67 T_h e stomach and duodenum ANATOMY OF THE STOMACH AND DUODENUM Blood supply ANATOMY OF THE STOMACH AND DUODENUM Blood supply Arteries The stomach has an arterial supply on both the lesser and greater curves ( Figure 67.1 ). On the lesser curve, the left gastric artery , a branch of the coeliac axis, forms an anastomotic arcade with the right gastric artery , which arises from the common hepatic artery . Branches of the left gastric artery pass up towards the cardia. The gastroduodenal artery , also a branch of the hepatic artery , passes behind the first part of the duodenum, which is highly relevant with respect to a bleeding duodenal ulcer. Here it divides into the superior pancreaticoduodenal artery and the right gastroepiploic artery . The superior pancreaticoduodenal artery supplies the duodenum and pancreatic head and forms an anastomosis with the inferior pancreaticoduodenal artery , a branch of the superior mesenteric artery . The right gastroepip loic artery runs along the greater curvature of the stomach, eventually forming an anastomosis with the left gastroepiploic artery , a branch of the splenic artery . This vascular arcade, important during construction of a gastric conduit in oesoph ageal resection (see Chapter 66 ), is often variably incomplete. The fundus of the stomach is supplied by the vasa brevia (or short gastric arteries), which arise from near the termination of the splenic artery . Veins In general, the veins accompany the arteries; those along the lesser curve drain into the portal vein and those on the greater curve drain into the splenic vein. On the lesser curve, the coronary vein is particularly important. It runs along the lesser curve towards the oesophagus and then passes left to right to join the portal vein. This vein becomes markedly dilated in portal hypertension. To be able to: Decide on the most appropriate investigation of patients • with complaints relating to the stomach and duodenum Treat peptic ulcer disease and its complications • Recognise the presentation of gastric cancer and • understand the principles involved in treatment Aetiology Aetiology Gastric cancer is a multifactorial disease. Epidemiological studies point to a role for H. pylori ; however, there is insu ffi cient evidence to support eradication programmes in asymptomatic patients . H. pylori seems to be principally associated with carci noma of the body , stomach and distal stomach rather than the proximal stomach. Patients with pernicious anaemia and gastric atrophy are at increased risk, as are those with gastric adenomatous polyps. P atients who have had peptic ulcer surgery , particularly those w ho have had drainage procedures such as Billroth II or Pólya gastrectomy , gastroenterostomy or pyloroplasty , are at approximately four times the average risk; this is thought to be related to bile reflux and intestinal metaplasia. Carcinoma is associated with cigarette smoking and dust ingestion from a variety of industrial processes. Diet appears to be important, as illustrated by the example of the decline in the incidence of gastric cancer among Japanese families living in the USA. The high incidence of gastric cancer in some pockets in China is probably environmental and probably diet related. Excessive salt intake, deficiency of antioxidants and exposure to N -nitroso compounds are also related. The aetiology of proximal gastric cancer remains an enigma. It is not associated with H. pylori but is associated with obesity and higher socioeconomic status. Genetic factors are also important but not fully elucidated (see /uni00A0 The molecular pathology of gastric cancer ). Angiography Angiography Angiography is used most commonly in the investigation of upper gastrointestinal bleeding not identified using endoscopy . Giulio Bizzozero , 1846–1901, pathologist, University of Turin, Italy . John Robin Warren , b. 1937, pathologist, Royal Perth Hospital, WA, Australia. Barry Marshall , b. 1951, physician, University of Western Australia, WA, Australia. Robert Koch , 1843–1910, Professor of Hygiene and Bacteriology , Berlin, Germany , stated his ‘postulates’ in 1882 that define the conditions that must be met before an organism can be shown to be causative of a particular condition. Therapeutic embolisation may also be of value in the treat - ment of bleeding; in some centres, embolisation has replaced surgery in the majority of cases. (a) Aortic enteric fistula Aortic enteric fistula This diagnosis should be considered in any patient with haematemesis and melaena that cannot be otherwise explained. Contrary to expectation, the bleeding from such patients is not always massive. V ery often there is nothing much to distinguish between the bleeding from the aortic enteric fistula and any other recurrent upper gastrointestinal bleeding. The vast Robert William Sengstaken Sr , 1923–1978, surgeon, Garden City , New Y ork, NY , USA. Arthur Blakemore , 1897–1970, surgeon, The Columbia College of Physicians and Surgeons, New Y ork, NY , USA. - majority of patients will have had an aortic graft; however, it is occasionally seen in patients with an untreated aortic aneurysm. A CT scan with intravenous contrast will confirm the diagnosis. Treatment requires aortic aneurysm or aortic graft excision/replacement and carries a high mortality (see Chapter 61 ). Oesophageal aspiration channel Oesophageal balloon: 40 mmHg Gastric balloon: at least 300 mL of air Gastric aspiration channel Figure 67.24 Balloon tamponade of gastric and oesophageal varices with a Sengstaken–Blakemore tube. The balloons should be de /f_l ated every 12 hours to prevent pressure necrosis. Autoimmune gastritis Autoimmune gastritis This is an autoimmune condition in which there are circulating antibodies to parietal cells that results in atrophy of the parietal cell mass, hence hypochlorhydria and ultimately achlorhydria. As intrinsic factor is also produced by parietal cells there is malabsorption of vitamin B , which, if untreated, may result 12 in pernicious anaemia. The antrum is not a ff ected; thus, hypochlorhydria leads to production of high levels of gastrin from antral G cells, resulting in chronic hypergastrinaemia with consequent hypertrophy of ECL cells in the body of the stomach not a ff ected by autoimmune damage. Over time, microadenomas develop in the ECL cells, sometimes becoming identifiable tumour nodules that rarely can become malignant; endoscopic screening of such patients may be appropriate. Bleeding peptic ulcers Bleeding peptic ulcers The epidemiology of bleeding peptic ulcers mirrors that of perforated ulcers. In recent years, the population a ff ected has become older and bleeding is commonly associated with the ingestion of NSAIDs. Diagnosis can normally be made endoscopically , although occasionally the nature of the blood - loss precludes accurately identifying the lesion. However, the more experienced the endoscopist, the less likely this is to be a problem. Medical and minimally interventional treatments - Medical treatment has limited e ffi cacy . All patients are commonly started on either an H antagonist or a proton 2 pump inhibitor, and recent evidence confirms the benefit of PPI administration to prevent rebleeding after endoscopy . Meta-analysis of studies suggests that tranexamic acid, an inhibitor of fibrinolysis, may reduce overall mortality . Therapeutic endoscopy can achieve haemostasis in approx - imately 70% of cases, with the best evidence supporting a combination of adrenaline injection with heater probe and/or clips. Therapeutic endoscopy will probably never be e ff ective 80 Pulse >100 /uni00A0 bpm Systolic BP <100 /uni00A0 mmHg Circulatory failure/coronary Renal failure artery disease Liver failure Disseminated malignancy Blood/adherent clot/visible or spurting vessel gastrointestinal tract the majority of the mortality is associated. In patients where the source of bleeding cannot be identi fied or in those who rebleed after endoscopy , angiography with transcatheter embolisation may o ff er a valuable alternative to surgery in expert centres. The risk of significant ischaemia fol lowing embolisation is low because of the rich collateral blood supply of the