Endoscopic and surgical treatment of early gastric cancer

Joost Rothbarth, Arjun D. Koch and J. Jan B. van Lanschot

Introduction

Early gastric cancer (EGC) is defined as a tumour that is limited to the mucosal or submucosal layers (T1 cancer) and by definition absence of invasion into the proper muscle layer. This is irrespective of the presence of lymph node metastasis.¹

Risk and development of early gastric cancer

The incidence of gastric cancer has steadily declined over many decades, yet it remains worldwide one of the most common malignancies. Most gastric cancers arise as a result of lifelong colonisation with Helicobacter pylori, inducing chronic active gastritis. An abundance of research over the past 20 years has yielded endoscopic and non-invasive methods to recognise both this infection and the various stages of the cascade leading from chronic gastritis via atrophic gastritis, intestinal metaplasia and dysplasia to early and advanced gastric cancer. Cohort studies with these methods have revealed the cancer risks associated with each premalignant condition, and showed that these risks increase with each subsequent stage of the cascade.² These advances have led to common identification of patients with dysplasia and early cancer of the stomach, a development which likely will be further enhanced by the recent introduction of a guideline for surveillance of patients with intestinal metaplasia and dysplasia of the stomach,³ in particular when present in both antrum and corpus.⁴ This chapter deals with the management of early gastric cancer.

Classification of early gastric cancer

Early gastric cancer usually arises in a mucosa that has undergone atrophic and metaplastic changes. These are recognisable with modern high-definition endoscopic equipment, in particular when combined with additional image enhancement techniques such as narrow-band imaging (NBI). Against this background, most EGCs amenable for endoscopic resection can be recognised by experienced endoscopists.⁵ Complete staging and classification of EGCs is usually done in three steps. The first step is a pre-interventional endoscopic staging determining depth of tumour infiltration (with or without endoscopic ultrasonography) combined with histopathological sampling. The second step is the actual endoscopic resection, where the most valuable information is gathered from the submucosal lifting properties of the lesions. The third step is the final histopathological staging of the resected lesion.

Experienced endoscopists performing endoscopic mucosal resections (EMRs) or endoscopic submucosal dissections (ESDs) are trained to recognise and delineate early neoplasia, which includes assessment of invasion depth and thus the endoscopic resectability of the lesion. EGCs are classified by their endoscopic appearance according to the Paris classification (Fig. 8.1).¹ Superficial lesions are classified as either protruding (Paris 0-I), elevated (0-IIa), depressed (0-IIc) or excavated and often ulcerated lesions (0-III). Lesions that have both elevated and depressed components are classified into two groups: depressed lesions in which most of the surface is depressed and there is elevation in a portion of the peripheral ring are classified as 0-IIc + IIa, while elevated lesions with a central depression encircled by the elevated ring at the periphery are called 0-IIa + IIc. The combined patterns of excavation and depression are called 0-III + IIc or 0-IIc + III, depending on the relative surface area of the ulcer and of the depressed area. The classification helps to predict the extent of invasion into the submucosal layer and thus the choice between endoscopic or surgical treatment (Table 8.1). For instance, true protruding lesions in the stomach demonstrate a 57% relative frequency of submucosal invasion, whereas non-protruding, non-excavated lesions demonstrate submucosal invasion in frequencies between 20% and 40%. In excavated lesions, often the proper muscle layer is already involved. Although the exact percentage of involvement of the proper muscle layer is not reported in the literature, this number comes close to 100% and the Paris 0-III excavated types of lesions are usually not resectable by endoscopic means.

Table 8.1

Paris classification of type 0 superficial lesions

Figure 8.1 Paris classification. Endoscopic appearance of superficial neoplastic lesions.

Additional characteristics that predict submucosal or deeper invasion are larger tumour size (> 30 mm), presence of discoloration (remarkable redness) and ulceration.⁵ Lesions that are confined to the mucosa tend to move over the peristaltic waves, whereas peristaltic waves seem to curve around tumours that have invaded the proper muscle layer. The latter provides a strong argument against endoscopic resection.

