Gastric neoplasms

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Contents

Introduction

Whilst most developed countries have seen dramatic reductions in the overall incidence of stomach cancer it remains the second commonest malignancy worldwide. Whilst adenocarcinoma account for more than 90% of all malignant stomach tumours, two other tumours should be considered, these are gastric lymphoma and gastric GI stromal tumours. The majority of this chapter will deal with adenocarcinoma.

Gastric adenocarcinoma

Fifty years ago adenocarcinoma of the stomach was the most frequently seen cancer in most countries, and whilst it has decreased rapidly in incidence it remains an important cancer in terms of cancer registrations and deaths. Gastric cancer overall has a poor prognosis in most countries outside of Japan, with overall 5 years' survival rate being around 10%.

Epidemiology

Gastric cancer is generally a disease of the elderly, with average age at presentation being 70 years and a 2 to 1 male to female predominance. The overall incidence varies from 6 per 100,000 in the USA to 70 per 100,000 in Japan.

There has been an important change in the epidemiology of adenocarcinoma of the stomach over the past 50 years. The commonest site of cancers was in the antrum of the stomach, with proximal third gastric cancers being unusual. Over the past 5 decades, antral gastric cancer has become less common whereas proximal third cancers more common - to a point where proximal cancers are now the most commonly seen in most developed countries. Whilst all the reasons behind this change are not clear some factors have been identified. The key identified aetiological factors for non-cardia gastric cancer are Helicobacter pylori infection, high nitrite intake, low intake of fruit and vegetables, smoking and high salt intake. Reductions in the incidence of H. pylori infection, higher fruit and vegetable intake and lower nitrite intakes have probably accounted for the reductions in the incidence of non-cardia gastric cancer. The reasons behind the increase in proximal gastric cancer are far from clear.

Pathogenesis

Although a simplification there are two broad histological types of gastric cancer, intestinal type cancers and diffuse type cancers (around 20–30% have a mixed picture). There is little evidence to support the two types' having different aetiological factors although the molecular pathways involved in the pathogenesis are different. The diffuse type is associated with abnormalities of the CDH1 gene, which codes for the protein e-cadherin. Mutations of this gene are responsible for the only identified hereditary form of gastric cancer, hereditary diffuse gastric cancer (HDGC).

Diagnosis

Patients with gastric cancer present with a range of symptoms including dyspepsia, upper abdominal pain, bloating and fullness, weight loss and vomiting. They can also bleed and present with anaemia; it is relatively uncommon for these tumours to present with haematemesis. There are no uniquely diagnostic symptoms and therefore a high index of suspicion is required to make the diagnosis.

Patients who have obvious physical signs on clinical examination (abdominal mass, supraclavicular lymph nodes etc.) almost invariably have incurable disease.

The main diagnostic test in upper gastrointestinal endoscopy and any patient with new or changed upper gastrointestinal symptoms should have an endoscopy. Abnormalities are biopsied to confirm the diagnosis of gastric adenocarcinoma, Management of gastric adenocarcinoma.

Management of gastric adenocarcinoma

In Japan with its very high incidence of gastric cancer there exists a population-based screening programme but no other country has an incidence high enough to justify such a programme.

Staging

Having established the diagnosis of malignancy the next phase of patient management is to stage the tumour. Staging coupled with an overall assessment of the patient will enable the appropriate treatment to be planned. Staging of gastric cancer is optimally carried out by a combination of helical CT scan and where available endoscopic ultrasound examination. Endoscopic ultrasound (EUS) is a relatively new modality that is complementary to gastroscopy and computed tomography (CT). The normal stomach wall has five distinct layers. Endoscopic ultrasound with a high frequency (7.5–12 MHz) transducer is relatively accurate at assessing the T stage. Its sensitivity for detecting nodal metastases is better than that of CT, but it still cannot reliably exclude nodal disease.

Computed tomography scanning is important in excluding hepatic metastases, and also in showing gross nodal involvement. It is poor at assessing the T stage of the primary tumour and frequently fails to show small-volume peritoneal disease.

The combination of CT and EUS will have an overall accuracy of 80–85% for the staging of gastric cancer; most of the inaccuracy is as a result of understaging. Laparoscopy is becoming established as an essential part of the preoperative staging of gastric cancer. In about 15% of cases small-volume hepatic or peritoneal disease is discovered laparoscopically, which was undetected by CT. The information obtained from the staging information is described using the TNM system, which for gastric cancer is detailed as follows

  • T Stage
    • T1, tumour in mucosa or submucosa
    • T2, tumour into/through muscularis propria
    • T3, tumour through serosa
    • T4, tumour invading other structures
  • N Stage (requires at least 15 nodes to be examined)
    • N0, no nodes involved
    • N1, 1–6 nodes involved
    • N2, 7–15 nodes involved
    • N3, more than 15 nodes involved
  • M Stage
    • M0, no distant metastases
    • M1, distant metastases