stomach and duodenum. The surgeon should be mindful that rescue surgery after failed embolisation is associ ated with poor outcome and it may be advantageous to pro ceed directly to sur gery . Surgical treatment Patients who continue to bleed require surgery except in expert centres with experience of angiographic embolisation where attempts may be made to arrest bleeding and avoid surgery . The surgical team should be immediately available, and an operation should not be delayed if bleeding persists. Patients with a visible vessel in the ulcer base, a spurting vessel or an ulcer with a clot in the base are likely to require surgical treatment. Frail and elderly patients are more likely to die as a result of bleeding than younger patients; thus, paradoxically , they should have early surgery . In general, a patient who has required more than six units of blood needs surgical treatment. The aim of the operation is to stop the bleeding. Preop erative endoscopy can usually identify the site of bleeding, which is most often from a peptic ulcer in the duodenum. At operation it is important that the duodenum is fully mobilised before it is opened as it makes the ulcer much more accessible and also allows the surgeon’s hand to be placed behind the gastroduodenal artery , which is commonly the source of major bleeding. Following mobilisation, the duodenum, and usually the pylorus, is opened longitudinally as in a pyloroplasty . This allows good access to the ulcer, which is usually found posteri orly or superiorly . Accurate haemostasis is important and can be achieved initially by direct pressure. It is the vessel within the ulcer that is bleeding and this should be controlled using well-placed sutures on a small round-bodied needle that under- run the v essel. The pyloroplasty is then closed with interrupted sutures in a transverse direction in the usual fashion. In the case of a large ulcer, the first part of the duodenum may be destroyed, making primary closure impossible. In this circum stance one should proceed to distal gastrectomy with Roux en-Y reconstruction. The duodenal stump may then be closed with T-tube drainage or around a drain to create a controlled fistula. The management of bleeding gastric ulcers is essentially the same. The stomach is opened at an appropriate site ante rior ly and the vessel in the ulcer under-run. Consideration is then given to local excision of the ulcer. If the ulcer is not e xcised, the ulcer margins must be biopsied to exclude malig nancy . Gastrectomy for b leeding is associated with a high perioperative mortality , even if the incidence of recurrent bleeding is less. Bearing in mind that most patients nowadays are elder and unfit, the minimum surgery that stops the bleeding is prob ably optimal (damage control surgery). Acid can be inhibited Georges Dieulafoy , 1851–1919, physician and surgeon, Hôtel-Dieu de Paris, Paris, France, later President of the French Academy of Medicine (1910). ap y will prevent ulcer recurrence. Definite acid-lowering sur - - gery is not now required. Patients on long-term NSAIDs can be managed as outlined in Treatment of peptic ulceration . - Chief cells Chief cells These lie proximally in the gastric crypts and produce pepsino gen. Two forms of pepsinogen are described: pepsinogen I and pepsinogen II. The ratio between pepsinogens I and II in the serum decreases with gastric atrophy . Pepsinogen is activated in the stomach to produce the digestiv e protease pepsin. Clinical examination Clinical examination Examination of the patient may reveal epigastric tenderness but, except in gastric outlet obstruction, there is unlikely to be much else to find (see Chapter 63 ). Clinical features of peptic ulcers Clinical features of peptic ulcers The clinical features of gastric and duodenal ulceration cannot be di ff erentiated on the basis of symptoms. The demographic characteristics of groups of patients with gastric and duodenal ulceration do di ff er but this does not allow discrimination. Pain Epigastric pain, often described as gnawing and sometimes radiating to the back, is characteristic. Eating may sometimes relieve the discomfort. The pain is normally intermittent rather than intractable. Symptoms may disappear for weeks or months only to return again. This periodicity may be related to the spontaneous healing of the ulcer. Vomiting While this occurs, it is not a notable feature unless stenosis has occurred. Alteration in weight Weight loss or, sometimes, weight gain may occur. Patients with gastric ulceration are often underweight but this may precede occurrence of the ulcer. Bleeding Bleeding may be chronic and presentation with microcytic anaemia is not uncommon. All such patients should be investigated with endoscopy . Acute presentation with Christian Albert Theodor Billroth , 1829–1894, Professor of Surgery , Vienna, Austria. and melaena . Clinical features Clinical features In benign gastric outlet obstruction, there is usually a long history of peptic ulcer disease. The vomitus is characteristically of undigested food and is totally lacking in bile. Weight loss is a feature, and the patient appears unwell and dehydrated. On examination the distended stomach may be visible and a succussion splash may be audible. Gastric outlet obstruction /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF Gastric outlet obstruction is most commonly associated with longstanding peptic ulcer disease and gastric cancer The metabolic abnormality of hypochloraemic alkalosis is usually only seen with peptic ulcer disease and should be treated with isotonic saline with potassium Endoscopic biopsy is essential to exclude malignancy Aggressive medical therapy for peptic ulcer disease often leads to resolution Endoscopic dilatation of the gastric outlet may be effective in benign stenosis Operation is frequently required, with a drainage procedure being performed for benign disease or appropriate resection of malignancy Clinical features The features of advanced gastric cancer are usually obvious. Unfortunately , early gastric cancer has no specific features to distinguish it from benign dyspepsia and a high index of suspicion is necessary . In advanced cancer, early satiety , bloating, distension and vomiting may occur. The tumour frequently bleeds, resulting in iron deficiency anaemia. Obstruction leads to dysphagia, epigastric fullness or vomiting. Weight loss can be profound. W ith pyloric involvement the presentation may be of gastric Armand Trousseau , 1801–1867, physician, Hôtel-Dieu de Paris, Paris, France. The sign led him to suspect that he personally had gastric cancer, however it proved to be pancreatic cancer on post-mortem. Pekka August Laurén , 1922–2016, pathologist, University of Turku, Finland. Robert Borrmann , 1870–1943, pathologist, Bremen, Germany . - nounced than when duodenal ulceration leads to obstruction. Non-metastatic e ff ects of malignancy are seen, particularly thrombophlebitis (Trousseau’s sign) and deep venous throm - bosis. These features result fr om the e ff ects of the tumour on thrombotic and haemostatic mechanisms. Complications of peptic ulceration Complications of peptic ulceration The common complications of peptic ulcer are perforation, bleeding and stenosis. Bleeding and stenosis are considered below in the relevant sections. y Perforated peptic ulcer Epidemiology Despite the widespread use of gastric antisecretory agents and eradication therapy , the incidence of perforated peptic ulcer has changed little. However, there has been a steady increase in the age of the patients with this complication and an increase in the numbers of females, such that perforations now occur most commonly in elderly female patients. NSAIDs appear to be responsible for most of these perforations. Clinical features The classical presentation of perforated duodenal ulcer is instantly recognisable ( Figure 67.21 ). The patient, who may have a history of peptic ulceration, develops sudden-onset severe generalised abdominal pain due to the irritant e ff ect of gastric acid on the peritoneum. Although the contents of an acid-producing stomach are relatively low in bacterial load, bacterial peritonitis