Helicobacter pylori

Since the bacterium Helicobacter pylori was first reported in 1983, a wealth of evidence has been gathered concerning its role in the etiology of gastric cancer.^26–28 In 1994, the IARC classified H. pylori as carcinogenic to humans. Evidence supporting an etiologic association between H. pylori and gastric cancer can be found in ecologic studies, case-control studies, and prospective cohort studies.^27,29–31 Meta-analyses of prospective studies suggest that the risk of gastric cancer is increased twofold to threefold in individuals with chronic H. pylori infection.^32,33 One prospective, nested case-control study found a significant association between prior H. pylori infection and gastric adenocarcinoma overall, but there was no association with cancer of the cardia.³⁴ Individuals without H. pylori colonization seem to have a minimal risk of gastric carcinoma.³⁵

H. pylori contributes to the causation of gastric cancer via mechanisms that involve the development and progression of chronic gastritis.³⁶ Infection causes chronic gastritis in almost all infected individuals and accounts for almost all cases of chronic gastritis.³⁷ H. pylori–induced gastritis may progress over time from superficial nonatrophic gastritis to more severe forms, including severe atrophic gastritis with intestinal metaplasia.

Chronic gastritis is present in most cases of gastric cancer and is associated with an increased cancer risk.³⁶ The risk of developing gastric cancer increases with the severity of gastritis, with reported risks greater than 10-fold for severe atrophic antral gastritis.^36,38 Intestinal-type gastric cancer seems to be more strongly associated with severe atrophic gastritis, whereas the diffuse type is more common in nonatrophic gastritis.³⁶

There is strong evidence for a role for virulence factors in H. pylori carcinogenesis. The Cag A virulence factor is strongly associated with the risk of adenocarcinoma. The absence of Cag A carries, at most, a low risk of developing diffuse-type adenocarcinoma.³⁹

Peptic Ulcer Disease

H. pylori infection is a common risk factor for gastric ulcer, duodenal ulcer, and gastric cancer. An association between peptic ulcer disease and gastric cancer would be expected. However, studies have found duodenal ulceration to be inversely associated with gastric cancer risk.⁴⁰

One possible explanation for this apparent paradox was suggested by Parsonnet,⁴¹ who argued that H. pylori infection can progress to gastric cancer or duodenal ulcer but seldom to both. Other factors, such as the genetic characteristics of the individual and the organism, may play a significant role in determining which disease would occur. The age at which infection was acquired may also influence the outcome. It has been suggested that infection early in life predisposes to atrophic gastritis and cancer but reduces duodenal ulcer risk owing to decreased acid production associated with the gastritis. If infection is acquired later in life, atrophic gastritis is less likely, and gastric cancer risk is decreased.⁴¹ More recent evidence supports a moderate association between gastric ulcer and noncardia gastric cancer.^42,43

Dietary Factors

Several observational studies have shown a protective association with fresh fruits and vegetables, independent of other dietary factors. The association has been less impressive in limited cohort studies.⁴⁴ Possible protective nutrients include vitamin E, carotenoids, selenium, and vitamin C.⁴⁴ The evidence is stronger for vitamin C. In a case-control study, a high intake of vitamin C decreased the risk of gastric cancer by half compared with low vitamin C intake.⁴⁵ However, a large 5-year intervention trial in China involving adults did not show any change in the risk of gastric cancer in individuals receiving supplemental vitamin C.⁴⁶

High salt consumption has been fairly consistently associated with an increased risk of gastric cancer in ecologic and case-control studies.^47–49 However, good quantitative data linking salt consumption with gastric cancer are still lacking.

N-nitroso compounds have been shown to be carcinogenic in animal studies.⁵⁰ In the human stomach, these compounds may be formed from dietary nitrite or nitrate, leading to the hypothesis that a diet high in nitrite or nitrate predisposes to gastric cancer. Case-control studies examining dietary intake of nitrate and the risk of gastric cancer have consistently found a negative association. Because the major sources of nitrate and nitrite are vegetables and preserved meats, nitrate intake was probably an index of vegetable intake, and the negative association is not surprising.⁴⁴ Case-control studies have reported a weak, statistically insignificant increased risk of gastric cancer (relative risk 1.12 to 1.28) for high versus low nitrite intake.^51–54 It is difficult to isolate the effect of nitrate consumption in gastric cancer because of the fact that diets high in nitrite may also be high in antioxidants that are frequently found in vegetables and in fruits.⁵⁴

It has been postulated that virulent strains of H. pylori release reactive oxygen metabolites that could destroy neighboring glandular cells leading to gastric glandular atrophy, hastened by other factors such as high salt intake but retarded by antioxidants such as vitamin C.⁵⁵ The invention of refrigeration, the availability of fresh food, and the accompanying decreased consumption of preserved foods may have contributed to a decline in gastric cancer incidence in the second half of the 20th century.

Socioeconomic Status

Worldwide, a low socioeconomic status has been consistently shown to be associated with an increased risk of gastric cancer.¹⁶ The higher prevalence of gastric cancer among individuals with lower socioeconomic status is matched by a similar high prevalence of H. pylori infection in these individuals.^56,57 An increased incidence of cancer of the cardia has been observed predominantly in individuals with higher socioeconomic status.¹⁴

Gastric Surgery

An increased risk of gastric cancer after gastric surgery has been reported, particularly after 15 or more years.^58,59 The association is strongest for gastrectomy performed for gastric ulcer but less persuasive for either vagotomy or gastrectomy performed for duodenal ulcer. This association does not extend to cancer of the gastric cardia.⁴⁰

Gastric Polyps

Single hyperplastic polyps are often found in the background of chronic gastritis, and they are mainly seen in the body of the stomach. At most, 0.3% of hyperplastic gastric polyps may contain a focus of adenocarcinoma. However, approximately 3% of multiple hyperplastic polyps are associated with a synchronous carcinoma elsewhere in the stomach.⁶⁰ The presence of multiple hyperplastic polyps is considered a precancerous condition.

Fundic gland polyps do not have malignant potential when they occur sporadically or in association with proton pump inhibitor therapy. Hundreds of fundic gland polyps may be present in association with polyposis coli. Dysplasia has been reported in a few of these patients.⁶¹ Gastric adenocarcinoma associated with fundic gland polyposis in familial polyposis coli has been reported.⁶²

Adenomatous polyps occur in the setting of intestinal metaplasia and associated chronic gastritis. Endoscopic features that increase the risk of malignant transformation include large size and a red, erosive surface color. A carcinoma may be contained in 40% of pyloric gland adenomas and generally 10% of tubular adenomas.^60,63 Approximately 11% of patients with adenomatous polyps have a synchronous or metachronous gastric adenocarcinoma.⁶³

Genetic Factors

Genetic predisposition may play a role in the development of gastric cancer, with a twofold to fourfold increased risk in first-degree relatives. Similarly, patients who have hereditary lesions, such as Lynch syndrome II, have an increased risk of gastric cancer.^64,65

Miscellaneous Factors

A higher risk for gastric cancer has been reported in patients with Ménétrier’s disease, ataxia telangiectasia, and blood type group A.^66–68 Pernicious anemia and its association with autoimmune chronic gastritis increases the risk of developing gastric cancer by twofold to threefold, according to population-based studies.^69,70 Regular endoscopic surveillance in young patients with pernicious anemia has been advocated.⁷¹

Smoking may increase the incidence of premalignant gastric lesions and dysplasia; however a dose-response relationship has not been clearly shown.^72–74 No clear relationship between alcohol consumption and gastric cancer has been shown.^29,72,74

Molecular Abnormalities

Abnormalities at the molecular level have been described in patients who develop gastric cancer. These include allelic deletions of the atrial premature complex (APC) gene, the migrating motor complex (MCC) gene, and the tumor-suppressor gene TP53. Allelic deletions of TP53 can be found in 64% of gastric cancers. These deletions are common late events in gastric cancer.⁷⁵ In addition, mutations of the APC gene and loss of heterozygosity on chromosomes 1q, 5q, and 17p have been reported in gastric carcinoma.⁷⁶

