Definition of early gastric cancer

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.

Endoscopic appearance

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.

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

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.

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.

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

Complete resections

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

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.

Proximal gastrectomy

Total gastrectomy with D1 or D2 lymphadenectomy is still the standard treatment for tumours in the upper third of the stomach. This type of resection is associated with the postgastrectomy syndrome, including dumping, epigastric pain, diarrhoea, hypoglycaemia, malnutrition and anaemia. As nodal metastases in the distal gastric lymph nodes (stations 5 and 6) are rare in EGC of the proximal stomach, less extensive resections have been proposed. Proximal gastrectomy (Fig. 8.3a) was developed as an alternative to total gastrectomy in order to reduce the long-term postoperative problems without compromising the oncological outcome. In proximal gastrectomy the proximal half of the stomach is resected, including a D1 or D1 + lymphadenectomy.³⁰ Several techniques for surgical reconstruction after proximal gastrectomy have been described, including reconstruction by jejunal interposition and a gastric tube (Fig. 8.3b,c), but the optimal method remains controversial.

As could be expected due to the relatively high incidence of EGC in the East, most studies on proximal gastrectomy are from Japan and Korea,31–35 while data from Western countries are scarce.³⁶ Several studies have shown that proximal gastrectomy for upper EGC is a safe procedure with comparable 5-year survival rates.^31–34,36 However, conflicting data have been reported on the long-term complications and quality of life. Some studies showed an improved clinical outcome after proximal gastrectomy with oesophagogastrostomy or jejunal interposition, while others report a markedly higher complication rate including anastomotic stenosis and reflux oesophagitis.^32–35 Therefore, further evaluation on this type of gastric resection for proximal EGC is needed. As yet, randomised data are not available.

Pylorus-preserving gastrectomy

PPG is a function-preserving procedure initially described for the treatment of peptic ulcer disease³⁷ (Fig. 8.4). For patients with EGC, favourable functional results have been reported with PPG compared to conventional distal gastrectomy. PPG is feasible for early tumours in the middle third of the stomach with the distal border at least 4 cm proximal to the pylorus. In PPG a distal gastrectomy is performed with preservation of the pylorus and both the right gastric artery and the pyloric branch of the vagal nerve, followed by a stomach-to-stomach anastomosis.³⁸ As a result, it is assumed that the pyloric function remains intact, preventing gastrointestinal symptoms such as dumping syndrome, epigastric fullness, reflux oesophagitis, bile regurgitation and cholelithiasis.³⁹ In contrast to conventional distal or total gastrectomy, the suprapyloric (second-tier) lymph nodes are not resected in PPG. In EGC this is probably justified as 80–90% of EGCs are negative for lymph node metastases and the vast majority of positive lymph nodes are located in the first-tier lymph nodes only. Retrospective data of a Japanese database of 3646 T1 tumours located in the middle third of the stomach showed only 0.2% metastases to the pyloric lymph nodes.⁴⁰ High 5-year survival rates up to 98% are reported after PPG with modified D2 lymph node dissection in patients with clinically diagnosed mucosal or submucosal gastric cancer (cT1) without lymph node metastases (cN0).⁴¹ Similar to studies on proximal gastrectomy, most data on PPG are derived from studies done in Japan and Korea. In Western countries PPG is still considered investigational.

Local (or wedge) segmental resection

Local or wedge resection involves removal of only the tumour including the nearby lymph nodes and primary closure of the stomach (Fig. 8.5). In a segmental resection a limited segment between the lesser and the greater curvature of the stomach is resected including the nearby lymph nodes and a formal gastro-gastrostomy is performed (Fig. 8.6). Local and segmental gastric resections for (early) gastric cancer have the obvious potential advantage of a better functional postoperative outcome, because digestive and reservoir functions of the stomach are mostly preserved. Several small studies show superior results on nutritional status and the occurrence of dumping and reflux oesophagitis after local or segmental resection, compared to a total or distal gastrectomy.^42–45 These procedures can be safely performed in EGC with favourable features that cannot be resected by EMR or ESD for technical reasons. As mentioned before, the likelihood of lymph node metastases in these patients is very low and local or segmental resection with a limited lymphadenectomy seems justified.