supervenes over a few hours, usually accompanied by a deterioration in the patient’s condition. Initially , the patient may be shocked with a tachycardia, but a pyrexia is not usually observed until some hours after the event. The abdomen exhibits a board-like rigidity , and the patient is disinclined to move because of the pain. The abdomen does not move with respiration. Patients with this form of presentation need an operation, without which the patient will deteriorate with a septic peritonitis. is observed less commonly than in the past. V ery frequently the elderly patient will have a less dramatic presentation, per haps because of the use of potent anti-inflammatory drugs (steroids). The board-like rigidity seen in the abdomen of younger patients may also not be observed and a higher index of suspicion is necessary to make the correct diagnosis. In other patients, the leak from the ulcer may be contained such that they present with pain in the epigastrium and right iliac fossa as the fluid may track down the right paracolic gutter. Sometimes perforations will seal owing to the inflammatory response and adhesion within the abdominal cavity , and so the perforation may be self-limiting. All of these factors may combine to make the diagnosis of perforated peptic ulcer di ffi cult. Investigations An erect chest radiograph will reveal free gas under the diaphragm in more than 50% of cases with perforated peptic ulcer ( Figure 67.22 ), but CT imaging is now most commonly used and is more accurate. All patients should have serum amylase performed, as distinguishing between peptic ulcer, perforation and pancreatitis can be di ffi cult. Measuring the serum amylase, however, may not remove the diagnostic di ffi culty . It can be elevated following perforation of a peptic ulcer, although, fortunately , the levels are not usually as high as the levels commonly seen in acute pancreatitis. A CT scan will normally be diagnostic in both conditions. Treatment The initial priorities are resuscitation and analgesia. Analgesia should not be withheld for fear of removing the signs of an intra-abdominal catastrophe. In fact, adequate analgesia makes the clinical signs more obvious. It is important, however, to titrate the analgesic dose. Following resuscitation, the treatment is principally surgical. Laparotomy is performed, usually through an upper midline incision if the diagnosis George Kenneth Mallory , 1900–1986, Professor of Pathology , Boston, MA, USA. Soma Weiss , 1899–1942, Professor of Medicine, Boston, MA, USA. Alternatively , laparoscopy may be used. The most important component of the operation is a thorough peritoneal toilet to - remove all of the fluid and food debris. If the perforation is in the duodenum, it can usually be closed by several well-placed sutures, closing the ulcer in a transverse direction as with a pyloroplasty . It is important that su ffi cient tissue is taken in the suture to allow the edges to be approximated, and the sutures should not be tied so tight that they tear out. It is common to place an omental patch over the perforation in the hope of enhancing the chances of the leak sealing. If the perforation is di ffi cult to close primarily it is frequently possible to seal the leak with an omental patch alone, and many surgeons now employ this strategy for all perforations. When securing the omental patch, it is important not to tie the sutures too tight so as to obliterate the omental blood supply . Gastric ulcers should, if possible, be excised and closed, so that malignancy can be excluded. Occasionally a patient is astric perforation such seen who has a massive duodenal or g that simple closure is impossible; in these patients a distal gas - trectomy with Roux-en-Y reconstruction is the procedure of choice ( Figure 67.20 ). Perforated peptic ulcers can often be managed by mini - if the expertise is available. The prin - mally invasive techniques ciples of operation are the same: thorough peritoneal toilet and closure of the perforation by intracorporeal suturing. Following operation, it is important that the stomach is kept astric suction, and that gastric empty postoperatively by nasog antisecretory agents are commenced to promote healing in the H. pylori eradication is mandatory . residual ulcer. A minority of patients who have small leaks from a perfo - rated peptic ulcer and relatively mild peritoneal contamination may be managed with intravenous fluids, nasogastric suction and antibiotics. Any deterioration should prompt immediate surgical interv ention. Patients who have had one perforation may have another. Therefore, they should be managed aggressively to ensure that this does not happen. Lifelong treatment with PPIs is a rea - sonable option, especially in those w ho have to continue with NSAID treatment. Figure 67.22 Erect chest radiograph showing air under the right diaphragm in a patient with a perforated duodenal ulcer. Computed tomography positron emission tomography Computed tomography/positron emission tomography Positron emission tomography (PET) is increasingly being used in the preoperative staging of gastro-oesophageal cancer as it will detect otherwise occult tumour spread in up to 10% of patients who might otherwise have undergone a major surgical resection ( Figure 67.7 ). PET/CT may also be used to determine the response to neoadjuvant chemotherapy in oesophagogastric malignancies, although this is the subject of ongoing studies (see Chapter 8 ). Computed tomography scanning and magnetic resonanc Computed tomography scanning and magnetic resonance imaging CT is increasingly used in the investigation of the stomach, especially in the context of gastric malignancies. Although it is much less accurate in ‘T’ staging than endoluminal can be easily detected and is reasonably accurate in detecting nodal involvement with tumour. However it is important to understand that microscopic tumour deposits in lymph nodes cannot be detected and lymph nodes may undergo reactive enlargement but not contain tumour. Hepatic metastases from gastric cancer may be di ffi cult to identify as they are often of the same density as liver and may not handle the intravenous contrast di ff erently . At present, magnetic resonance imaging (MRI) scanning does not o ff er an y specific advantage in assessing the stomach, although it has a higher sensitivity for the detection of gastric cancer liver metastases than conventional CT imaging. Contrast radiology Contrast radiology Upper gastrointestinal radiology is not used as much as in previous years, as endoscopy is a more sensitive investigation. Computed tomography (CT) imaging with oral contrast has replaced contrast radiology in many of the areas where anatomical information is sought, e.g. large hiatus hernias of the rolling type and chronic gastric volvulus. In these conditions it may be di ffi cult for the endoscopist to determine exactly the anatomy or, indeed, negotiate the deformity to see the distal stomach (see Chapter 66 ). DUODENAL OBSTRUCTION DUODENAL OBSTRUCTION Duodenal obstruction in adults is usually due to malignancy , and cancer of the pancreas is the most common cause. Treat ment is usually by gastroenterostomy , but duodenal stenting is increasingly being used. In patients having a surgical biliary bypass for pancreatic cancer, g astric drainage may be necessary . A variety of other malignancies can cause duodenal obstruction, including metastases from colorectal and gastric cancer. Primary duodenal cancer is much less common as a cause of obstruction than these other malignancies. Annular pancreas may rarely cause duodenal obstruction. Obstruction usually follows an attack of pancr eatitis, and, on occasions, the obstruction may be mistaken for malignancy . Arteriomesenteric compression is an ill-defined condition in which it is proposed that the fourth part of the duodenum is compressed between the superior mesenteric artery and the vertebral column; when it is convincingly demonstrated and causing weight loss , duodenojejunostomy may be performed. DUODENAL TUMOURS Benign duodenal tumours DUODENAL TUMOURS Benign duodenal tumours Duodenal villous adenomas occur principally in the