Loss of E-cadherin–dependent cell-cell adhesion secondary to mutation of beta-catenin has been found in gastric cancer.⁷⁷ Reduced expression of E-cadherin has been found to be significantly associated with recurrence of cancer and decreased survival.⁷⁸ Microsatellite instability has also been found in gastric carcinoma.⁷⁹ Higher expression of Sialyl-Tn has been associated with a poor prognosis in patients with gastric cancer.⁸⁰ Patients with overexpression of c-erbB protein have been found to have a poorer prognosis than patients without c-erbB expression in poorly differentiated gastric adenocarcinoma.⁸¹ Germline truncating mutations in the E-cadherin gene (CDH1) have been found in several families with hereditary diffuse gastric cancer.^82,83

Early Gastric Cancer

Observational studies have shown that approximately 70% of patients with EGC have symptoms of dyspepsia but no anemia, dysphagia, or weight loss. It is uncommon to find gastric cancer at an early stage (<20% of diagnosed cases) in countries with a relatively low risk for the disease. In countries with high risk such as Japan, endoscopic screening has been practiced since the 1960s, and as a result, the incidence of EGC is 40% to 50%. In the absence of suggestive symptoms, detecting EGC requires a high index of suspicion and a low threshold for endoscopic examination, especially in patients belonging to relatively high-risk groups.

Advanced Gastric Cancer

Most patients with gastric adenocarcinoma present with advanced disease. Accompanying symptoms, such as weight loss, vomiting, anorexia, early satiety, abdominal pain, and anemia, may mimic peptic ulcer disease and other GI conditions. Typically, patients have been symptomatic for less than 12 months, and 40% of patients have been symptomatic for less than 3 months. Signs and symptoms are due to cancer invasion beyond the muscularis propria by direct extension or by distant metastasis. Liver and lungs are the most common sites of gastric cancer metastases (40%); bone and peritoneum are less frequent sites (10%). Occasionally, patients may present with a paraneoplastic syndrome, such as Trousseau’s syndrome (thrombosis), acanthosis nigricans (pigmented skin lesion, classically of the axilla), or dermatomyositis.^84,85

Intestinal Type

Grossly, intestinal adenocarcinoma is a well-demarcated neoplastic tumor that tends to be nodular, polypoid, or ulcerated. Histologically, intestinal adenocarcinoma is characterized by a well-formed glandular pattern, which may contain solid or papillary areas. The malignant cells are columnar or cuboidal, with a basally located nucleus.

Diffuse Type

Grossly, diffuse adenocarcinoma is more likely to have a plaquelike surface and ill-defined infiltrating growth. Histologically, the infiltrating growth is composed of individual cells or cords of cells, and a fibrous or mucoid stroma is present between the cells or cords of cells. Many cells of diffuse carcinoma contain mucin droplets that sometimes produce a signet-ring appearance. Most cases of linitis plastica are classified as diffuse carcinomas. Most diffuse carcinomas are poorly differentiated.

Histologic Typing

The histologic classification should be based on the predominant pattern of tumor.⁹⁰

Indications and Contraindications

The main indications for treatment can be classified according to the goal of the therapeutic intervention:

Preoperative History and Considerations

Appropriate patient selection and accurate diagnosis and staging are essential to ensure good outcomes from endoscopic therapy. Unnecessary risks should be avoided. Is the lesion amendable to surgical or endoscopic removal? Should endoscopic therapy be performed at the same time as the staging procedure or deferred to a subsequent intervention? Referral to a tertiary care center with extensive experience in cancer resection and therapeutic endoscopy should be considered. Overnight observation may be appropriate for patients undergoing high-risk endoscopic procedures and for patients who have significant comorbidities.

Gastroscopy

During gastroscopy, the stomach should be well distended to allow full inspection of the entire gastric lining. The intestinal type of gastric cancer is found mostly in the antropyloric region and along the lesser curvature. Biopsy specimens should be obtained of areas with discoloration (erythema or pallor), ulceration, nodularity, or protrusion or depression. A high index of suspicion is very important for the diagnosis of EGC.

A morphologic staging classification based on the macroscopic endoscopic appearance of EGC has been described by Japanese investigators, as follows⁹⁶:

Types I, IIa, and IIc are considered to be endoscopically resectable. Certain adjuncts to morphologic staging also help to predict that a lesion is amendable to minimally invasive (endoscopic) therapy and is likely to have the same outcome as surgery: lesions less than 1 cm in size, absence of a scar or ulcer histologically and endoscopically (0.2% lymph metastasis), and a well-differentiated histology (<1% lymph metastasis).^1,92

Narrow Band Imaging and Magnification Endoscopy

Diagnosis of gastric neoplasia using magnification endoscopy has been attempted in the past decades.⁹⁷ However, compared with the colonic surface, standardized systemic classification of the magnified gastric surface has not been established owing to diverse histology of gastric carcinomas; the existence of three different types of proper gastric mucosa; and various changes on mucosal structures by atrophy, chronic inflammation, metaplasia, and erosions. The narrow band imaging system provides very clear images of fine superficial structure and microvasculature of the gastric mucosa and has improved the endoscopic diagnosis of superficial gastric cancers. Nakayoshi and coworkers^98,99 reported that significant correlation between histopathology and microvascular pattern obtained with narrow band imaging magnification enables the sensitive diagnosis of superficial depressed gastric cancer, and the modality can assist in determining feasibility of EMR of gastric cancer.

Nakayoshi and coworkers⁹⁸ measured the correlation between the magnified images obtained with narrow band imaging and the histologic findings, especially with regard to the microvascular pattern; 165 cases of superficial depressed gastric carcinoma (109 well-differentiated adenocarcinomas and 56 poorly differentiated adenocarcinomas) were evaluated. Microvascular patterns on the mucosal surface were classified into two patterns: fine network pattern and corkscrew pattern. The fine network pattern appears as a mesh, and abundant microvessels are well connected with one another. In contrast, the corkscrew pattern has isolated and tortuous microvessels and looks like a corkscrew. A fine network pattern was recognized in 72 cases (66.1%) of 109 well-differentiated adenocarcinomas (intestinal type). The corkscrew pattern was observed in 48 cases (85.7%) of 56 poorly differentiated adenocarcinomas (diffuse type). For the magnifying endoscopic diagnosis of superficial depressed gastric carcinoma, both the existence of irregular microvessels and the disappearance of fine superficial structure are essential.

Endoscopic Ultrasound and Endoscopic Ultrasound–Guided Fine Needle Aspiration Cytology

EUS is now established as the best local staging modality for esophageal, gastric, and rectal cancer with a T stage accuracy of about 90%.^100,101 Kelly and associates⁹¹ reported that T staging by EUS was more accurate for gastric cancer than for esophageal cancer, although there was no difference for nodal staging. EUS has been shown to be the most accurate imaging modality for staging EGC,^101,102 with an accuracy of greater than 90% for assessing the depth of tumor invasion.^103,104

Early-generation conventional echoendoscopes had limited image resolution for the gastric wall because of relatively low transducer frequencies of 7.5 to 12 MHz. Newer echoendoscopes provide a wider range of frequencies from 5 to 20 MHz. Higher frequencies allow more detailed assessment of superficial lesions.

Long-term disease-free survival in GI malignancies is a function of lymphatic and distant tumor spread. The linear-array echoendoscope has enabled the endoscopist to place a needle precisely under real-time EUS guidance and obtain tissue samples both from the primary tumor and from transluminal lesions such as lymph nodes and liver metastasis. Other imaging modalities, such as CT scan, are still necessary to exclude more distant metastases. The overall performance of EUS with fine needle aspiration (FNA) cytology for benign versus malignant lymph node involvement has been found to have a sensitivity of 92% (range 84% to 97%), specificity of 93% (range 75% to 100%), and accuracy of 92% (range 82% to 98%).¹⁰⁵ Disadvantages of dedicated echoendoscopes include inability to traverse critical stenoses and technical difficulty of evaluating superficial lesions in some areas of the stomach such as the cardia.