In most EMR and ESD techniques, submucosal injection of fluid is used to lift the early cancer from the proper muscle layer. This method has three major benefits: (i) it provides information on invasion depth and thus endoscopic resectability; (ii) it facilitates endoscopic resection; and (iii) it provides a safety fluid cushion for resecting the superficial lesion without damaging the deeper layers when using snares, knives or electrocautery.⁶

The amount of lifting provides information on the invasion depth of the lesion. Mucosal or superficial submucosal lesions usually demonstrate complete lifting (m–sm1), whereas the lesions that infiltrate into the deeper submucosal layers often lift incompletely (sm2–sm3). A non-lifting sign most often represents invasion deeper than sm3.⁶

Lymph node metastasis

Endoscopic staging before resection does provide useful information on the prediction of lymph node metastasis. Differentiation grade can be assessed through simple biopsy. A large retrospective study from Japan assessed the occurrence of lymph node metastasis in 5265 patients who had undergone gastrectomy with lymph node dissection for early gastric cancer.⁷ All specimens were reassessed for macroscopic appearance, size, ulceration, invasion depth and extent of submucosal invasion, differentiation grade and lymphovascular involvement.

The results are summarised in Table 8.2 and define the criteria for EMR and ESD.^7,⁸

Table 8.2

Criteria for EMR and ESD, according to the proposed guidelines

CS, consider surgery; EMR, suitable for endoscopic mucosal resections; ESD, suitable for endoscopic submucosal dissection; S, surgery.

It turned out that depressed or ulcerated lesions, larger than 30 mm in size, of the undifferentiated histological type or with lymphovascular involvement, were associated with an increased risk of nodal metastases (7.3%). In contrast, none of the differentiated EGCs less than 30 mm in size, regardless of ulceration, were associated with lymph node metastases. None of the differentiated lesions without ulceration were associated with nodal metastases regardless of the size of the lesion and none of the undifferentiated lesions without ulceration, less than 20 mm in size, were associated with positive lymph nodes. The results of this study provided the necessary evidence to widen the indications for endoscopic resections of EGCs.⁷

Endosonography

The role of endosonography remains debatable in EGCs. Endosonography lacks sufficient diagnostic accuracy in discriminating T1 from T2 lesions. The combined results of large recent studies show a diagnostic accuracy for T3 and T4 tumours of 88–100%, with 64–85% accuracy for T2 lesions and 75–82% accuracy for T1 tumours.^9,¹⁰ T1 lesions are often overstaged, probably because of submucosal fibrosis, connective tissue hyperplasia or ulceration. Diagnostic accuracy can be improved using mini-probes; however, complete assessment of larger lesions is difficult and bears the risk of underestimating the deepest invasion when parts of the lesion are missed and subsequently not assessed.¹¹ Many endoscopists rely, for these reasons, on endoscopic assessment alone followed by histopathological assessment of the resected specimen. A German study demonstrated a similar diagnostic accuracy of 83.4% and 79.6% using either high-resolution endoscopy or endosonography, respectively, in assessing infiltration depth in early neoplasia in the oesophagus.¹² The authors believe the same applies for early neoplasia in the stomach.

Conventional endoscopic assessment of depth of infiltration in EGC has a similar accuracy compared to endosonography. For this reason, most highly experienced interventional endoscopists rely on endoscopic assessment and do not routinely perform endosonography before proceeding to EMR or ESD.¹²

Revised Vienna classification

Large discrepancies between Western and Japanese pathologists in the diagnostic criteria for adenoma, dysplasia and carcinoma in the gastrointestinal tract have led to considerable problems in the comparison between Western and Japanese data. This led to a consensus meeting in 1998 in Vienna, ultimately resulting in the Vienna classification of gastrointestinal epithelial neoplasia and the revised Vienna classification in 2002.¹³ This classification allows not only for a more universal nomenclature of gastrointestinal epithelial neoplasia but also corresponds more properly with clinical management. The revised Vienna classification is shown in Table 8.3.