periamp ullary region. Although generally uncommon, they are often found in patients with FAP . The appearances are similar to those adenomas arising in the colon and, as they hav e malig nant potential, they should be locally excised with histologically clear margins. Dieulafoy lesion Dieulafoy lesion This is essentially a gastric arterial venous malformation that has a characteristic histological appearance. Bleeding due to - this malformation is one of the most di ffi cult causes of upper - gastrointestinal bleeding to treat. The lesion itself is covered by normal mucosa and, when not bleeding, it may be invisible. If it can be seen while bleeding, all that may be visible is profuse bleeding coming from an area of apparently normal mucosa. If this occurs, the cause is instantly recognisable. If the lesion - can be identified endoscopically ( Figure 67.23 ) bleeding can be stopped by injection of sclerosant or application of endo - scopic clips. If it is identified at operation, only local excision - is necessary . Duodenal adenocarcinoma Duodenal adenocarcinoma Most duodenal tumours originate in the periampullary region and commonly arise in pre-existing villous adenomas. Patients present with anaemia due to ulceration of the tumour or obstruction. Direct involvement in the ampulla leads to obstruc tive jaundice. Histologically , the lesion is an adenocarcinoma. Metastases are commonly to regional lymph nodes and the liver. At presentation, about 70% of patients have resectable Abraham Vater , 1684–1751, Professor of Anatomy and Biology , Wittenberg, Germany . Allen Oldfather Whipple , 1881–1963, surgeon, Columbia-Presbyterian Medical Center, New Y ork, NY , USA. Duodenal tumours - /uni25CF /uni25CF /uni25CF /uni25CF disease with an expected 5-year survival rate of approximately 20%. Poor prognostic features include regional lymph node - metastases, transmural involvement and perineural invasion. Curative surgical treatment will normally involve a pancreati - coduodenectomy (Whipple’s procedure). Patients with FAP , which is due to a mutation in the APC gene on chromosome 5, - are predisposed to periampullary cancer, which is one of the - most common causes of death in patients who have had their colon removed. Other duodenal malignancies include GISTs (see Gastrointestinal stromal tumours ) and neuroendo - crine tumours. - Duodenal villous adenomas are commonly found around the ampulla of Vater and are premalignant The duodenum is the most common site for adenocarcinoma of the small intestine Regular endoscopic screening is advisable in patients with FAP Pancreatic cancer is the most common cause of duodenal obstruction Duodenal ulceration Duodenal ulceration Incidence There have been marked changes in the demography of patients presenting with duodenal ulceration in the West. In part, this may relate to the widespread use of gastric antisecretory agents and H. pylori eradication therapy in patients with dyspepsia. Second, the peak incidence is now in a much older age group and, although still more common in men, gender di ff erence is less marked. These changes mirror the changes, at least in part, in the epidemiology of H. pylori infection. In eastern Europe, - the disease remains common, and the incidence is rising in resource-poor nations. Pathology Most ulcers occur in the first part of the duodenum ( Figures 67.10 and 67.11 ). A chronic ulcer penetrates the mucosa into - the muscle coat, leading to fibrosis. The resulting scarring may cause a deformity such as pyloric stenosis. When an ulcer heals, a residual scar can be observed in the mucosa. Sometimes there may be more than one duodenal ulcer. The situation in which - there is both a posterior and an anterior duodenal ulcer is referred to as ‘kissing ulcers’. Anterior ulcers tend to perforate Figure 67.10 Duodenal ulcer at gastroduodenoscopy (courtesy of Dr GNJ Tytgat, Amsterdam, The Netherlands). while posterior duodenal ulcers tend to bleed, sometimes by eroding into the gastroduodenal artery . Occasionally , the ulceration may be so extensive that the entire duodenal cap is ulcerated and devoid of mucosa. With respect to the giant duodenal ulcer, malignancy in this region is so uncommon that under normal circumstances surgeons can be confident that they are dealing with benign disease, even though from external palpation it may not appear so. In the stomach the situation is di ff erent. Figure 67.11 Duodenal ulcer shown by barium meal. Duodenum Duodenum The duodenum is lined by a mucus-secreting columnar epithe lium. In addition, Brunner’s glands lie beneath the mucosa and are similar to the pyloric glands in the pyloric part of the stom ach. Endocrine cells in the duodenum produce cholecystokinin and secretin. Endocrine cells Endocrine cells The stomach has numerous endocrine cells that are critical to its function. In the gastric antrum, the mucosa contains G cells, which produce gastrin. Throughout the body of the stomach, enterochroma ffi n-like (ECL) cells are abundant and produce histamine, a key factor in driving gastric acid secretion. In addition, there are large numbers of somatostatin-producing D cells throughout the stomach. Somatostatin has a negative regulatory role. The peptides and neuropeptides produced in the stomach are discussed in Gastric acid secretion . Erosive gastritis Erosive gastritis This is caused by agents that disturb the gastric mucosal barrier; NSAIDs and alcohol are common causes. The NSAID-induced gastric lesion is associated with inhibition of cyclo-oxygenase type 1 (COX-1) receptor enzyme, reducing production of cytoprotective prostaglandins. Many of the anti-inflammatory activities of NSAIDs are mediated by COX-2 and use of specific COX-2 inhibitors reduces the incidence of gastritis. FURTHER READING FURTHER READING Al-Batran S-E, Homann N, Schmalenberg H et al . Perioperative che - motherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecit - abine (ECF/ECX) for resectable gastric or gastroesophageal junc - tion (GEJ) adenocarcinoma (FLO T4-AIO): a multicenter, random - ized phase 3 trial. J Clin Oncol 2017; 35 (15 suppl): 4004. Cristescu R, Lee J, Nebozhyn M et al . Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med 2015; 21 (5): 449–56. Lee SS, Chung HY , Kwon OK, Y u W . Long-term quality of life after distal subtotal and total gastrectomy: symptom- and behaviour - oriented consequences. Ann Surg 2016; 263 (4): 738–44. Smyth EC, Nilsson M, Grabsch HI et al . Gastric cancer. Lancet 2020; 396 (10251): 635–48. Wilson MS, Blencowe NS, Boyle C et al. ; AUGIS. A modified Delphi process to establish future research priorities in malignant oesoph - agogastric surgery . Surgeon 2020; 18 (6): 321–6. Flexible endoscopy Flexible endoscopy Flexible endoscopy is more sensitive than conventional radiology in the assessment of the majority of gastroduodenal conditions, particularly peptic ulceration, gastritis and duodenitis. In upper gastrointestinal bleeding, endoscopy is far superior to any other investigation and o ff ers the possibility of endoscopic therapy . In most circumstances it is the only investigation required. It is generally a safe investigation, but it is important that all personnel undertaking these procedures are adequately trained. Careless and rough handling of the endoscope during intubation of a patient may result in perforations of the phar ynx and oesophagus. Any other part of the upper gastrointes tinal tract may also be perforated. An inadequately performed endoscopy is also dangerous as a serious condition may be curable gastric cancer, the appearances of which ma y often be extremely subtle and may be missed by inexperienced endos - copists. Spraying the mucosa with dy e endoscopically may allow better discrimination between normal and abnormal mucosa, so allowing a small cancer to be more easily seen. In the future, advances in technology may allow ‘optical biopsy’ to determine the natur e of mucosal abnormalities in real time (see Chapter 9 ). Summary box 67.2 Investigation of gastroduodenal symptoms /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF Upper gastrointestinal endoscopy can be performed with - out sedation, but when sedation