The information can also be used to place the patient's tumour into a stage group, I through IV. For example a T3 N0M0 tumour is in stage II whereas a T3 N2 M0 tumour would be stage III. There is a clear relationship between stage and survival. Five-year survival rate for stage I to IV tumours is approximately 90%, 60%, 30% and 5% respectively. Unfortunately the vast majority of gastric cancers in the Western world are stage III or IV at the time of diagnosis although in Japan with screening and aggressive diagnosis the majority of patients present with curable stage I or II disease. T1 cancer is known as ‘early gastric cancer’ (EGC), irrespective of the state of the lymph nodes. Early gastric cancer is subdivided according to the macroscopic appearance into protruded (type I), superficially elevated (IIa), flat (IIb), superficially depressed (IIc) and excavated (III).

Treatment

Having staged the tumour and assessed the whole patient in terms of their general fitness, the next stage is to decide on the appropriate treatment. This should involve a careful discussion with the patient regarding the diagnosis and the benefits and risks of the proposed interventions. The treatment planning should where possible involve a multi-disciplinary team of surgeon, gastroenterologist, oncologist, nurse and pathologist. The team should also include when appropriate a palliative care specialist.

Endoscopic treatment

A small number of patients will be diagnosed with early stage T1 tumours. Of these a proportion are suitable for endoscopic mucosal resection. In Japan nearly half of all cancers are treated in this way and as a consequence there are carefully derived systems for deciding which tumours are appropriate for such treatment. There are clearly considerable advantages for the patient if surgery can be appropriately and safely avoided

Surgery

The majority of patients with potentially curable disease will have a surgical resection as the mainstay of their treatment. The operation may involve resection of the distal stomach or the entire stomach. There has been very considerable debate around whether the operation should involve extensive resection of the lymph nodes draining the stomach. The Japanese with their very high incidence of gastric cancer are convinced that such a lymph node dissection adds to the chance of achieving a cure. Two large randomised controlled trials and several smaller trials carried out in Western countries have failed to show a conclusive benefit for the more radical lymph node dissections although further analysis has shown potential benefit for patients with stage II and early stage III disease. Following gastric resection intestinal continuity is usually restored with a Roux-en — Y type reconstruction that reduces the risk of bile reflux into the remaining stomach or oesophagus. There is some evidence from meta-analysis that the use of a jejunal pouch may improve the functional outcome after total gastrectomy.

When informing patients about major gastric resection it is important that they are aware that there is a 2–5% associated mortality and a 20–30% incidence of significant complications. The risk of mortality is related to the volume of operations carried out in the surgical unit and high volume units report mortality rates of 1% or less.

EARLY COMPLICATIONS

The post-operative course for a patient having a gastric resection for cancer can be stormy, especially if the patient has a total gastrectomy. Potential complications include the usual cardiac, respiratory and wound complications that may occur in any patient undergoing abdominal surgery. There is a risk of anastomotic leakage, especially after total gastrectomy and oesophagojejunal anastomosis. The suture or staple line where the duodenum has been divided may also break down. Fluid collections or abscesses are common, particularly if extensive lymph node dissection has been performed. Dissection of lymph nodes from the pancreas risks causing acute pancreatitis. Sometimes the gastric remnant does not drain well into the jejunum and the patient may have prolonged nasogastric drainage or vomiting. This may be due to a mechanical obstruction (efferent loop obstruction) or to poor motility of a partially denervated gastric remnant. Obstruction of the afferent loop can occur early in the post-operative course and lead to disruption of the duodenal stump. It can also occur late and lead to post-prandial pain and nausea commonly relieved by vomiting. Afferent loop obstruction is due to a poorly constructed afferent loop, and usually requires surgical correction.

LATE COMPLICATIONS
  • Late complications are due to changes in the anatomy and the physiology of the upper gastrointestinal tract. The complications include reflux gastritis and/or oesophagitis, dumping syndromes, diarrhoea and nutritional deficiencies. Most of the problems are most marked in the few months after surgery and most fade within about one year.
  • Reflux gastritis is due to loss of the pylorus and easy passage of alkaline biliary and pancreatic fluid into the stomach. There is endoscopic evidence of gastritis in most patients who have had a loop jejunostomy as a reconstruction, but only a small proportion have significant symptoms. Medical therapy is not very effective, and some patients require surgery to divert the small bowel fluid from the stomach via a Rouxen- Y gastrojejunostomy.
  • Dumping refers to an array of gastrointestinal and vasomotor symptoms attributed to rapid gastric emptying. The symptoms include fullness, abdominal pain, nausea, vomiting and diarrhoea. The vasomotor symptoms are due to rapid fluid shifts into the bowel lumen, and are the typical symptoms of hypovolaemia. ‘Late’ dumping is due to an insulin surge soon after a meal, followed by reactive hypoglycaemia. The treatment of dumping is dietary. Patients should eat small frequent meals, try to separate dry foods from liquids, and avoid simple sugars. The severity of symptoms settles with time.
  • Nutritional deficiencies may result from changes in appetite, from gastritis or dumping syndromes, or from recurrence or progression of the cancer. It is normal for patients to lose about 10% of their preoperative weight after a total gastrectomy and 5% after distal gastrectomy.
  • Anaemia is common after gastrectomy. This may be due to vitamin B12 deficiency from loss of intrinsic factor after total gastrectomy and/or poor iron absorption due to failure of conversion of iron from the ferric to the ferrous form through the absence of acid. After total gastrectomy patients require regular vitamin B12 injections.
  • Both osteoporosis and osteomalacia are more common after gastrectomy. The reasons for this are not entirely clear but may result from reduced absorption of calcium and/or vitamin D.