High-Frequency Ultrasound Probes

High-frequency ultrasound (HFUS) probes provide a higher range of frequencies (12 to 30 MHz), allowing the gut wall to be visualized in finer detail. These miniature probes can be passed through the operating channel of any standard gastroscope. Acoustic contact is ensured by filling a transparent plastic bag with water around the probe. At high frequencies, a nine-layer wall can be identified, with the muscularis mucosa as the fourth layer. We prefer a double-channel therapeutic gastroscope for catheter probe examination because of its larger working channel; the second channel can be used to immerse the gastric lesion in water for better acoustic contact and for introducing a second device when using the “cut and lift” endoscopic resection technique. It is sometimes technically easier to position a miniature probe at a small target lesion in the gastric fundus that could not be easily accessed with a conventional echoendoscope. However, HFUS probes do not have the depth of penetration to visualize regional lymph nodes or metastases for TNM (primary tumor, regional nodes, metastases) staging.

The miniature probe can also be used to evaluate a lesion after saline injection, to confirm complete separation of the lesion from the underlying muscularis propria layer of the gastric wall before EMR.¹⁰⁶ Inability to separate the lesion from the muscularis propria after saline injection is a predictor of unresectability and obviates the need for additional imaging to determine endoscopic resectability.

High-Frequency Ultrasound Staging of Early Gastric Cancer

A classification system for EGC has been developed based on depth of tumor penetration into the mucosa (m) and submucosa (sm), as defined by using HFUS probes. The superficial cancers are divided further into the upper, middle, and lower third of the layer involvement as m1, m2, m3, sm1, sm2, and sm3.¹⁰³

An overall T staging accuracy of about 80% has been reported using HFUS in patients with EGC.^103,107,108 T staging accuracy is greater for Tm1 (92.1%) than for Tsm1 (62.8%) or T2 muscularis propria (42.9%).¹⁰⁹ The curative effect of EMR is excellent for intramucosal cancers (m1, m2, and probably m3) but not for submucosal cancers (sm1 to sm3).¹⁴ The ability to distinguish between m3 and sm1 lesions is crucial. Using a 20-MHz frequency probe, Yanai and colleagues¹¹⁰ were able to distinguish EGC involving the mucosa from EGC involving the submucosa with an accuracy of 72.3%.

The usefulness of HFUS was evaluated in 33 patients referred for endoscopic management of superficial or submucosal neoplastic lesions.¹¹¹ The depth of invasion was accurately predicted by HFUS before EMR in 25 of 26 patients (96%). Of the nine gastric lesions removed, eight had HFUS before EMR. There was 100% agreement between the depth of invasion determined by HFUS and pathologic staging. Almost half of the resected lesions were gastroduodenal, including gastric adenocarcinoma, gastric and duodenal adenoma, gastric and duodenal carcinoid, pancreatic rest, fibrovascular submucosal polyp, ampullary adenoma, and duodenal lipoma. The diagnostic accuracy of HFUS probes for small gastric lesions (<4 cm) has been found by some researchers to be comparable to dedicated (standard) echoendoscopes.¹¹²

Endoscopic Mucosal Resection

EMR involves the lifting of a lesion from the deep muscle layer of the gut wall, either by injection or by suction of the lesion into a cap fitted to the tip of the endoscope, followed by snare removal of the lesion (Fig. 33.5). Complete removal of the lesion en bloc during a single therapeutic procedure is ideal, although large lesions may require piecemeal resection. The availability of the resected specimen for pathologic examination is a distinct advantage of EMR over ablation therapies. Because EUS and HFUS cannot reliably distinguish between tumor infiltration and inflammation that may be associated with a malignant lesion, EMR provides both curative benefit and final staging confirmation.

Fig. 33.5 En bloc endoscopic mucosal resection (EMR). A, Lesion involving the mucosal layer. B, Marking of incision around the lesion with a needle-knife from the distal to proximal edge. C, Submucosal injection of sodium hyaluronate below the lesion and around the lesion from the distal to proximal edge. D, Incision of marked area around the lesion with a needle-knife from the distal to proximal edge of lesion. E, Snare excision of entire lesion. F, Retrieval of lesion with Roth net.

The following EMR techniques have been described^113–115:

Inject and Cut Technique

In the inject and cut technique, the lesion is lifted from the underlying muscularis propria by injecting a solution submucosally to produce a bleb beneath the lesion. The lesion is captured and resected by using an electrosurgical snare (Fig. 33.6). The required volume of submucosal injection varies according to the size of the lesion, provided that the bleb is sufficient to ensure a good lift of the entire lesion so that it can be safely captured and resected.

Fig. 33.6 Inject and cut. A, Lesion involving the mucosal layer. B, Submucosal injection at the distal edge of the lesion. C, Submucosal injection at the proximal edge of the lesion. D, Snaring of raised lesion. E, Tightening of snare and excision of raised lesion.

One technical caveat is to perform the initial injection at the periphery and distal margins of the lesion (farthest away from the tip of the endoscope), followed by injection at the lateral margins and at the periphery of the lesion closest to the endoscope. This injection sequence minimizes the problem of obscuring the endoscopic view of the distal margins of the lesion yet to be injected. The submucosal bleb provides a pseudostalk for the snare and a protective cushion beneath the lesion, decreasing tissue resistance and minimizing electrocautery injury to the deeper wall layers.

Various solutions are available for injection. A hypertonic saline and epinephrine solution is widely used in the hopes of decreasing the risk of bleeding¹¹⁶; other solutions have been used to obtain a more durable lift of the lesion.¹¹⁷ The use of hypertonic solutions except for glycerol has been questioned more recently because of concern about possible tissue damage. A study by Fujishiro and associates¹¹⁸ concluded that a combination of hyaluronate and glycerol is the most favorable submucosal injection solution, taking into consideration tissue damage and lesion-lifting ability. Also, various snares and currents (e.g., blended, ERBE, Tübingen, Germany) are preferred by different endoscopists. To date, no randomized trials have been conducted to compare the safety and effectiveness of different types of snares and injectants.

The advantage of the inject and cut technique is its simplicity and the fact that it does not require additional equipment. A disadvantage is that most solutions used to lift the lesion dissipate very rapidly making it difficult sometimes to capture the lesion safely with the snare.

Inject, Lift, and Cut Technique (Strip Biopsy)

With the inject, lift, and cut technique, the submucosal injection is performed in the standard manner, as already described. A snare and grasping forceps are passed through the operating channels of a dual-channel endoscope. First, the grasping forceps is captured by the open snare, and the snare is closed over the forceps. Working as a unit, the forceps is used to grasp the lesion, the snare is opened, and the lesion is pulled through the open snare. The snare is closed over the lesion, and resection of the lesion is performed (Fig. 33.7).^119–121 This technique is more cumbersome than the inject and cut technique and requires a dual-channel endoscope and two assistants to perform EMR.

Fig. 33.7 Strip biopsy. A, Lesion involving the mucosal layer. B, Submucosal injection at the distal edge of the lesion with double-channel endoscope. C, Submucosal injection at the proximal edge of the lesion. D, Grasping forceps pulling the lesion into the open snare. E, Tightening of snare and excision of lesion. F, Mucosal defect created after removal of lesion.