Table 8.3

The revised Vienna classification of gastrointestinal epithelial neoplasia

Category	Diagnosis	Clinical management
1	Negative for neoplasia	Optional follow-up
2	Indefinite for neoplasia	Endoscopic follow-up
3	Mucosal low-grade neoplasia	Endoscopic resection or follow-up
	Low-grade dysplasia
	Low-grade adenoma
4	Mucosal high grade neoplasia	Endoscopic or local surgical resection
4.1	High-grade adenoma/dysplasia
4.2	Non-invasive carcinoma (carcinoma in situ)
4.3	Suspicious for invasive carcinoma
4.4	Intramucosal carcinoma
5	Submucosal invasion by carcinoma	Surgical resection

Endoscopic treatment

Endoscopic mucosal resection

The basic principle of what is nowadays termed endoscopic mucosal resection (EMR) is the removal of a mucosal lesion by resecting it from its deeper layers using a snare instrument. This method does not allow for lesions larger than 2 cm to be removed en bloc.¹⁴ Larger lesions can be removed by EMR, but only in a piecemeal fashion. The technique is fundamentally different from ESD, where the submucosal layer is carefully and stepwise dissected. Using EMR, early neoplasia is often lifted from the proper muscle layer before resection using different solutions of saline for submucosal injection.^15–17 The lesions can then be sucked into a cap that is placed at the tip of the endoscope with a snare preloaded on to the rim of the cap. After sucking the lesion into the cap, the snare is pulled. The content of the snare is then resected using high-frequency current. An alternative resection method that is frequently used is the so-called ‘band-and-cut’ method. A lesion is sucked into a modified multiband ligator. By ligating the mucosa bearing the lesion, a pseudopolyp is created that can be resected using a snare. This multiple band mucosectomy allows for larger segments of neoplasia to be completely resected.¹⁸ This method is increasingly used in larger Barrett’s segments but is also applicable in the cardia and the antrum of the stomach.

Endoscopic submucosal dissection

Endoscopic submucosal dissection (ESD) was originally developed in Japan for the local treatment of superficial EGC limited to the mucosal layer or with a minimal invasion of the submucosal layer. The main goal of submucosal dissection is to retrieve the lesion en bloc for histopathological staging and to minimise the chance for local recurrence. ESD is performed in several steps. First, the lesion is delineated by placing circumferential dots using electrocautery around the lesion with a few millimetres of free margin. The lesion is then lifted from the proper muscle layer by submucosal injection in the same fashion as in EMR.15–17 The solutions used are often stained with either indigo carmine or methylene blue. This dye will colour the submucosal layer and facilitate recognition of the separate layers and blood vessels. After lifting the lesion a circumferential incision of the mucosal layer is made, placing the markers just inside the circumferential cut. From this point onwards the submucosal layer is carefully dissected from the muscle layer, often with additional submucosal injections. In Fig. 8.2 an example of a Paris 0-IIa + IIc is shown, which is subsequently removed by ESD. Different speciality knives have been developed for ESD. A breakthrough in ESD was the development of the insulated tip (IT) knife in 1996.¹⁴ This is a speciality endoscopic knife with an insulated tip. An insulated small ceramic sphere is mounted on the top of a high-frequency needle knife, allowing safe and easy incision and separation of the mucosal and submucosal layers. Subsequently, the design of the original IT knife has been further adapted leading, for example, to the IT-2 knife, the hook knife, the flex knife, the triangular tip (TT) knife and the hybrid knife, the latter combining radiofrequency with a water-jet application.¹⁹ This novel technique combines radiofrequency with a distance-dependent water-jet application, allowing for easier and safer submucosal lifting and cutting in ESD.^20,²¹

Figure 8.2 Early gastric cancer removed by ESD. (a) A Paris 0-IIc + IIa early gastric cancer located in the antrum. (b–e) Markings are placed around the lesion (b) and after submucosal lifting and circumferential incision (c), the lesion is stepwise dissected (d) and finally fully removed (e). Histopathological assessment demonstrated a well-differentiated adenocarcinoma confined to the mucosal layer with a maximum extent into the muscularis mucosae and tumour-free resection margins.