is required incremental doses of a benzodiazepine are usually administered. Sedation is of particular concern in the case of gastrointestinal bleeding as it may have a more pr ofound e ff ect on the patient’s car - diovascular stability . It has now become the standard to use pulse oximetry to monitor patients during upper gastrointes - tinal endoscopy , and nasal oxygen is often also administered. Hyoscine butylbromide (Buscopan) is useful to abolish duode - nal motility for examina tions of the second and third parts of the duodenum. Examinations of this type are best carried out using a side-viewing endoscope such as is used for endoscopic retr ograde cholangiopancreatography . Some patients ar e relatively resistant to sedation with ben - zodiazepines, particularly those who are accustomed to drink - ing alcohol. Increasing the dose of benzodiazepines in these patients may not result in any useful sedation, but merely make the patient more restless and confused. Such patients are better endoscoped fully awake using a local anaesthetic throat spray and a narrow-gauge endoscope. Whatever the circumstances, it is important that resuscitation facilities are available includ - ing agents that reverse the e ff ects of benzodiazepines, such as flumazenil. The technology associated with upper gastrointestinal endoscopy is continuing to advance. Instruments that allow both endoscopy and endoluminal ultrasonography to be perfor med simultaneously (see Ultrasonography ) are used routinely . Bleeding from the stomach and duodenum can be - treated using a number of haemostatic measures, including - injection with adrenaline (epinephrine), diathermy , heater probes, lasers and clip application. neuropeptides in the stomach. Function Source Stimulate secretion Gastrin G cells Histamine ECL cells Acetylcholine Neurones Neurones and mucosa Gastrin- releasing peptide CCK Duodenal endocrine cells Inhibit secretion Somatostatin D cells and neurones Secretin Duodenal endocrine cells Enteroglucagon Small intestinal endocrine cells Prostaglandins Mucosa Neurotensin Neurones GIP Duodenal and jejunal endocrine cells PYY Small intestinal endocrine cells Stimulate motility Acetylcholine Neurones 5-HT Neurones Histamine ECL cell Substance P Neurones Substance K Neurones Motilin Neurones Gastrin G cells Angiotensin Inhibit motility Somatostatin D cells and neurones VIP Neurones Nitric oxide Neurones and smooth muscle Noradrenaline Neurones (norepinephrine) Encephalin Neurones Dopamine Neurones CCK, cholecystokinin; ECL, enterochromaf /f_i n-like cells; G, gastrin receptor; GIP , gastric inhibitory polypeptide; 5-HT, 5-hydroxytrypt amine; PYY , peptide YY; VIP , vasoactive intestinal peptide. Flexible endoscopy is the most commonly used and sensitive technique Great care is needed to avoid complications and missing important pathology Axial imaging, particularly multislice computed tomography (CT), is useful in staging gastric cancer Endoscopic ultrasonography is the most sensitive technique for evaluation of the ‘T’ stage of gastric cancer and assessment of duodenal tumours Laparoscopy is very sensitive in detecting peritoneal metastases, and laparoscopic ultrasound provides an accurate evaluation of lymph node and liver metastases Figure 67.5 Endoscopic ultrasonography of the stomach. Five layers can be identi /f_i ed in the normal stomach. A gastric cancer is shown invading the muscle of the gastric wall (courtesy of KeyMed (Medical and Industrial Equipment Ltd)). Foreign bodies in the stomach Foreign bodies in the stomach A variety of ingested foreign bodies reach the stomach, and very often these can be seen on a plain radiograph. If possible, they should be removed endoscopically but, if not, most can be left to pass normally . Even objects such as needles, with which there is understandable anxiety , will seldom cause harm. In general, an object that leaves the stomach will pass spontaneously . In contrast, attempted removal at laparotomy can be very di ffi cult as the object may be much more di ffi cult to find than might be expected. Most adults who swallow foreign bodies have psychiatric problems and may appear to relish the attention associated with serial laparotomies. The treatment should therefore be expectant, and intervention reserved for - patients with symptoms in whom the foreign body is failing to progress. GASTRIC CANCER GASTRIC CANCER Carcinoma of the stomach is a major cause of mortality world - wide. Its prognosis tends to be poor, with cure rates little better than 5–10%, although better results are obtained in Japan, where the disease is common. Gastric cancer is actually an eminently curable disease and early diagnosis is key to success. Unfortunately , la te presentation is common and the cause of poor overall survival figures. The only curative treatment is resectional surgery . Summary box 67.6 Gastric cancer /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF y Gastric cancer is one of the most common causes of cancer death The outlook is generally poor, owing to the advanced stage at presentation Better results are obtained in Japan, which has a high population incidence, screening programmes and high-quality surgical treatment The aetiology of gastric cancer is multifactorial H. pylori is important in distal but not proximal gastric cancer Early gastric cancer is associated with high cure rates Gastric cancer can be classi /f_i ed into intestinal and diffuse types, the latter having a worse prognosis Spread may be by lymphatics, blood, transcoelomic or direct Distant metastases are uncommon in the absence of lymph node involvement Radical surgery and removal of second tier of nodes (around the principal arterial trunks) may be advantageous Chemotherapy improves survival in patients having surgery and in advanced disease GASTRIC OUTLET OBSTRUCTION GASTRIC OUTLET OBSTRUCTION The two common causes of gastric outlet obstruction are gastric cancer (see Gastric cancer ) and pyloric stenosis secondary to peptic ulceration. With the decreasing incidence of peptic ulceration gastric outlet obstruction should be considered malignant until proven otherwise. In this circum - stance the metabolic consequences may be somewhat di ff erent from those of benign pyloric stenosis because of the relative hypochlorhydria found in patients with gastric cancer. GASTRITIS GASTRITIS The great variety of names and classification systems used in gastritis is confusing. Thankfully , the understanding of gastritis has increased markedly following elucidation of the role of gastritis should be classified according to the underlying aeti ology . Gastritis describes any histologically confirmed inflam mation of the gastric mucosa. In most modern classification systems, the amount of inflammatory infiltrate and the degree of gastric atrophy will be included. Summary box 67.3 Helicobacter and gastritis /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF Helicobacter pylori is critical in the development of gastritis, peptic ulceration and gastric cancer Infection appears to be acquired mainly in childhood and the infection rate is inversely associated with socioeconomic status Eradication, recommended speci /f_i cally in patients with peptic ulcer disease, can be achieved in up to 90% of patients with a combination of a PPI and antibiotics, and reinfection is uncommon (<0.5%) Erosive gastritis is usually related to the use of NSAIDs Autoimmune gastritis is associated with development of pernicious anaemia and gastric cancer GASTROINTESTINAL STROMAL TUMOURS GASTROINTESTINAL STROMAL TUMOURS Gastrointestinal stromal tumours (GISTs) may arise in any part of the gastrointestinal tract but 50% will be found in the stomach. Previously named leiomyoma and leiomyosarcoma, the term GIST is now used, recognising the distinct phenotype. They are tumours of mesenchymal origin and are observed equally commonly in males and females. The tumours are universally associated with a mutation in the tyrosine kinase c-kit oncogene. These tumours are sensitive to the tyrosine kinase antagonist imatinib, and an 80% objective response rate can be observed. Tumours with mutations in exon 11 of are particularly sensitive