Endoscopic Mucosal Resection with Ligation

In the EMR with ligation technique, the lesion is removed with or without previous submucosal injection (Fig. 33.8).^122–124 More recently, a conventional band ligation device (MBL; Wilson-Cook Medical, Inc, Winston-Salem, NC) was modified by widening the threading channel of the cranking device from 2 to 3.2 mm.¹²⁵ This device allows for the insertion of a 7-Fr catheter through the threading channel of the cranking device into the 3.7-mm working channel of the endoscope. Band ligation can be performed with the polypectomy snare still within the working channel without any increased friction during winding of the thread; this enables sequential banding and snare resection of esophageal mucosa without the need to change the endoscope.¹²⁵

Fig. 33.8 Endoscopic mucosal resection (EMR) with ligation. A, Lesion involving the mucosal layer. B, Submucosal injection at the distal edge of the lesion. C, Submucosal injection at the proximal edge of the lesion. D, Suction of lesion into the hood and ligation with rubber band. E, Snaring and excision of the lesion below the rubber band. F, Mucosal defect created after removal of lesion.

An advantage of this technique is that it requires only conventional devices and instruments. A disadvantage is suboptimal visualization of the margins of the lesion when the variceal ligation device is loaded. No serious procedure-related complications have been reported.

Cap-Assisted Endoscopic Mucosal Resection

In cap-assisted EMR, a specially designed transparent plastic cap is used.^126,127 The plastic cap is fitted over the tip of the endoscope; various cap sizes are available. Submucosal injection of the lesion is performed in the standard manner. A crescent-shaped snare is prelooped into the groove of the rim of the specialized cap by gently suctioning normal mucosa into the cap and opening the snare to allow it to rest along the inside groove of the rim of the cap (SD-221L-25 or SD-7P-1; Olympus America, Inc). After prelooping the snare, the suction is turned off to release the normal mucosa. The cap is now used to suction the lesion while maintaining a constant medium to high vacuum. When the lesion is trapped completely inside the cap, the snare is closed over the lesion. After the lesion is tightly strangulated by the snare, the suction is turned off, and the lesion with the snare around it is allowed to leave the cap. Resection of the lesion is then performed with application of current. Gentle suction of the specimen into the cap allows safe and complete recovery of the specimen (Fig. 33.9). This technique is particularly useful for upper GI lesions.^127–129 Matsuzaki and colleagues¹²⁸ reported the use of a soft 18-mm diameter cap for en bloc resection of larger gastric lesions up to 1.4 times the size that can be removed with a standard cap.

Fig. 33.9 Endoscopic mucosal resection (EMR) cap. A, Lesion involving the mucosal layer. B, Submucosal injection at the distal edge of the lesion. C, Submucosal injection at the proximal edge of the lesion. D, Preloaded snare in the groove of EMR cap. E, Suction of ion into EMR cap and capture of the pseudostalk by the snare. F, Release of suction with continuous tight grasp of the lesion by the snare. G, Suction of lesion into EMR cap for retrieval after snare excision.

For larger lesions greater than 3 cm, some endoscopists have used a more viscous material, sodium hyaluronate, for submucosal injection. A small-caliber tip transparent hood that accommodates a needle-knife or an insulated thermal knife with a ceramic cap is used to cut around the lesion on its entire circumference. The final step is the complete removal of the lesion using a large snare.^130,131

Endoscopic Submucosal Dissection

The concept and technique of ESD are markedly different from conventional EMR. The procedure begins by making circumferential markings all around the lesion at about a 5-mm distance, at 2-mm intervals. Injection of sodium hyaluronate or another solution to create a long-lasting submucosal fluid cushion between the lesion and the muscle layer is performed to prevent perforation during ESD (Fig. 33.10).¹¹⁷

Fig. 33.10 Endoscopic submucosal dissection (ESD). A, Markings with knife or argon plasma coagulation (APC) probe around the edge of the lesions. B, Submucosal injection around the edge of the lesions. C, Incision hole with a needle-knife or hook knife. D, Margin cutting with insulated-tip (IT) knife at the incision hole. E, Circumferential margin cutting. F, Submucosal dissection with IT knife beneath the muscularis mucosa.

Sodium hyaluronate is harmless to the injected tissue because of its isotonicity, but it needs to be diluted when used for ESD because of its high viscosity. Among different mixtures tested, a mixture of high-molecular-weight sodium hyaluronate with a sugar solution, with or without glycerin, seems to be the most cost-effective.¹³² Adding indigo carmine dye (0.004%) to the mixture is optional. To minimize resistance to injection, a high-flow injection needle with a large inner lumen should be used. The solution is first injected just outside the marking spots, where a circumferential incision to isolate the lesion to be resected from the normal mucosa is made using the electrosurgical knives selected for the procedure. For the insulated-tip (IT) knife, a small initial incision is made with a standard needle-knife to allow for its insertion into the submucosal layer. Several electrosurgical knives have been developed for ESD.

Needle-Knife

First used by Hirao and colleagues¹¹⁶ in 1988, the needle-knife (KD-10Q-1; Olympus) has a fine tip and a small contact area, which allows a sharp incision. The cutting power required for mucosal incision (150 W) is so high that perforation is likely to occur unless the operator is highly skilled.

Insulated-Tip Knife

The IT knife (KD-610L; Olympus; Fig. 33.11A) is a needle-knife that is equipped with a ceramic ball at the top of the incising needle. The tip is blunted and insulated to prevent perforation; the knife was developed by Hosokawa and Yoshida¹³³ for safe performance of ESD. The IT knife is most frequently used for ESD of the stomach; special care should be taken when operating in the colon. The second-generation IT knife (ITKnife2; KD-611L; Olympus; Fig. 33.11B) has an additional electrode at the back of its insulating tip that makes cutting easier, especially in the lateral direction.

Fig. 33.11 Endo-knives used for endoscopic submucosal dissection (ESD). A, Insulated-tip (IT) knife. B, Second-generation IT knife. C, Hook knife. D, Flex knife. E, Triangle-tip knife. F, ESD knife, insulated sapphire ball tip. G, Hybrid knife.

Hook Knife

The hook knife (KD-620LR; Olympus; Fig. 33.11C) is a needle-knife with 1 mm of the tip bent to form a right angle. Submucosal tissue can be hooked and pulled before incision, which improves safety. Safety can be enhanced further by the concomitant use of a transparent hood. This knife has a rotating function so that operators can select any direction for hooking. Because of its high maneuverability, the hook knife is a useful endo-knife for esophageal ESD.¹³⁴

Flex Knife

The flex knife (KD-630L; Olympus; Fig. 33.11D) has a rounded tip with a twisted wire similar to a snare, with a length that can be adjusted according to circumstances. The outer sheath of the knife is soft and flexible with a thick tip that functions as a stopper. Because of all these characteristics, perforation is less likely to occur with this needle, which can be used independently on the location of the lesion.¹³⁵ A transparent hood for better visualization of the operating field is usually used.

Triangle-Tip Knife

The triangle-tip knife (KD-640L; Olympus; Fig. 33.11E) has a triangle-shaped conductive tip at the distal end, facilitating cutting of the mucosa. This knife can be used for any step in the ESD procedure: marking, precutting, incision, and dissection.

ESD Knife

The ESD knife (MTW, Fig. 33.11F) is a needle-knife that is equipped with a sapphire ball tip at the top of the incisioning needle. When the circumferential incision has been completed, additional solution is injected in the center of the lesion to lift up the mucosa adequately. Small lesions can be resected with an electrosurgical snare in the same way as with the standard polypectomy technique.¹³⁶ Larger lesions require a more complex procedure, however, in which the submucosa is directly dissected using the electrosurgical knife until exfoliation of the entire tumor en bloc is obtained.¹³¹

Hybrid Knife

The hybrid knife (ERBE; Fig. 33.11G) is a stainless steel tube that incorporates a microcapillary lumen with a diameter of 150 mm to provide a water jet function.¹³⁷ The flexible instrument has an outer diameter of 2.0 mm and a length of 2.2 mm and can be used with any standard endoscope. This flexible device allows injection, hydrodissection with preselected pressure (maximal water pressure 80 bar, adjustable from 0 to 80 bar), or dissection with any electrical current after usage of the saline-only solution without having to exchange the catheter. This novel device is the latest entry of clinically available ESP knives.