For EGC with unfavourable features local or segmental resection with only limited lymphadenectomy is still investigational. In these patients the risk of lymph node metastases and local recurrence is relatively high and no clear evidence exists that similar recurrence and survival rates can be achieved compared to standard gastric resections. Intraoperative investigation of lymph nodes for tumour metastases by sentinel lymph node biopsy (SLNB) may lead to a better selection of patients eligible for a local or segmental resection, as will be discussed later.

Minimally invasive surgery

Over the past decade there has been a notable trend towards laparoscopic or laparoscopically assisted surgery for EGC, especially in Japan and Korea. The role of laparoscopy in gastric cancer is less clear in Western countries. Minimally invasive surgery has the obvious advantage of less postoperative pain for the patient, a faster recovery and better cosmetic results. In laparoscopic gastric cancer surgery the discussion has been mainly focused on whether the oncological outcome is comparable to open surgery.

Several large Japanese and Korean randomised controlled trials (RCTs) on laparoscopic versus open surgery have been conducted.

Some smaller studies from Europe and the USA showed similar results.^49,50 Thus, laparoscopic gastric resection for EGC is a technically safe procedure and seems to be justified for selected patients. However, results from RCTs will have to prove the oncological safety of laparoscopic gastrectomy.

Recently, natural orifice transluminal endoscopic surgery (NOTES) has been proposed as a new technique for the treatment of EGC. One study has reported the feasibility of a combined NOTES and laparoscopic resection of EGC in 14 patients.⁵¹ Further studies have to define whether there is a role for NOTES in the treatment of EGC.

Lymphadenectomy

In gastric cancer, lymph node status is one of the crucial prognostic factors,⁵² and the type of resection and the extent of lymphadenectomy are largely based on the likelihood of lymph node metastases to first- and second-tier lymph nodes. However, in parallel with many other tumours it is still debatable whether (extended) lymphadenectomy in gastric cancer really leads to improved survival.⁵³

As mentioned at the beginning of this chapter, mucosal and submucosal tumours with favourable features (Table 8.2)⁸ can be safely treated by EMR or ESD. This is based on the fact that these tumours have a very low risk of lymphatic dissemination. EGCs with unfavourable tumour characteristics harbour a high risk of lymph node metastases and are not amenable for endoscopic treatment. For these patients a gastric resection with lymphadenectomy is indicated. As discussed in Chapter 7, the extent of lymph node dissection in gastric cancer remains controversial. The discussion is mainly focused on the adequacy of a limited D1 lymphadenectomy versus the necessity of extended D2 or even D3 lymphadenectomy. In general, surgeons in Western countries tend to perform a more limited lymphadenectomy (D1), while surgeons in Japan and Korea perform a more extended lymphadenectomy (D2). The rationale for extended lymphadenectomy is improved staging, enhanced locoregional control and improved survival. The clearance of possible metastatic nodes in the region outside the perigastric nodes is presumed to have an impact on overall survival rates.

In Taiwan an RCT was performed comparing D1 with D3 lymphadenectomy; in the extended arm a level 3 lymph node dissection (hepatoduodenal ligament, retropancreatic region and superior mesenteric vein lymph nodes) and an optional hemipancreatosplenectomy were performed. This trial demonstrated an overall survival benefit in favour of a D3 lymphadenectomy, with 5-year overall survival rates of 59.5% versus 53.6%.⁵⁷ These data suggest that extended (D2) lymphadenectomy can result in survival benefit for patients with advanced gastric cancer.

The optimal extent of lymph node dissection for EGC remains controversial. The incidence of lymph node metastases for mucosal EGC is only 2–4%, but increases to up to 45% in mucosal tumours with unfavourable features such as depressed or ulcerated lesions, tumours larger than 30 mm in size, tumours with undifferentiated histological type or with lymphovascular involvement.^7,58 Most patients with mucosal EGC are safely treated by EMR or ESD without lymphadenectomy (Table 8.2). In submucosal EGC lymph node metastases are found in approximately 20%, with a wide range from 10% to 64%.^59–61 In addition, approximately 5% of lymph node metastases from submucosal EGC are located in second-tier lymph nodes (mainly node stations 7, 8a and 9).^62,63 Because of the relatively high risk of lymph node metastases in submucosal EGC and mucosal EGC with unfavourable features, a lymphadenectomy is generally performed in these patients. However, there is no consensus on the required extent of the lymphadenectomy. The Japanese Gastric Cancer Association (JGCA) recommends D2 lymphadenectomy for patients with EGC clinically positive node(s) (cN +),³⁰ but this guideline lacks clear evidence.

