be demonstrated.

The investigators of the double-EMR method1 pointed out that a major limitation of this novel technique is the creation of a large cautery-type perforation immediately after tissue resection. They suggested that the perforation must be sealed in a timely manner by using reliable methods of tissue apposition, including hemoclips supplemented with an omental patch, prototype tissue anchors, or suture. The risk of peritonitis remains from soiling of the peritoneal cavity by the seepage of gastric fluid and contents from a well-circumscribed hole in the gastric wall (gastrotomy). The investigators1 indicated that the ideal procedure to reduce this risk has yet to be identified. To minimize the risk of serious complications (mostly bleeding and perforation) of conventional EMR, a recent review on the subject stated that only experienced endoscopists should undertake EMR in an appropriate environment.8 The same admonition applies to the double-EMR method for full-thickness biopsy.

In addition to the techniques mentioned by Rajan et al1 to manage the biopsy-induced gastric perforation, interested investigators may want to consider evaluating a variation of the band-ligation method9, 10 for closure of the perforation. After the first cap-assisted EMR has been completed to expose the underlying muscle layer, the cap is replaced by an endoscopic band ligator. A rubber band is applied before removal of the second cap-assisted EMR performed on the exposed muscle layer. Such an approach may seal the perforation even before its creation. Additional application of hemoclips may further minimize the risk of seepage of gastric content.

The investigators of the double-EMR technique1 concluded that once full-thickness tissue of sufficient size can be safely obtained, future efforts will be directed at introducing the technique into clinical practice. Should the assessment of the full-thickness biopsy specimens obtained by double EMR reveal fewer abnormalities than expected in the components enumerated by the investigators (inflammatory cells, enteric neurons, interstitial cells of Cajal, and/or smooth muscle cells), which are based on the old paradigm of neuromuscular inflammation and postinfection changes1 in the common condition of functional dyspepsia, what other pathologic features should be looked for in these specimens? Investigators with interest in various pathophysiologic mechanisms will offer suggestions when the full-thickness biopsy specimen can be obtained safely. One example is described here to illustrate the opportunity to test paradigm-changing hypotheses. Reports have described dyspepsia as the initial symptom of splanchnic vascular insufficiency,11 and reduction in blood flow to the gut as the cause of biphasic motility changes (initial increase in motility followed by inhibition of motor activity)12; therefore, the full-thickness biopsy specimens obtained from study patients with functional dyspepsia should be evaluated for abnormalities of the vascular components (from serosal arteries and veins to mucosal capillaries). If abnormalities are demonstrated, the data will support the possibility that functional dyspepsia, dysmotility, and altered gut perfusion may be linked. The new paradigm would consider functional dyspepsia or dysmotility as a spectrum of conditions with varying degrees of “gut ischemia—the associated symptoms and dysfunctions being proportional to the degree of “impaired gut perfusion.”

In conclusion, the double-EMR technique, by providing novel tissue specimens for pathologic assessment, may indeed stimulate interest in the evaluation of a variety of new hypotheses related to common functional GI disorders. Until a definite diagnostic connection between unique pathologic findings and specific subgroups of patients and development of effective therapeutic interventions based on the biopsy results are established, it is prudent to conduct the double-EMR full-thickness biopsy in well-defined clinical research settings.

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Acknowledgments 

Supported in part by Veterans Affairs Medical Research Funds and ASGE Endoscopic Career Development Award (FWL 1985).

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Disclosure 

The author reports that there are no disclosures relevant to this publication.

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References 

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PII: S0016-5107(07)02594-1

doi:10.1016/j.gie.2007.08.031

Gastrointestinal Endoscopy
Volume 67, Issue 2 , Pages 304-306, February 2008

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