Endoscopic Mucosal Resection and Endoscopic Submucosal Dissection for Early Gastric Cancer

Endoscopic resection is now considered a curative procedure for EGC and has increasingly replaced surgical resection for this indication in Japan, although the technique is not universally accepted as a first-line treatment in the West. Endoscopic resection has also been used as a histologic staging technique to assess the depth of penetration in EGC to help determine the best definitive treatment.

Correct diagnosis of the depth of invasion and the absence of lymph node metastasis are crucial for achieving a cure with endoscopic therapy. The important endoscopic points to consider are the following:

1 The extension of the surface and the morphology of the lesion determine the procedure. EMR is not recommended for lesions greater than 2 cm in size. ESD is recommended for lesions without ulcer or scar up to 3 cm in size and lesions with ulcer or scar less than 2 cm in size.

2 The depth of invasion should be no deeper than the mucosa and sm1. This needs to be determined by EUS before endoscopic resection and should be corroborated by pathologic examination of the resected specimen.

3 High-grade dysplasia is the earliest stage of malignancy. A high degree of differentiation favors endoscopic treatment. Even though poorly differentiated lesions have a higher risk of distant spread, lesions less than 5 mm in size could be treated endoscopically.

4 Multifocal EGC can be treated endoscopically provided that the entire morphology is compatible with an intramucosal cancer.¹³⁸

5 The degree of difficulty in performing endoscopic resection depends on the location in the stomach. Lesions in the posterior wall and lesser curvature technically are more difficult to remove.

6 The success or failure of curative endoscopic resection is assessed by clear lateral and vertical margins seen on pathology and by endoscopy and biopsy obtained during follow-up.

7 Assessment of the results is based on the rates of complete removal or destruction, rates of en bloc resection, rates of recurrence, and survival.

The Japanese Research Society for Gastric Cancer has developed the following criteria for lesions that are suitable for endoscopic resection: (1) well differentiated, type I or IIa, limited to the mucosa, without histologic ulceration and less than 2 cm; (2) well differentiated, type IIc, limited to mucosa without ulceration and less than 1 cm. When these criteria are followed, the risk of lymph node involvement is only 1.7%. The use of morphologic staging is subjective, however, and its generalization has not been evaluated.

A retrospective evaluation of 210 cases of EGC treated with EMR and followed up for 14 years reported a 5-year survival of 86% and a 10-year survival of 56%; there were no cancer-related deaths.¹¹⁹ EMR as a curative treatment has been evaluated in 102 patients.¹⁰⁸ No distant or local metastases were seen during 9 years of follow-up.

A total of 106 patients with EGC up to 2 cm in diameter were treated with complete resection of the lesion in a single procedure, either by en bloc resection for lesions less than 10 mm (64%), or by piecemeal resection for larger lesions (36%).¹³⁹ No recurrence after either technique was found in patients with tumor-negative margins. The overall recurrence rate of cancer in this particular study was 2.8%. Tumors that recurred all were greater than 15 mm initially and treated with piecemeal resection. Because histologic reconstruction to confirm complete resection by piecemeal method is often difficult, patients should be followed very closely after piecemeal resection.

In a retrospective study, Amano and coworkers¹⁴⁰ evaluated endoscopic therapy in patients with EGC that does not meet the Japanese Research Society for Gastric Cancer morphologic criteria for lesions suitable for EMR. Endoscopic therapy consisted of EMR, thermal therapy, or both. The study included poorly differentiated and well-differentiated tumors 1 to 3 cm. Some patients with submucosal invasion limited to the most superficial layer (sm1) were included. Curative resection was achieved in 95%. The rate of cure in this group was statistically similar to the cure rate of cases that fulfilled the standard morphologic criteria for EMR resection (98%).¹⁴⁰

Adequacy of EMR can be assessed by measuring the distance from the edge of the resected specimen to the margin of the cancer. In a prior study, no patient with a distance of more than 2 mm developed recurrence of the cancer, whereas 16% of patients with a distance of less than 2 mm developed recurrence.¹⁴¹ Presence of cancer at the edge of the specimen was associated with a recurrence of 45.8%. No recurrence was observed if the distance from the edge of the specimen to the cancer was more than 7 mm, suggesting that adequate distance (preferably at least 2 mm) between the edge of the specimen and the cancer needs to be achieved to ensure a complete resection.¹⁴² Margin-negative resections are more likely (81.2%) in cancers that are less than 1 cm in diameter than in cancers that are more than 2 cm in diameter.¹⁴²

In a prospective analysis of 479 EGCs treated with EMR over an 11-year period at Tokyo National Cancer Center,¹³⁰ the following selection criteria were used: well-differentiated or moderately well-differentiated gastric cancer; morphologic types I, IIa, and IIc; no histologic evidence of ulceration; diameter of less than 3 cm with histologic confirmation of intramucosal carcinoma; no lymphovascular invasion; and clean margins. EMR was used to treat 405 patients, and complete resection was achieved in 69%. The recurrence rate was only 2%, and all recurrences were treated successfully with a modified combination therapy of EMR and laser. There was no subsequent recurrence in any of the 278 patients after a median follow-up period of 38 months (range 3 to 120 months). No cancer-related deaths were reported. More recently, EMR and ESD have become established alternatives to surgical therapy for EGC in Japan and Korea.^143–145

The current criteria for endoscopic therapy are (1) elevated-type intramucosal cancer (0 to IIa) less than 20 mm; (2) depressed-type mucosal cancer without ulceration (0 to IIb, 0 to IIc) less than 10 mm; and (3) well-differentiated or moderately well-differentiated intestinal-type ADC. Depressed cancers were associated with lymph node metastases (86%) when there was submucosal infiltration, size of 20 mm or greater, or lymphatic vessel involvement.¹⁴⁶

Extended indications for EMR in EGC have been proposed as follows¹⁴⁰: (1) well-differentiated lesions up to 30 mm, without an ulcer or ulcer scar; (2) mucosal cancers less than 20 mm, with an ulcer or ulcer scar; (3) sm1 lesions less than 20 mm, without an ulcer or ulcer scar; and (4) poorly differentiated lesions less than 10 mm.

The risk for node metastasis is approximately 0.4% for differentiated cancers. Undifferentiated mucosal cancers should not be treated by EMR because the risk for node metastasis is approximately 4%. Poorly differentiated and signet-ring cell carcinomas less than 5 mm in size could be managed, however.¹⁴⁷ The proposed extended criteria for endoscopic resection in the ESD era are summarized in Fig. 33.12.

Fig. 33.12 Proposed extended criteria for endoscopic resection in the endoscopic submucosal dissection (ESD) era. SM, submucosal cancer; UL, ulcer.

By expanding the criteria for EMR, the need for gastrectomy in EGC can be reduced. Because it is difficult to resect large and ulcerative lesions by conventional EMR, however, the technique of ESD was developed. Over the years, substantial experience in the use of this technique has been gained, and ESD with the IT knife has become a standard practice in Japan for the treatment of EGC.^148,149

In Europe, ESD has been performed in 10 patients (9 EGCs and 1 adenoma, with a median diameter of 22 mm) using a new double-channel endoscope (the R-scope; Olympus Co, Tokyo, Japan). ESD was successful in six cases. Perforation occurred in two cases and were treated by surgery.¹⁵⁰ In another study, ESD was performed in 19 patients with gastric superficial lesions (15 to 30 mm), with high-grade (n = 15) or low-grade (n = 4) noninvasive epithelial neoplasia. ESD was performed in all cases, with 89% R0 resection and 79% en bloc resection rates observed. Major bleeding was reported in 1 case (5%); there were no cases of perforation. With a median follow-up of 10 months, a single recurrence (5%) was observed.¹⁵¹