to this drug. The biological behaviour of these tumours is unpredictable but size and mitotic index are the best predictors of metastasis. Peritoneal and liver metastases are most common but spread to lymph nodes is extremely rare. The incidence of the condition is uncertain as small stro mal tumours of the stomach are probably quite common and remain unnoticed. Clinically obvious tumours are consider ably less common than gastric cancer. GISTs constitute 1–3% of all g astrointestinal neoplasia. Many GISTs are noticed incidentally at endoscopy or diagnosed if the overlying mucosa ulcerates with bleeding and anaemia ( Figur e 67.32 ). Because the mucosa ov erlying the tumour is normal, endoscopic biopsy can be uninformative unless the tumour has ulcerated. Targeted biopsy by endoscopic ultrasonography is more helpful. Larger tumours present with non-specific gastric symptoms, and, in many instances, they may be thought to be gastric cancer initially ( Figure 67.33 As the biological behaviour is di ffi cult to predict, the best guide is to consider the size of the tumour. Tumours over 5 /uni00A0 cm in diameter should be considered to have metasta tic potential. If easily resectable surgery is the primary mode of treatment. Smaller tumours can be treated by wedge excision although the appropriate management of asymptomatic diminutive tumours found incidentally at endoscopy is unclear. Larger - - c-kit - - tumours may require a gastrectomy or duodenectomy , but lymphadenectomy is not required. Larger tumours that require ). multivisceral resection may be better treated with 3–6 months of imatinib prior to operation as this will usually radically reduce the size and vascularity of the tumours. Adjuvant ima - tinib for resected tumours of high malignant potential should probably be continued indefinitely . The prognosis of advanced metastatic GISTs has been dra - y but resection matically improved with imatinib chemotherap of metastases has an important role. Figure 67.32 Gastrointestinal stomal tumour (GIST) on the greater curve of the stomach with ulceration. Figure 67.33 Computed tomography scan of the upper abdomen showing a 3.5-cm gastrointestinal stromal tumour arising from the gastric wall. Unlike gastric carcinoma, the incidence of lymphoma seems to be increasing. It is most common in the sixth decade and presen tation is similar to that of gastric cancer. Acute presentation with haematemesis, perforation or obstruction is uncommon. Primary gastric lymphoma accounts for approximately 5% of all gastric neoplasms. It is important to distinguish primary gastric lymphoma from the more common in volvement of the stomach in a di ff use lymphoma. Primary gastric lymphomas are B-cell derived, the tumour arising from mucosa-associated lymphoid tissue (MALT). Primary gastric lymphoma remains in the stomach for a prolonged period before involving lymph nodes. At an early stage , the disease takes the form of a di ff use mucosal thicken ing, which may ulcerate. Diagnosis is made as a result of the endoscopic biopsy and seldom on the basis of the endoscopic features alone, which are not specific. Follo wing diagnosis, adequate staging is necessary , primar ily to establish whether the lesion is a primary gastric lym phoma or part of a more generalised process. CT scans of the chest and abdomen and bone marrow aspirate are required. Although the treatment of primary gastric lymphoma is somewhat contro versial, it seems most appropriate to use sur gery alone for localised disease. Chemotherapy is appropriate for patients with systemic disease . Lymphocytes are not found to any degree in normal gastric mucosa but are found in associ ation with Helicobacter infection. Early gastric lymphomas may regress and disappear when the Helicobacter infection is treated. Patients with gastric involvement of a di ff use lymphoma are treated with chemotherapy , sometimes with dramatic and rapid responses. The two common surgical complications are bleeding and perforation. Both may follow the chemotherapy when there is rapid regression and necrosis of the tumour and normally require gastrectomy . Gastric acid secretion Gastric acid secretion Secretion of gastric acid and pepsin tends to run in parallel, although the understanding of the mechanisms of gastric acid secretion is considerably greater than that of pepsin. Numerous factors are involved to some degree in the production of the gastric acid. These include neurotransmitters, neuropeptides and peptide hormones. This complexity need not detract from the fact that there are basic principles that are relatively easily understood ( Figure 67.4 ). Hydrogen ions are produced in the parietal cell by the proton pump. Although numerous factors can act on the parietal cell, the most important of these is hista - mine, which acts via the H -receptor. Histamine is produced, in 2 turn, by the ECL cells of the stomach and acts in a paracrine (local) fashion on the parietal cells. These relationships explain why PPIs can abolish gastric acid secretion, as they act on the final common pathway – hydrogen ion secretion. H -receptor 2 - antagonists have profound e ff ects on gastric acid secretion, but this is not insurmountable. The ECL cell produces histamine - - - Distension of stomach M 1 Chemical in food Release of acetylcholine HCI Gastric ECL cell G cell Release of Release of gastrin histamine M 3 G H 2 Figure 67.4 The parietal cell in relation to the mechanism of gastric acid secretion. ECL, enterochromaf /f_i n-like; G, gastrin receptor; H, histamine receptor; HCl, hydrochloric acid; M, muscarinic receptor. nerve and gastrin. Gastrin is released by the G cells in response to the presence of food in the stomach. The production of gastrin is inhibited by acid, creating a negative feedback loop. Various other peptides, including secretin, inhibit gastric acid secretion. Classically , three phases of gastric secretion are described. The cephalic phase is mediated by vagal activity , secondary to sensory arousal as first demonstrated by Pavlov . The tric phase is a response to food within the stomach, which is mediated principally , but not exclusively , by gastrin. In the intestinal phase , the presence of chyme in the duodenum and small bowel inhibits gastric emptying, and acidification of the duodenum leads to the production of secretin, which inhibits gastric acid secretion, along with numerous other peptides originating from the gut. The stomach also possesses somatostatin-containing D cells. Somatostatin is released in response to a number of factors, including acidification. This peptide acts probably on the G cell, the ECL cell and the pari etal cell itself to inhibit the production of acid. Gastric emptying studies Gastric emptying studies These are useful in the study of gastric dysmotility problems, particularly those that follow gastric surgery . The principle is that a radioisotope-labelled liquid and solid meal is ingested by the patient and emptying of the stomach is followed on a gamma camera. This allows the proportion of activity in the remaining stomach to be assessed. It is possible to follow liquid and solid gastric emptying independently ( Figure 67.8 ). Gastric erosions Gastric erosions Erosive gastritis has a variety of causes, especially NSAIDs. Fortunately , most such bleeding settles spontaneously , but it can be a major problem to treat. In general terms, although there is a di ff use erosive gastritis, there is one (or more) specific lesion that has a significant-sized vessel within it. This should be dealt with appropriately , preferably endoscopically , but sometimes - surgery is necessary . Gastric mucus and the gastric mucosal barrier Gastric mucus and the gastric mucosal barrier The gastric mucous layer is essential to the integrity of the gastric mucosa. It is a viscid layer of mucopolysaccharides produced by the mucus-producing cells of the stomach and the pyloric glands. Gastric mucus is an important physiolog ical barrier that protects the gastric mucosa from mechan ical damage and also the e ff ects of acid and pepsin. It has considerable bu ff ering capacity , enhanced by the presence of bicarbonate ions within the