CAPSULE ENDOSCOPY

CE is an ingestible miniature camera that is capable of producing images throughout the small bowel to depict its entire mucosal lining. CE was introduced first in 2000. CE is used most commonly to evaluate the small bowel for a source of occult gastrointestinal bleed (OGIB).

Generally, CE is safe and widely used as a diagnostic test.¹⁵ The only contraindications to its use are patients having swallowing disorders or bowel obstruction, with the possibility of capsule retention. There is a 2% capsule retention rate in most series.¹⁶ Other limitations to CE are that it is time consuming; there is no biopsy potential, and no therapeutic capability.

A large meta-analysis completed by Triester et al.¹⁷ demonstrated the incremental yield of CE over enteroscopy and small bowel barium radiography to be 35% and 59%, respectively. Although not statistically significant, the rate of identifying lesions was higher with CE. This is not surprising given CE’s ability to evaluate more mucosal surface area than other modalities. Lewis et al. performed a meta-analysis of CE compared to small bowel barium swallow, EGD, colonoscopy, and small bowel enteroscopy. Detection rate for CE was 87% and missed lesion rate was 10%. The combination of the other 4 modalities yielded a 13% detection rate and missed lesion rate of 73%. Both large meta-analyses demonstrate the CE capability and superiority.¹⁸

There are several capsules in use around the world. For example, the Given M2A imaging CE (Given Imaging; Yokneam, Israel) is a pill-shaped capsule measuring 11 mm × 26 mm. Within the capsule, the contents consist of a light source, an imaging chip, a battery source, and a radio transmitter with an internal antenna. Its visual field is 140 degrees and is magnified 8 times. This capsule travels through most of the small bowel with peristalsis and is excreted in the feces. The camera is able to take two images every second and transmits image to an external recording device. The capsule has a battery life lasting between 6 and 8 hours. At the completion of the study there are 50,000 images. There is software available to help the interpreter evaluate for a suspected bleeding source. There is no consensus on preprocedural bowel preparation, but some advocate for bowel prep. Prokinetics may be beneficial because there is a 20% incomplete small bowel transit.¹⁹

SMALL BOWEL ENTEROSCOPY

The difficulty to evaluate the small bowel is based on its location and length. The scope needed to properly evaluate it is too long to have manual control of the tip. The bowel lies freely in the peritoneal cavity with essentially no fixation. Navigation with an endoscope has been traditionally difficult for this reason. Fixation points allow for proper evaluation of the foregut and colon in traditional endoscopy, but this is not the case for small bowel. DE utilizes a fixation point provided by the scope and the small bowel is brought to the viewing tip of the scope. Traditional endoscopy utilizes pushing the endoscope through the gastrointestinal tract which is impossible without external intraoperative manipulation of the bowel over the scope. Using this new method for evaluation has provided endoscopists with a steep learning curve and added length of time to complete the evaluation.

5 The disadvantages of CE are difficulty with orientation, inability to biopsy, possible obstruction, and capsule retention. Small bowel enteroscopy, DAE, or DE, are excellent alternative modalities.

DE allows the operator to obtain biopsies and to perform therapeutic interventions. There are three methods for DE available today.

Double-Ballon Enteroscopy

This technique was developed in 2001 by Hironi Yamamoto,²⁰ and introduced into Korea in 2004 where it found its way to the United States. This endoscope consists of a balloon at the tip of an endoscope that has a length of 140 cm. An overtube, also containing a balloon at the tip, fits over the scope to employ a push-and-pull technique.²¹ This allows for examination of 240 to 360 cm. While the overtube balloon is inflated, the scope is advanced with its balloon deflated. The inflated overtube balloon will allow for a fixation point for the scope to maneuver through the small bowel. Once a significant advancement has occurred, the endoscope balloon is inflated, and the overtube balloon deflated. The overtube then slides along the endoscope to the end of the scope. The overtube balloon is reinflated to provide another fixation point as the endoscope balloon is taken down and advanced once more. This outlines the push technique as the endoscope is advanced with the overtube balloon inflated. The pull technique is when both balloons are inflated and the endoscopist pulls back on both. This will reset the ability to start the push technique again. This progression continues until the entire small bowel is evaluated.