Endoscopic resection has also been performed for undifferentiated-type intramucosal cancer.¹⁵² In 38 patients with 42 undifferentiated intramucosal gastric cancers who declined surgical resection, ESD was performed with dedicated devices by experienced expert endoscopists. The en bloc resection rate was 83.3%; complete resection rate was 80.9%. Clinical remission was achieved in 92.8% with recurrence during follow-up seen in only 7.14%. In undifferentiated gastric cancer, grossly normal gastric mucosa surrounding the resected lesion could contain cancer cells beneath the epithelium¹⁵³; this may explain why the complete resection rate of ESD for undifferentiated–type cancer is lower than that reported for well-differentiated cancer. The en bloc resection rate is better with ESD than with conventional EMR. The procedure time is longer in ESD, although this disadvantage might be improved with experience.¹⁵⁴

Ablation Techniques

Argon Plasma Coagulation

APC uses a high-frequency current and an ionized argon gas for coagulating tissue. In the early 1990s, an APC delivery catheter that could be inserted through a flexible endoscope was invented by Farin and Grund.¹⁵¹ Initially introduced as a hemostatic device, the technology subsequently was used for ablation of superficial neoplastic lesions. A noncontact coagulation device, APC can deliver a tangential current to coagulate a target lesion uniformly.¹³⁵

The standard equipment consists of a high-frequency generator and an automatically regulated argon source. The APC current and argon gas are delivered via a flexible probe introduced through the operating channel of the endoscope. Straight fire and side fire probes are available. The recommended settings for ablation of gastric lesions using the APC 300/ICC 200 electrosurgical system (ERBE USA Incorporated Surgical Systems, Marietta, GA) are as follows: mode, auto coag; power setting, 60 to 80 W; coagulation type, forced; and argon plasma flow rate, less than 1.0 L/min. The VIO300D-APC2, a new second-generation APC system released by the same manufacturer, achieves similar results at power settings approximately half of the APC 300 unit.

Enteral Stents

Enteral stents are indicated for malignant luminal obstruction of the GI tract. Patients who have gastric outlet obstruction secondary to gastric cancer can be treated with surgical palliative bypass (via laparoscopy in some centers).¹⁸⁹ Patients who are not good candidates for surgical palliation may benefit from percutaneous gastrostomy for decompression and enteral feeding.¹⁹⁰ Another alternative is the use of an enteral self-expandable metal stent (SEMS). SEMS have been used as palliative therapy for obstructing gastroesophageal junction tumors.¹⁹¹ SEMS are made of various metal alloys in varying sizes and shapes. Covered and uncovered SEMS are available.¹⁹² Many of the published series on placement of SEMS in the upper GI tract have used either modified or standard esophageal stents.^193,194

A through the scope technique is used to place enteral SEMS, typically made of stainless steel or nitinol. Two important caveats for successful placement of SEMS are the ability to pass a guidewire across the stricture and the selection of a stent that is at least 3 to 4 cm longer than the obstruction, to allow an adequate margin on both sides of the obstruction.¹⁹⁵

Epidemiology

GI lymphoma accounts for 4% to 20% of all NHL and 30% to 40% of all extranodal cases.¹⁹⁶ The incidence rate for NHL has been increasing with this trend being more prevalent for extranodal disease. Even though primary gastric lymphoma accounts for less than 5% of all gastric malignant neoplasms, an increase in incidence of primary gastric lymphoma has been observed in the United States.¹⁹⁷

Time trend analysis based on a population-based registry has shown increased incidence rates for gastric (6.3%) and small bowel (5.9%) NHL; there is a concomitant decrease in GI NHL of unknown site, suggesting that the increased incidence at least partly may be a result of more accurate diagnosis. In this particular study, the most common site of GI NHL for all age groups was gastric (43.3%), followed by small bowel (27.4%) and large bowel (11.1%); NHL of unknown site accounted for the remaining 16.1%.¹⁹⁶

Pathogenesis

An association between H. pylori infection and gastric NHL has been shown in several studies.^198,199 Acquired mucosa-associated lymphoid tissue (MALT) in the stomach provides the background for lymphoma to develop. H. pylori is the only well-established chronic antigenic stimulus that causes gastric MALT.²⁰⁰ Parsonnet and colleagues²⁰¹ showed that prior H. pylori infection gives a statistically significant sixfold increased risk of developing gastric NHL, with the association being stronger for high-grade lymphoma. Complete regression of MALT after eradication of H. pylori infection has been described, with subsequent relapse of the lymphoma after reinfection with the organism.^200,202,203 The link between H. pylori gastritis and low-grade gastric lymphoma of the MALT type has also been supported by published data from case-control and epidemiologic studies.²⁰²

Although the rate of H. pylori infection in patients with gastric lymphoma has been found to be higher (91%) than in the general population (64%) in some areas throughout the world, the incidence of gastric lymphoma only partially parallels the incidence of H. pylori gastritis.²⁰⁴ In some areas of Africa, the prevalence of H. pylori infection is very high, but the incidence of gastric lymphoma is very low. A study using population-based registries showed that the incidence of gastric lymphoma parallels the incidence of all NHL, indicating that H. pylori infection is not the only factor in the pathogenesis of MALT lymphoma.²⁰⁴ A 22% rate of H. pylori–negative status based on histologic and serologic tests has been reported in patients with low-grade gastric lymphoma.²⁰⁵ Rarely, low-grade lymphoma may develop in the background of Helicobacter heilmannii–associated gastritis.²⁰⁶

In some H. pylori–negative gastric MALT lymphomas, an association with autoimmune diseases such as Sjögren’s syndrome has been described, but no association with viruses known to be present in other types of lymphomas has been detected.²⁰⁷ Epstein-Barr virus infection, an early pathogen in the development of nodal lymphoma, is only very rarely found in gastric MALT lymphoma.²⁰⁸ Occupational exposure to solvents and pesticides was suggested to play a pathogenic role in some gastric lymphomas in an Italian study.¹⁹⁸ The development of MALT that gives rise to gastric lymphoma is probably a multifactorial process involving both antigenic and host-related factors, but other mechanisms are unknown.

Clinical Features

Low-grade gastric lymphoma typically occurs in the fifth decade, whereas high-grade lymphoma occurs in the sixth decade, suggesting that the progression from low-grade to high-grade lymphoma takes about a decade.²⁰⁹ Patients with gastric lymphoma generally present with nonspecific dyspepsia or with symptoms suggestive of peptic ulcer disease. Some patients may present with GI bleeding or anemia. The finding of an abdominal mass at presentation is rare.²⁰⁹

Endoscopic Diagnosis

Endoscopically, patients with low-grade lymphoma may display normal-appearing gastric mucosa, nonspecific macroscopic gastritis, thickened gastric folds, or ulcerative lesions. High-grade lymphoma generally displays large ulcers on more protruding tumors.²¹⁰ The diagnosis is based on gastric biopsies and enhanced by immunohistochemistry.²¹¹

Endoscopic Ultrasound Staging

EUS provides accurate staging of gastric lymphoma. Based on EUS criteria, gastric lymphoma can be divided into four types: superficially spreading (with thickening of the second or third layers or both), diffusely infiltrating (diffuse transmural irregular thickening of the gastric wall), mass-forming (localized hypoechoic mass with a clear margin located in the third layer or in the third and fourth layers), and mixed (combination of mass-forming and superficially spreading).²¹² Superficially spreading and diffusely infiltrating lymphomas are seen only in patients with low-grade MALT lymphoma. Mass-forming lymphomas are of the same histologic type as intermediate-grade lymphomas, either diffuse large cell or mixed cell type.²¹²

EUS is considered the most accurate technique for locoregional staging of MALT lymphoma.^212,213 EUS had a T staging accuracy of 91.5% when resected specimen histology was the “gold standard.”²¹³ The accuracy of EUS for detection of lymph node metastasis was reported to be 83% compared with resected histology in the same study.²¹³