mucus. Many factors can lead to the breakdown of this gastric mucous barrier . These include bile, non-steroidal anti-inflammatory drugs (NSAIDs), alcohol, trauma and shock. Tonometry studies have shown that, of the entire gastrointestinal tract, the stomach is the most sensitive to ischaemia following a hypovolaemic insult and also the slowest to recover. This may explain the high incidence of stress ulcer ation in the stomach. Gastric ulcers Incidence Gastric ulcers Incidence As with duodenal ulceration, H. pylori and NSAIDs are the important aetiological factors. Gastric ulceration is also asso ciated with smoking. Gastric ulceration is much less common than duodenal ulceration. The gender incidence is equal and patients with gastric ulcers tend to be older. Gastric ulceration is more prevalent in low socioeconomic groups and is consid e common in resource-poor than in resource-rich erably mor countries. Gastroduodenal motor activity Gastroduodenal motor activity The motility of the gastrointestinal tract is modulated by its intrinsic nervous system. Critical in this process is the migrat - - ing motor complex (MMC). In the fasting state, and after food has cleared, there is a period of quiescence in the small bowel lasting in the region of 40 minutes (phase I). There follows a series of waves of electrical and motor activity , also lasting about 40 min utes, propagated from the fundus of the stomach in a caudal direction at a rate of about three per minute (phase II). These pass as far the pylorus, but not beyond. Duodenal slow waves are generated in the duodenum at a rate of about 10 per minute, which potentiate into the small bowel. The - amplitude of these contractions increases to a maximum in - phase III, which lasts for about 10 minutes. This 90-minute cycle of activity is then repeated. From the duodenum, the MMC moves distally at 5–10 /uni00A0 cm/min, reaching the terminal ileum after 1.5 hours. Following a meal, the stomach exhibits receptive relax - ation, which allows the proximal stomach to act as a reservoir. Most of the peristaltic activity is found in the distal stomach (the antral mill) and the proximal stomach demonstrates only tonic activity . The pylorus, which is most commonly open, con - - tracts with the peristaltic wav e and allows only a few millilitres of chyme to pass into the duodenum at a time. The antral con - traction against the closed pylorus is important in the milling activity of the stomach. Although the duodenum is capable of generating 10 waves per minute, after a meal it only con - tacts after an antral wave reaches the pylorus. Coordination of the motility of the antrum, pylorus and duodenum means that only small quantities of food reach the small bowel at a - time. This control of gastric emptying can be abolished after g astric surgery , leading to significant symptoms (discussed in Sequelae of peptic ulcer surgery ). - HAEMATEMESIS AND MELAENA HAEMATEMESIS AND MELAENA Upper gastrointestinal haemorrhage remains a major medi - cal problem with an incidence of over 100/100 000 per year in Western practice. The incidence increases with age. Haemorrhage is strongly associated with NSAID use. Despite improvements in diagnosis and the proliferation in tr eatment modalities over the last few decades, an in-hospital mortality of 5–10% can be expected. This rises to 33% when bleeding is first observed in patients who are hospitalised for other reasons. In patients in whom the cause of bleeding can be found, the most common causes are peptic ulcer, erosions, Mallory–Weiss tear and bleeding oesophageal varices ( Table 67.4 ). Whatever the cause, the principles of management are identical. First, the patient should be adequately resuscitated and, following this, should be investigated urgently to deter mine the cause of the bleeding. Intravenous access should be established and, for those with severe bleeding, central venous pressure monitoring should be established and bladder catheterisation performed. Blood should be cross-matched and the patient transfused as clinically indicated, usually when >30% of blood volume has been lost (see Chapter 2 ). There is no evidence for the use of intravenous PPI prior to endos copy . As a general rule, most gastrointestinal bleeding will stop, albeit temporarily , but there are sometimes instances when this is not the case. In these circumstances, resuscita tion, diagnosis and treatment should be carried out simultaneously . There are occasions when life-saving manoeuvres have to be undertaken without the benefit of an absolute diagnosis. In some patients, bleeding is secondary to a coagulopathy . The most important current causes are liver disease and anticoagulation therapy . In /uni00A0 these circumstances the coagulopathy should be corrected, Timothy Alexander Rockall , contemporary , Royal Surrey County Hospital, Guilford, Surrey , UK. factors with haematology advice. Upper gastrointestinal endoscopy should be carried out by an experienced operator as soon as practicable after the patient has been stabilised. In patients in whom the bleeding is r ela - tively mild, endoscopy may be carried out on the morning after admission; this is usually guided by local policy . In all cases of severe bleeding, it should be carried out immediately . A num - ber of scoring systems have been advocated f or the assessment of rebleeding and death after upper gastrointestinal haemor - rhage. The Rockall score ( Table 67.5 ) can be used in a pre - endoscopy f ormat to stratify patients to safe early discharge and, post endoscopy , it can relatively accurately predict rebleeding and death. Condition Percentage Ulcers 60 Oesophageal 6 Gastric 21 Duodenal 33 Erosions 26 Oesophageal 13 Gastric 9 Duodenal 4 Mallory–Weiss tear 4 Oesophageal varices 4 Tumour 0.5 Vascular lesions 0.5 Others 5 TABLE 67.5 The Rockall scoring system of bleeding severity. Score 0 1 2 3 Age <60 60–79 Pulse >100 /uni00A0 bpm Shock Pulse <100 /uni00A0 bpm Systolic BP <100 /uni00A0 mmHg Systolic BP 100 /uni00A0 mmHg Comorbidities None Endoscopic signs None/dark spot of bleeding All other diagnoses Malignancy of the upper Diagnosis Mallory–Weiss syndrome/no pathology BP , blood pressure; bpm, beats per minute. HELICOBACTER PYLORI HELICOBACTER PYLORI H. pylori is involved in the aetiology of a number of common gastroduodenal diseases, such as chronic gastritis, peptic ulceration and gastric cancer. Although Bizzozero identified the presence of spirochaetal organisms in gastric mucosa, it was not until the early 1980s that Warren and Marshall confirmed Koch’s postulates with respect to H. pylori and gastritis. Both received the Nobel Prize in Medicine or Physiology in 2005. (b) 120 Liquid Solid 100 80 60 40 Proportion remaining 20 0 0 40 60 10 30 50 20 Time (min) Figure 67.8 Dual-phase solid and liquid gastric emptying. The use of two isotopic labels allows the liquid and solid phases of the emptying to be followed separately. (a) Image acquisition. (b) Gastric emptying curves in a normal individual showing a typical lag period in the solid phase before linear emptying (courtesy of Dr V Lewington, Southampton, UK). lyse urea, resulting in the production of ammonia, a strong alkali. The e ff ect of ammonia on the antral G cells is to cause release of gastrin via a negative feedback that is responsible for the modest, but inappropria te, hypergastrinaemia in patients with peptic ulcer disease, which, in turn, may result in gastric acid hypersecretion. The organism’s obligate urease activity is utilised by various tests used to detect the presence of the organ 13 14 ism, including the C and C breath tests and the CLO test (a commercially available urease test kit), which is performed on gastric biopsies. The organism can also be detected histo logically ( Figure 67.9 ), using the Giemsa or the Ethin–Starry silver stains, and cultured using appropriate media. Previous or current infection with the organism may also be detected ser ologically . Breath tests or faecal antigen tests are recom mended for the pretreatment diagnosis of H. pylori infection in the community . Less accurate, hospital-based serology tests have a place within a non-invasive test-and-treat