Complete resections

The aim of both EMR and ESD is to strive for complete resection of the neoplastic lesion.

In the endoscopic treatment for early gastric cancer conventional EMR has been proven to be inferior to ESD, especially when it comes to lesions larger than 20 mm or with ulceration. Piecemeal resection of these lesions leads to lower rates of complete resection and higher local recurrence rates up to 26%, even when histopathology of piecemeal fragments suggested complete resection. Even en bloc EMRs of lesions smaller than 20 mm resulted in no more than a 45% margin-free resection rate, where ESD was clearly superior with an 87% margin-free resection rate.¹⁴ Lesions up to 10 mm can be removed either by EMR or ESD, with a comparable recurrence-free rate.²²

In theory, using the ESD technique, lesions of all sizes can be removed. However, attempts at curative resection are limited by a number of anatomical factors that relate to the primary lesion. These factors are related to the relative frequencies of lymph node metastasis, as described earlier in this chapter. Larger lesions, poorer differentiation or deeper penetration in the submucosal layer are associated with a rapidly increasing incidence of lymph node metastases.

Routinely, after endoscopic resection, the resected specimens are stretched and pinned on cork or paraffin and sent for pathological assessment. This final staging step by the pathologist should provide the necessary information on (i) quantitative criteria (lateral margins, deeper margins, maximum extent of submucosal invasion) and (ii) qualitative criteria (differentiation grade, lymphovascular involvement), which correspond with the risk of lymph node metastasis.^7,⁸ This ultimate information is pivotal for further management. It mandates additional surgery or allows for a surveillance policy. Because of an approximately 14% chance of metachronous gastric cancer over a 5-year period²³ and possible remnant neoplastic tissue, surveillance is usually carried out after endoscopic resection at 6-month intervals during the first year, followed by annual surveillance thereafter. Early detection of metachronous neoplasia can be treated by repeated endoscopic resection.

Complications of endoscopic resections

Endoscopic treatment is now accepted worldwide for early gastrointestinal neoplasia as it replaces the need for major surgery associated with considerable morbidity and mortality. Endoscopic treatment is also superior in terms of post-procedural functional results. The obvious example is the avoidance of gastrectomy by endoscopic resection of an early neoplastic lesion.

However, these novel endoscopic techniques also come with a risk of complications, ranging from bleeding and perforation to post-treatment strictures and, potentially, leading to considerable morbidity and even mortality.

Most bleeding complications occur during the procedures and can be dealt with instantly. Superficial bleeding vessels are identified and treated either by using coagulation, adrenaline injections or clips. Delayed bleeding also occurs and might necessitate subsequent re-intervention. A large prospective study found no risk factors for bleeding besides the presence of a gastric malignancy itself.²⁴

In expert hands, perforations occur during EMR and ESD in about 0.2% and 1–4% of cases, respectively. A recent European study reported a 20% perforation rate after ESD at a tertiary referral centre.²⁵ This study clearly demonstrates a difference in expertise in some Western referral centres compared to Japanese and Korean expert centres. This is mostly due to a much lower incidence of EGCs in the Western world, resulting in an insufficient exposure to this type of pathology and resection techniques. Recently, a panel of European experts has attempted to set standards for quality criteria for ESD in European countries.²⁶ Perforations can lead to pneumoperitoneum and in severe cases to generalised peritonitis. Usually, perforations are recognised immediately during the procedure and endoscopic management is possible and frequently adequate.²⁷ Closure with clips is a safe treatment option together with nasogastric drainage and fasting.²⁸ Recently, in a small case series the use of the over-the-scope clip (OTSC) was described for closure of perforations in a clinical setting.²⁹ The OTSC device is a promising novel technique with a reported closure success rate of 92%.

Strictures after EMR and ESD occur mainly in the more narrow parts of the gastrointestinal tract such as the oesophagus, gastric cardia and pyloric region. Stricture formation is more frequent with circumferential resections or large size perimeters and is induced through ulcer scar healing. These strictures are often relatively easy to treat with balloon dilation, with the exception of strictures after circumferential ESD, which can prove quite difficult to treat because of severe scar fibrosis.