The two most common enteroscope systems used have scope diameters of 8.5 mm and 9.3 mm with working channels of 2.2 mm and 2.8 mm. The working channels allow for the therapeutic and diagnostic options provided by these systems.

Double-balloon enteroscopy (DBE) is the most studied method to date and shows a diagnostic yield of 60% to 80% in patients with occult GI bleeding and other small bowel pathologies.²² However, it may not be feasible in all patients and success rates vary from 16% to 86%.^20,23 This variation is due to differing patient populations across the world and the specific disease processes.

The main limitations to DBE are the invasive nature and prolonged duration of the procedure. The complication rate overall is reported as 0.8% but can be higher while performing therapeutic procedures such as electrocautery for a GI bleed, polypectomy, or dilation. The main complications are pancreatitis, ileus, and perforation.^24–26

Single-Balloon Enteroscopy

This system was developed in 2007 and is similar to DBE, but the distinguishing trait is that this system lacks the endoscope balloon. There is still a balloon on the overtube used over the scope. Substituting in the endoscope balloon’s place, the scope tip is hooked to hold the scope fixed to aid in the advancement of the overtube. Overall, the concept is the same as to fix a portion of the small bowel to allow for advancement of the endoscope.

The overtube is referred to as the splinting tube which has a hydrophilic coating that is activated with application of 30 mL of water. Radiopaque material is present at the tip to aid in the advancement with fluoroscopy.

Spiral Enteroscopy

Also in 2007, spiral enteroscopy (SE) was introduced which provides potential benefits with regard to shorter procedure time. A raised spiral on the exterior of the scope pulls the small bowel over the scope as it advances. This scope is 118 cm in length and has a diameter of 9.8 mm. The raised spiral grooves are 16 mm high. Clockwise rotation of the scope will advance the scope and counterclockwise rotation will withdraw the scope.

Studies for SE demonstrate shorter insertion depths with faster procedure times. There is variation in the insertion depth varying from 176 cm to 262 cm.^27,28 The complication rate is noted to be 0.3% with a perforation rate of 0.27%.²² Overall, the device is simple to use with a learning curve of 5 cases.^22,29

Exploratory Laparoscopy

The role of laparoscopy has improved the management of small bowel lesions over the last decades.^30,31 The advantages of DAE and imaging have been discussed at length, but the role for laparoscopic assessment of the peritoneal cavity for small bowel tumors plays a significant role in both diagnosis and treatment. Furthermore, the improvements in laparoscopy and surgeons abilities with a laparoscope have enabled minimally invasive management of small bowel tumors. Johnson et al.³² evaluated all small bowel obstructions in a single institution requiring surgery. Successful completion of a laparoscopic approach was possible in 32% of patients (conversion to an open procedure was necessary in 40% of patients, with 20% of the conversions secondary to tumor. Small bowel was resected in 8% of the laparoscopic cases, 64% of the converted cases, and 41% of the case done completely open. Length of stay of patients with a purely laparoscopic approach was 7.7 days versus 11 days in the converted cases and 11.4 in the purely open cases.

There are distinct advantages to laparoscopy when the ability of the surgeon allows this approach. Direct visualization of the small bowel on the extraluminal side adds significant value to the management of small bowel tumors. Complete evaluation of the small bowel can be obtained laparoscopically by examining the entire small bowel in a systematic approach in order to visualize all aspects of the small bowel including the mesentery. In conjunction with endoluminal approaches, like small bowel enteroscopy, lesions can be located, biopsied, and if needed, resected.

The laparoscopic approach is limited by the extent of the disease process being investigated. Local spread of small bowel tumors will likely affect directly adjacent small bowel or other nearby organs. This invasion can make it impractical to proceed laparoscopically if one is to provide the patient with the best outcome. Also, most common tumors of the small bowel affect the mucosal surface only and extraluminal visual examination may be inadequate to identify the lesion. Exceptions to this would be utilizing small bowel enteroscopy to tattoo the lesion which can be easily seen from the extraluminal side. This would also facilitate a sound oncologic resection of the tumor. Hand-assisted laparoscopy is also helpful if palpation is essential and a small incision is desired.