A previous study evaluated the accuracy of a 12-MHz miniprobe for the staging of low-grade gastric MALT lymphoma compared with conventional EUS.²¹⁴ The study retrospectively reviewed 39 patients before treatment who had histologically confirmed low-grade MALT lymphoma. The accuracy of T and N staging using miniprobe and conventional EUS were similar in this study. The advantage of performing staging with the miniprobe is that this examination can be performed as a single-step procedure during diagnostic gastroscopy. We believe, however, that conventional EUS and EUS-guided FNA is the procedure of choice for staging MALT lymphoma because miniprobes cannot detect distant metastatic lymph node involvement (e.g., nodes in the celiac region) or provide a specimen for cytologic evaluation.^214,215

Pathology

NHL are malignant neoplasms of the B and T lymphocytes and their precursor cells.²¹⁶ In Western countries, B-cell lymphoma is more common (>80%). In the Western world, B-cell lymphoma of the MALT type is the most common. Most of these lymphomas arise in the stomach.^{202,217–219} In southern Japan, T-cell lymphomas predominate, accounting for greater than 75% of GI cases.^{202,217–219}

In the presence of H. pylori infection, B-lymphoid and T-lymphoid cells and neutrophils are brought to the gastric mucosa to form acquired MALT. In low-grade lymphoma, the autoreactive B-cell proliferation is secondary to a specific activation of reactive T cells by H. pylori and cytokines rather than to the bacteria per se.²²⁰ The two main groups of gastric lymphomas are extranodal marginal zone B-cell lymphoma, MALT-type lymphoma, and diffuse large B-cell lymphoma.²²¹ Marginal zone B-cell lymphoma and MALT-type lymphoma are composed of a monotonous, diffuse infiltrate of small lymphoid cells, whereas diffuse large B-cell lymphoma is characterized by a diffuse infiltrate of large malignant lymphoid blasts resembling centroblasts, plasmablasts, and immunoblasts.²²²

Low-grade MALT lymphoma characteristically displays small cleaved cells or centrocytelike cells and is more frequently found in the stomach. As with nodal NHL, low-grade MALT lymphoma may progress to high-grade lymphoma. In the stomach, low-grade MALT lymphoma may extend over a large area or be multifocal.²²³ A subset of patients with low-grade B-cell MALT lymphoma can have a focal high-grade component histologically. A lower survival rate has been found in this subset of patients.²²⁴ Conventional biopsy specimens do not always yield a histologic diagnosis of low-grade B-cell MALT lymphoma.²¹¹ EUS detection with EMR histologic confirmation has been reported in one patient.²²⁵ Coexistence of gastric carcinoma and gastric lymphoma is uncommon but has been reported in the literature.^226–228

Treatment

The strong association between H. pylori and B-cell lymphoma of MALT dictates that H. pylori eradication should be a routine treatment for superficial gastric lymphoma. A combination of two antibiotics (clarithromycin and metronidazole or amoxicillin) with a proton pump inhibitor results in more than 90% eradication of H. pylori.²²⁹ When H. pylori eradication is achieved, more than 70% of low-grade MALT-type lymphomas regress at an early stage. Complete histologic remission of lymphoma can be achieved 2 to 18 months after H. pylori eradication.^203,205,230 In H. pylori–positive patients with localized gastric lymphoma who have no lymph node involvement assessed by EUS, a complete remission can be achieved in 79% of cases. A significant difference in response rate was found between lymphomas restricted to the mucosa and lymphomas involving the deeper layers.²⁰⁵ Patients who have persistent tumor and fail antibiotic treatment and patients with H. pylori–negative status could benefit from radiotherapy or radical surgery with curative intent.²³¹ Elderly patients and patients in whom surgery is contraindicated should receive radiotherapy.²⁰⁹

Epidemiology

Epidemiologically, carcinoid tumor is a rare lesion, constituting only 0.5% of all malignancies. It is found in less than 1% of all cancer autopsy cases, and the approximate incidence is only 1 to 2 per 100,000 population.^197,232 The largest epidemiologic series to date indicates that the incidence of gastric carcinoid, as a percentage of all carcinoid tumors, has increased from 2.25% (1950–1971) to 5.58% (1992–1999).²³³ The percentage of gastric carcinoid in relation to all gastric tumors also has increased from 0.4% in the early Surveillance, Epidemiology and End Results (SEER) data (1973–1999) to 1.77% in the late SEER data (1992–1999). It is unclear, however, if these findings represent a true increase in the incidence or are a result of increased awareness, more frequent use of endoscopy, or changes in reporting methods.²³³

Pathogenesis

Carcinoid tumors are slow-growing tumors that are derived from neuroendocrine cells known as enterochromaffinlike cells. The enterochromaffinlike cell is the main endocrine cell type of the corpus-fundus mucosa. Enterochromaffinlike cells are known to be highly sensitive to gastrin stimulus and able to trigger parietal cell acid secretion by releasing histamine.²³⁴ Gastrin, fibroblast growth factor, and H. pylori all have been shown to have trophic effects on enterochromaffinlike cells. These factors potentially may be relevant in the development of carcinoids.^234,235

Nearly 67% of carcinoid tumors arise from the GI tract, with the tracheobronchopulmonary system being the most frequent site for carcinoid formation outside the GI tract.²³³ Most carcinoid tumors in the GI tract occur in the small intestines (41.8%), rectum (27.4%), or stomach (8.7%). A slight female predominance for this tumor has been found.²³³

The etiology of carcinoid tumor is unknown. Most tumors are considered to be due to sporadic somatic mutations, although there have been reports of a familial predisposition to the disease.²³⁶ Carcinoid tumors have been classified into three types: tumors associated with chronic atrophic gastritis type A (type 1), tumors associated with multiple endocrine neoplasia type I and Zollinger-Ellison syndrome (type 2), and sporadic gastric carcinoid tumors unaccompanied by hypergastrinemia or any specific gastric pathology (type 3).²³⁷

Clinical Features

Clinical manifestations of carcinoid tumors are often absent or vague. In approximately 8% to 10% of patients, these tumors manifest with the carcinoid syndrome (flushing, watery diarrhea, abdominal pain, and wheezing). This syndrome is attributed to secretion of the bioactive mediator serotonin (5-hydroxytryptamine) into the systemic circulation from the primary tumor or, more commonly, from metastatic sites.²³⁸

An association between GI carcinoids and second primary malignancies has been reported with incidence ranging from 12% to 46%.^233,239 In the late SEER subset of data, carcinoid tumors in total were associated with other noncarcinoid tumors in 22.4%. Patients with gastric carcinoids had a decrease of 26% in the incidence of additional noncarcinoid neoplasms when the early SEER data (1973–1991) were compared with the late data (1992–1999). This findings prompted authors to speculate that the decrease might be related to higher identification and removal of these tumors endoscopically.²³³ The most common site of second primary malignancy is the GI tract, which is involved in 32% to 62% of cases, followed by the genitourinary tract (9% to 22%) and the lung and bronchial system (9% to 13%). Adenocarcinoma of the colon has been reported as the most common second primary malignancy.²⁴⁰

It has been speculated that some bioactive substances secreted by carcinoids, such as epidermal growth factor, CCK, VIP, secretin, bombesin, and gastrin, can promote the growth of tumor cells. It is probable that, over time, prolonged exposure to such growth factors may promote phenotypic changes in susceptible cells and induce neoplastic transformation.²⁴¹ Metastases from carcinoid tumors have been reported to occur in approximately 29% of patients; most (61.2%) originate from the small intestine. After lymph node metastasis (89.9%), the liver is the most frequent site of metastasis (44.1%) followed by lung (13.6%), peritoneum (13.6%), and pancreas (6.8%).²⁴²

Endoscopic Diagnosis

Endoscopically, gastric carcinoid tumors may be present as polyplike lesions or, more frequently, as smooth, rounded submucosal lesions.²⁴³ The presence of an irregular erythematous depression or ulceration on the lesion has been considered characteristic but not pathognomonic of gastric carcinoids.²⁴⁴