Adjuvant therapy

Even with potentially curative surgery with removal of all visible tumour and clear resection margins most series report 5-year survival between 30 and 40%. Therefore there is a clear need to look at whether additional adjuvant therapy can offer survival benefit. The literature in this area is not clear but trends are emerging which will guide future research. There is some evidence that neo-adjuvant chemotherapy can downstage gastric cancers although the post-operative survival benefits are not yet defined. Post-operative adjuvant chemotherapy has been shown to be of benefit in several of the randomised controlled trials carried out and a meta-analysis of all trials to date has shown a significant benefit in favour of chemotherapy. However despite the meta-analysis because of the very heterogeneous nature of the trials included in the analysis such treatment is not usual in the majority of centres. A recent large multicentre study looked at the use of post-operative chemoradiotherapy following surgery for gastric cancer and showed a significant survival benefit. Whilst further studies are needed it does appear that adjuvant therapy offers some benefit for patients with gastric cancer and such treatments should be considered.

Palliation

Unfortunately the majority of patients with gastric cancer either present with advanced disease or develop recurrence following surgery. Therefore palliation is very important. Whilst not universally accepted there seems to be little benefit at all for patients with advanced gastric cancer undergoing surgery where all of the detectable tumour is not removed. The overall survival in such patients is not different from those who do not undergo resection. One of the commoner indications for palliative surgery is gastric outlet obstruction from a stenosing distal gastric cancer and even in this situation the use of expandable metal mesh stents can offer better palliation in a significant proportion. The median survival in patients with non-curable gastric cancer is 4–6 months and it is important that soon after the diagnosis is made a clear management plan is established with the palliative care team to maximise the quality of the patients remaining life.

Gastric lymphoma

Lymphoma of the stomach accounts for 2–5% of all gastric neoplasms. In general they are of B cell origin although T cell lymphomas do occur. The commonest gastric lymphoma arises from mucosa associated lymphoid tissue (MALT) rather than lymph nodes. The occurrence of MALT in the stomach is thought to be a response to chronic inflammation most frequently occurring as a result of H. pylori infection. There is no longer any doubt that H. pylori is a very important cause of gastric lymphoma. B cell lymphomas of the stomach can be classified as either low grade or high grade depending upon their histological characteristics.

Following diagnosis patients with gastric lymphoma should be appropriately staged with a combination of CT scan and endoscopic ultrasound. The treatment of low grade MALT lymphoma is eradication of Helicobacter infection if present. This results in tumour resolution in 70–100% of cases. Treatment of those patients who do not respond or those with highgrade tumours is with chemoradiotherapy. Surgery is generally reserved for the treatment of tumour or treatment related complications such as haemorrhage or bleeding.

Gastric GIST

Gastrointestinal stromal tumours were until the last decade described as leiomXyomas or leiomyosarcomas and it is only with advances in molecular biology that this particular tumour has been recognised as a discrete entity. GI stromal tumours can arise anywhere in the GI tract but the stomach is the commonest site. They are mesenchymal tumours believed to originate from the interstitial cells of Cajal. They generally present as elevated submucosal swellings that ulcerate or bleed; a number are discovered as incidental findings at endoscopy. GIST's behave in a somewhat unpredictable manner with many appearing to be completely benign and others as an aggressive malignancy. Increased risk of malignant behaviour is associated with increasing size and the number of mitoses seen within pathological specimens.

GIST tend to spread through local invasion and haematogenous spread, lymph node metastases are unusual. Once diagnosed and staged through a combination of CT scanning and if available endoscopic ultrasound treatment is surgical resection. There is no role for associated lymph node dissection.

At a molecular level GIST's are characterised by an abnormality of one of several transmembrane growth factor receptors, the commonest (85–90%) being the molecule c-kit (CD117). Recently it has been demonstrated that the c-kit antagonist imatinib can produce very significant tumour regression of advanced GIST's. There is no current data to support the use of imatinib in the adjuvant setting.
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