A laparoscopic case should be converted to an open technique if conditions prevent oncologically sound technique in order to provide the patient with the best outcome.

MANAGEMENT

Benign

Adenomas are benign lesions that have malignant potential. This tends to follow the malignant degeneration seen in polyps of the large bowel, described in 1990,³³ and most commonly seen with periampullary tumors.³⁴ Interestingly, the distribution of adenomas tends to follow the small bowel’s exposure to bile, making the most common location immediately distal to the papilla in the second portion of the duodenum and progressively decreases in the more distal intestine.³⁵

Hamartomas are benign vascular tumors with a low malignant potential and usually associated with Peutz–Jeghers syndrome.¹³ Lipomas are encountered as a single mass or as multiple and are usually encountered incidentally. Hemangiomas are rare benign tumors in the small bowel that present as GI bleeding.

The only reason for operative management of a benign small bowel lesion is to control symptoms. Mass effect causing intussusception or obstruction, hemorrhage, or a questioned presence of malignancy generates the need for local resection of the lesion. The diagnostic dilemma is the most common reason for resection of an incidentally found mass on contrast study or endoscopy. Hemangiomatous lesions can be resected or managed with angiographic embolization. The use of angiographic isolation and intraoperative angiographic methylene blue injection can be very helpful to guide resection of a bleeding field of small bowel angiomas.

Malignant

Discovery of small tumors is rare. Within the group of malignant tumors found in the small bowel, there are four main types. The most recent data from a single-institution tumor registry show that carcinoid tumors of the small bowel have surpassed the incidence for adenocarcinomas of the small bowel.¹ A total of 1,260 tumors were examined and their distribution throughout the small bowel was discussed. Carcinoid tumors (33%), adenocarcinomas (30%), lymphoma (16%), GIST (7%), and other cell types found (13%). The authors separated the different tumor types based on location within the small bowel, which changed the order of the most common tumors seen in each portion.

Neuroendocrine Tumors

NETs of the small bowel have increased in incidence significantly over the last 40 years, and mirror the overall increase in gastrointestinal NETs throughout the entire gastrointestinal tract. This is reflected in the recent SEER data ranking gastrointestinal NETs second, only behind colorectal cancer, as the most common cancer of the GI tract.³⁶ This has also been shown in Sweden³⁷ and in England.³ NETs arise from a diffuse neuroendocrine system made up of secretory cells, called enterochromaffin cells, causing the propensity for these tumors to produce vasoactive substances. NETs, formerly known as carcinoid tumors, can be almost benign or very aggressive. Carcinoid syndrome was characterized in 1954 by Thorson et al. who associated the presence of the metastatic carcinoid tumor with the presence of some abnormal symptoms.³⁸ They related the increased production of serotonin causing systemic effects such as diarrhea, flushing, bronchospasm, cutaneous vasomotor symptoms, and cardiovascular dysfunction. Serotonin was actually extracted 1 year earlier from carcinoid tumors and labeled as the active ingredient in the symptoms.^39,40 Serotonin is derived from its precursor tryptophan, and when in circulation, it elicits particular symptoms. The liver will inactivate serotonin to make 5-hydroxyindoleacetic acid (5-HIAA) which is excreted by the kidney.⁴¹

The presentation of NETs comes from two basic components of the tumor. First, the tumor sizes can elicit effects such as obstructive symptoms or abdominal pain. Second, the hormonal secretion of the tumors can lead to symptoms, such as carcinoid syndrome. About 50% of NETs present in the ileum¹ and the majority of those are in the distal 60 cm of the ileum.⁴¹ Most commonly these tumors metastasize to the liver, mesentery, and peritoneum.⁴² The intraluminal effects of these tumors usually leads to the obstructive symptoms and the desmoplastic reaction of the small bowel mesentery produces the abdominal pain associated with the tumor burden.