Pathology

Type 1 tumors associated with chronic atrophic gastritis type A are the most common type of gastric carcinoids, characterized by multiple tumors and hypergastrinemia.²³⁷ The tumors are usually polypoid in appearance, are small (<1 cm), and are found in the body or fundus of the stomach. Type 1 tumors have a relatively benign course. Nodal involvement is reported in 16% of cases, and hepatic metastasis is reported in 4%.^245,246 Type 2 gastric carcinoids are typically also small lesions, but the adjacent mucosa is not atrophic. They have a low potential for malignancy. Type 3 carcinoids are usually solitary tumors greater than 2 cm in size; 40% are present in the antrum and prepyloric area. There is no hypergastrinemia or chronic gastritis. Type 3 tumors are characterized by deep invasion and high potential for metastasis, even when primary lesions are small.^237,247 Nodal metastasis is present in 55% of patients, and liver metastases are present in 25%. The 5-year survival is 50%. Histologically, tumors less than 1 cm or growth restricted to the mucosa are characterized as benign.²⁴⁸

Epidemiology

Gastrointestinal stromal tumors (GISTs) are rare; however, they are the most common mesenchymal tumors to arise in the GI tract. According to a population-based sample, the estimated incidence of GISTs is approximately 10 to 20 per 1 million per year.²⁴⁹ The annual incidence in the United States has been estimated to be 5000 to 6000 cases per year.²⁵⁰ The estimated incidence of malignant GISTs in southern Finland was 4 per 1 million.²⁵¹ GISTs rarely occur before age 40 and are slightly more common in men than in women. An association between GISTs and von Recklinghausen’s disease has been suggested.²⁵² GISTs are most commonly located in the stomach (60%), with the remainder being found in the small intestine (20% to 25%), colon and rectum (5%), and esophagus (<5%).²⁵⁰

Pathogenesis

Morphologically, GISTs are a heterogeneous group of neoplasms that arise anywhere in the GI tract. They represent a family of tumors that probably originates from the intestinal pacemaker cell, also known as the interstitial cell of Cajal (ICC).²⁵³ The ICC serves as a pacemaker system within the muscle layers of the gut and regulates GI motility.²⁵⁴ In the normal gut, these cells express vimentin, CD34, and CD117. The observation that immunohistochemical staining for several of these markers is identical between the ICC and GISTs prompted Kindblom and colleagues²⁵⁵ to propose that GISTs originate from the ICC or may originate from a pluripotential stem cell. The c-kit protein, or CD117, is now recognized as a very sensitive and specific marker for GI stromal cells.

Clinical Features

One-third of patients with GISTs are completely asymptomatic, and tumors are found incidentally during imaging, endoscopy, or surgical procedures being done for unrelated reasons.^249,251 Patients may present with vague symptoms, but the most common manifestations are intestinal bleeding (20% to 50%), abdominal pain (40% to 50%), or a palpable mass (25% to 40%).^251,256 Up to 30% of all GISTs are malignant. The most common site of extraintestinal metastasis is the liver, which is involved in 50% of malignant tumors, followed by lung (10%) and bone (<10%) involvement.²⁴⁹

Endoscopic Diagnosis

Most gastric stromal tumors appear as smooth, round, glistening masses covered with normal gastric mucosa. A defect in the overlying mucosa may occur when ulceration and resulting bleeding occur.²⁵⁶ Endoscopic mucosal biopsy specimens are inadequate to establish the histologic diagnosis in most patients, reemphasizing need for EUS in evaluating suspected GISTs and other subepithelial lesions.

Endoscopic Ultrasound Diagnosis

On EUS, GISTs appear as hypoechoic masses arising from the muscularis propria layer (fourth layer); infrequently, lesions may originate from the muscularis mucosa layer (second layer).²⁵⁷ When GISTs are occasionally found in the submucosal (third layer), they are thought to originate from the muscularis propria or the muscularis mucosa with subsequent extension into the submucosa.²⁵⁸

EUS features that may help to identify malignant tumors include size greater than 4 cm, irregular extraluminal borders, and presence of echogenic foci and cystic spaces. If at least two of these three features are present, the sensitivity of EUS for detecting malignancy is 80% to 100%.²⁵⁹ Palazzo and colleagues²⁶⁰ found that size less than 3 cm, homogeneous echo pattern, and regular margins were 100% specific for benign lesions. Whether EUS features alone can aid in the differentiation of high-risk versus low-risk tumors is less certain.²⁶¹

EUS-guided FNA of suspected GISTs has been used widely to obtain a cytologic diagnosis. A single-center study by Ando and colleagues²⁶² compared EUS-guided FNA with subsequently resected specimens. Using the surgical specimens as the “gold standard” for malignancy or benignity, they found that EUS-guided FNA had an accuracy of 91.3% and specificity of 100%. Sensitivity was only 66.7%, however, with two malignant lesions missed at FNA. Hunt and coworkers²⁶³ performed EUS-guided FNA in 40 patients for evaluation of spindle cell tumors. Of specimens, 17 stained positive for c-kit; tumors positive for c-kit were larger. Surgical resection was performed on 13 patients, 12 of whom had c-kit–positive tumors, and 3 of these 12 tumors had greater than 5 mitoses per 50 high-power fields. More recent data reinforce the idea that mutations in c-kit, high mitotic count, and larger tumor size are risk factors for poor prognosis in patients with localized GISTs and predict reduced relapse-free survival after curative resection.²⁶¹

Pathology

The most common histologic variant among gastric GISTs is a cellular, spindle cell type of tumor consisting of uniform eosinophilic cells. Some of these tumors have a prominent nerve sheath tumorlike nuclear palisading pattern, whereas others show prominent perinuclear vacuolization with moderate to slight interstitial collagen.²⁵⁰ Malignant GISTs may have a spindled, round cell, or epithelioid pattern, or a combination of these. Some malignant GISTs histologically resemble leiomyosarcomas, although they usually have a less eosinophilic cytoplasm.²⁵⁰ Pathologic features that have been used to predict malignancy include mitotic activity, nuclear pleomorphism, degree of cellularity, nuclear-to-cytoplasmic ratio, tumor size (>5 cm have a high risk), mucosal invasion, ulceration, and tumor necrosis.²⁶⁴

Endoscopic Therapy of Submucosal Neoplasms

Submucosal tumors of the stomach are uncommon and are usually found incidentally during endoscopy. These tumors traditionally have been approached in one of two ways: (1) observation with or without an attempt to make the tissue diagnosis or (2) surgical resection. The advent of EUS has enabled the etiology of submucosal tumors to be determined noninvasively. Some tumors have EUS characteristics that are so pathognomonic that no additional diagnostic testing is needed. One example is a small lipoma that on EUS shows the classic hyperechoic texture of a lesion arising from the submucosa.^265,266 In other situations, the EUS features alone are inadequate to establish the correct diagnosis. Mesenchymal tumors as a group typically arise from the fourth layer of the muscularis propria as a hypoechoic lesion; however, the EUS features alone do not distinguish gastric stromal tumors from other types of mesenchymal tumors. In this situation, cytopathology and immunocytochemistry obtained by EUS-guided FNA are quite helpful to establish the diagnosis and guide therapy. Patients with symptomatic disease and any submucosal tumors of the stomach with EUS features suggestive of local invasion require surgical consideration regardless of FNA results.

A practical problem with EUS-guided FNA is the fact that small submucosal tumors of the stomach are often difficult to target. A small leiomyoma with tightly packed spindle cells may not permit adequate sampling using standard techniques. Newly introduced EUS-guided core biopsy needles theoretically provide a better tissue sample, but these needles are technically difficult to deploy, they often yield suboptimal results, and the technique is not feasible for small lesions. In some instances, surgical removal of a submucosal tumor may be the only practical way to provide a histologic diagnosis as well as being curative. Small (<1 cm) gastric submucosal tumors rarely involve the lymph nodes, and in the absence of suspicious EUS characteristics, simple observation and follow-up may be all that is required.