For patients without suspicion of positive lymph nodes (cN0), currently no evidence exists that D2 dissection can improve survival rates in EGC. Considering the fact that in EGC the rate of lymph node metastases is relatively low and, when positive, generally confined to the first-tier lymph nodes, D2 resection can probably be omitted in EGC. Therefore, in Europe and the USA D1 resection is advocated for these patients, and also the JGCA recommends a D1 resection for all EGCs that are clinically node negative and do not meet the criteria for EMR or ESD. In Japan and Korea an additional so-called D1 + lymphadenectomy is advocated for submucosal EGC with unfavourable features (poorly differentiated, size > 1.5 cm) based on the 5% risk of second-tier lymph nodes.³⁰ D1 + lymphadenectomy includes a D1 lymphadenectomy plus a selective dissection of second-tier lymph nodes dependent on the location of the tumour (nodes 8a, 9 and 11p in total or proximal gastrectomy; 8a and 9 in distal or pylorus-preserving gastrectomy). However, no randomised controlled studies have been conducted that prove the usefulness of these selective additional lymphadenectomies.

Sentinel node biopsy

In breast cancer and melanoma surgery, sentinel lymph node biopsy (SLNB) has proved to be a valuable tool in lymph node mapping, with a sensitivity of more than 95%. When SLNB is negative in these tumours, lymphadenectomy can safely be omitted.

Obviously, gastric cancer patients with suspicious or proven lymph node metastases are not eligible for SLNB and a routine D2 lymphadenectomy is deployed. Also, in patients with advanced tumours (T3 and more) SLNB seems inappropriate. These patients already have a high probability of having first- or second-tier lymph node metastases. Moreover, in advanced tumours original lymphatic drainage routes might be obstructed or altered, resulting in a lower accuracy of the SLNB.

In EGC the incidence of lymph node metastasis is relatively low, i.e. approximately 3% for mucosal and 20% for submucosal tumours. Consequently, when D1 or D2 lymphadenectomy is performed for these tumours as part of standard surgical treatment, in the majority of patients no lymph node metastases are found. In these patients probably a less extensive resection without lymphadenectomy would probably have resulted in the same excellent disease-free survival rates, but without the inherent surgical morbidity and mortality.

Therefore, SLNB in EGC has been a focus for research in the past 10 years. Many different techniques and protocols have been employed. In most study protocols a double tracer method is preferred using a radioactive colloid, e.g. technetium-99 m, in combination with a dye agent such as isosulfan blue, patent blue violet or indocyanine green. The day before surgery the radioactive colloid is injected endoscopically in four quadrants into the submucosal layer at or in the vicinity of the primary lesion. The dye is injected intraoperatively in the same manner. By this means the sentinel node can be located by both a gamma probe for detection of a radioactive sentinel node and by visualisation of a blue or green coloured sentinel node.⁶⁴ Most studies show increased rates of successful identification of sentinel lymph nodes by combining both techniques.^65,66

Various studies have shown the technical feasibility of SLNB in EGC. However, the accuracy of SLNB in gastric cancer remains to be determined. The difficulty of the SLNB technique in gastric cancer is that, unlike the single-course lymphatic flow in breast cancer, the lymphatic flow of the stomach is multidirectional, which can result in multiple sentinel lymph nodes located in different first-tier lymph node stations (greater and lesser curvature), but also in second-tier stations.^67,68

However, although it has been suggested that SLNB in gastric cancer is a useful tool for individualising the extent of lymphadenectomy in patients,⁷⁰ these figures are currently too low to justify the introduction of SLNB as a standard procedure in EGC.

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