6 Metastasis of small bowel NETs is related to primary tumor size. A literature review of 185 patients with small bowel NET showed an 85% nodal metastasis and 47% distant metastasis with tumors greater than 2 cm. With tumors between 1 and 1.9 cm, 70% had nodal metastasis and 19% had distant metastasis. With tumors less than 1 cm, there was 12% nodal metastasis and 5% distant metastasis.⁴³ Even though small NETs can metastasize, the risk of metastases does correlate with size of the primary tumor. This is influenced by the early invasion of bowel wall lymphatics and blockage of the lymphatics in the mesentery, forcing cells to flow retrograde into lymphatics along the bowel.

The mitotic rate and Ki-67 index are measured in order to provide the histologic grade of these tumors, which correlates closely with clinical behavior. These measurements categorize the tumors into one of three categories by grade; low, intermediate, and high. The 5-year survival rates are 79%, 74%, and 40%, respectively. Low and intermediate grade typically fall into the well-differentiated category and high grade is considered poorly differentiated (Table 51-2). Resection to maximally debulk the tumor, or maximize cytoreduction, is the only chance for cure in NETs.

A formal TNM staging classification has recently been instituted. This stratifies tumors into localized, locally advanced, and metastatic categories with associated 5-year survivals of 95%, 84%, and 51%, respectively (Table 51-3). Shortly after, in 2007, the American Joint Committee on Cancer adopted a TNM staging system proposed by the European Neuroendocrine Tumor Society (ENETS) specifically for tumors of the lower jejunum and ileum. This factored out the poorer prognosis of the tumors in other parts of the body such as the colon, rectum, and appendix⁴⁴ (Tables 51-4 and 51-5). Five-year survival rates were much different showing 100% for stage I and stage II cancers, 91% for stage III cancers, and 72% for stage IV cancers. Survival rates were slightly improved with presentation of another 270 NETs by Jann et al.⁴⁵

7 Generally, diagnosis is made based on radiographic findings in conjunction with tumor markers. There are three common radiographic modalities used to diagnose these tumors, which include CT scan and MRI enterography and octreotide scanning.

Abdominal CT can help locate the primary tumor, but three-phase CT should be used for optimal evaluation of liver metastasis. The clinician should be mindful of the affinity of NETs to metastasize to the liver, especially in the setting of physical findings consistent with neuroendocrine peptide secretion. The arterial phase and the portal venous phase are typically the phases that maximize the ability to locate the metastatic lesions because NETs are typically rich in vascularity.⁴⁶ For the same reason, MRI can also be used to locate and evaluate metastatic lesions to the liver.

NETs often express somatostatin receptors rendering them detectable by imaging with radiolabeled forms of somatostatin called octreotide.⁴⁷ This was discovered during the refinement of the octreoscan, or SRS (somatostatin receptor scintigraphy). Five subtypes of somatostatin receptors have been identified and the somatostatin analogs from the octreotide scan bind with subtypes 2 and 5 which are present in 70% to 90% of NETs.⁴⁸ With the progression of diagnostic ability came the use of single-photon emission computed tomography (SPECT) to enhance the accuracy of differentiating areas of pathologic and physiologic uptake in the abdomen. This is a full-body scan that enables visualization of somatostatin uptake throughout the entire body.

Further use of radiolabeled markers has brought about advances in positron emission tomography with use of functional radiotracers for imaging. The advantages to this platform are the higher spatial resolution than the octreotide scanning. This also offers advantages for detecting smaller lesions than other scanning methods. Octreotide, MBIG, and PIET scanning are used for follow-up of patients and staging of patients for distant disease when planning aggressive, multiorgan resections.

Making the diagnosis of small bowel NET is often late in its course and the chances of metastatic lesions being present are high because of this. However, surgical management is still an option for patients in cases of localized tumor burden and distant metastasis. Survival outcomes are better for those patients with stage I and stage II diseases, as previously discussed, and surgical excision of the primary tumor and local node metastasis is still the only curative therapy for these patients.⁴⁹ The primary focus in any instance with the presence of NET is to control the functional disorder associated with the tumor present, such as carcinoid syndrome. Several options are applicable to the tumor itself once any functional disorder is controlled and treated. These include close surveillance of indolent tumors, radiofrequency ablation (RFA) therapy for liver metastases, systemic therapy with somatostatin analogs or interferon, or cytotoxic or molecular targeted therapies. These are all options that can be used and have never been compared in a controlled comparison, making these therapies highly individualized.

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