strategy . Infection with H. pylori leads to disruption of the gastric mucous barrier by the enzymes produced by the organism, and the inflammation induced in the gastric epithelium is the basis of many of the associated disease processes. The association of the organism with chronic (type B) gastritis is not in doubt. Some strains of H . pylori produce cytotoxins, notably the Cag A and Vac A products. Production of cytotoxins seems to be associated with the ability to cause gastritis, peptic ulceration and gastric cancer. The e ff ect of the organism on the gastric epithelium is to incite a classical inflammatory response that involves the migration and degranulation of acute inflamma tory cells, such as neutrophils, and also the accumulation of chronic inflammatory cells, such as macrophages and lympho cytes. It is evident how H. pylori infection results in chronic gastri tis and also how this may progress to gastric ulceration, but for a while it remained unclear how the organism could be involved in duodenal ulceration, as the normal duodenum is not col onised. As mentioned above, the production of ammonia does incr ease the level of circulating gastrin and it has been shown subsequently that eradication of the organism in patients with duodenal ulcer disease will reduce the acid levels to nor subjects and those with duodenal ulcers is considerable and the modestly increased acid levels in patients with Helicobacter - associated antral gastritis are insu ffi cient to explain the aetiol - ogy of duodenal ulceration. The explanation can probably be found in the phenome - non of duodenal gastric metaplasia. Gastric metaplasia is the - normal response of the duodenal mucosa to excess acidity . It can be thought of in the same way as any other metaplasia in the gastrointestinal tract: an attempt by the mucosa to resist an - injurious stimulus . Although normal duodenal mucosa cannot be infected with H. pylori , gastric metaplasia in the duodenum is commonly infected and this infection results in the same inflammatory process that is observed in the gastric mucosa. - The result is duodenitis, which is almost certainly the precursor of duodenal ulceration. Infection with H. pylori may be the most common human infection. The incidence of infection within a population increases with age, and in many populations infection rates of 80–90% are not unusual. Up to 50% of the world’s popu - lation may be infected with Helicobacter . It appears that most infection is acquired in childhood and the possibility of infec - tion is inversely related to socioeconomic group. The means of spread has not been identified, but the organism can occur in the faeces and faecal–oral spread seems most likely . The organ - ism is not normally found in saliva or dental plaque. There is evidence in di ff er ent environments and in di ff erent population groups that the manifestations of the infection may be di ff er - - ent. Predominantly antral gastritis, which is commonly seen in the W est, results initially in increased levels of acid production - and peptic ulcer disease, whereas gastritis a ff ecting the body , common in the dev eloping world, may lead to hypochlorhydria - and gastric neoplasia. It has been known since 1984 that Helicobacter infection is amenable to treatment with antibiotics. The profound hypo - - chlorhydria produced by PPIs combined with antibiotics is also e ff ective in eradicating the organism. Commonly used eradication regimes include a PPI and two antibiotics, such as metronidazole and amoxicillin. V ery high eradication rates, mal. in the r egion of 90%, can be achieved with combinations that include the antibiotic clarithromycin, although it may be that in the future antibiotic resistance will become a problem. Reinfection following successful eradication appears rare (<0.5%) but incomplete eradication is a more important clinical problem. At present, eradication therapy is recommended for patients with duodenal ulcer disease, but not for patients with non-ulcer dyspepsia or in asymptomatic patients who are infected. How - ever, r ecent data show that a proportion of patients with non-ulcer dyspepsia do respond to treatment. H. pylori is now classified by the World Health Organization as a class 1 carcin - ogen, and it may be that the further epidemiological studies on the risk of gastric cancer change current advice on treatment. Figure 67.9 Antral mucosa showing colonisation with Helicobacter pylori (modi /f_i ed Giemsa stain). Helicobacter pylori gastritis Helicobacter pylori gastritis H. pylori gastritis, previously described as type B gastritis, a ff ects the antrum and predisposes to peptic ulcer disease. Helicobacter -associated pangastritis is common, but gastritis a ff ecting the corpus alone is not. Chronic pangastritis with atrophy is associated with intestinal metaplasia and has signif icant malignant potential when associated with dysplasia. Endoscopic screening may be appropriate. Histopathology Histopathology Microscopically , the base of the ulcer is covered with granula tion tissue and there may be evidence of endarteritis obliterans. The pathological appearances of the healing ulcer must be carefully interpreted as some of the epithelial down growth can be misinterpreted as invasion. INVESTIGATION OF THE STOMACH AND DUODENUM INVESTIGATION OF THE STOMACH AND DUODENUM Incidence Incidence There are marked variations in the incidence of gastric cancer worldwide. In the UK, it is approximately 15 per 100 /uni00A0 000 per year; in the USA, 10 per 100 /uni00A0 000 per year; and in Eastern Europe, 40 per 100 /uni00A0 000 per year. In Japan, the disease is much more common, with an incidence of approximately 70 per 100 /uni00A0 000 per year. There are areas in China where the incidence even higher. These underlying epidemiological data make it clear that this is an environmental disease. In general, men are more a ff ected by the disease than women and, as with most solid organ malignancies, the incidence increases with age. in terms of the incidence and site of gastric cancer and the pop ulation a ff ected, changes that to date have not been observed in Japan. First, the incidence of gastric cancer is continuing to fall at about 1% per year. This reduction exclusiv ely a ff ects carcinoma arising in the body and distal stomach. In contrast, there appears to be an increase in the incidence of carcinoma in the proximal stomach, particularly the GOJ. Carcinoma of the distal stomach and body of the stomach is most common in low socioeconomic groups, whereas the increase in proximal gastric cancer seems to a ff ect principally higher socioeconomic groups. Proximal gastric cancer does not seem to be associated with H. pylori infection, in contrast with carcinoma of the body and distal stomach. Introduction INTRODUCTION The stomach acts as a reservoir for ingested food, where it is mechanically broken down and the process of digestion begins before the ingested content passes into the duodenum. Investigation of the patient with Investigation of the patient with Laparoscopy Laparoscopy Laparoscopy is routine in the assessment of patients with gastric cancer. Its particular value is in the detection of peri - toneal disease, which is di ffi cult by any other technique, unless the patient has ascites or bulky intraperitoneal deposits. The main limitation is evaluation of posterior extension but CT and endoluminal ultrasonography can provide this infor ma - tion. Samples are usually taken for peritoneal cytology unless laparotomy follows immediately . - Figure 67.6 A computed tomography scan of the abdomen showing a gastric cancer arising in the body of the stomach. Figure 67.7 Computed tomography/positron emission tomography of a patient with gastric cancer. The middle pair of images shows the primary tumour. The two images on the left show unsuspected liver metastases, whereas the two on the right show a left cervical node positive for metastases. Learning objectives Learning objectives To understand: The gross and microscopic anatomy and pathophysiology • of the stomach and duodenum The critical importance of gastritis and Helicobacter pylori • in upper gastrointestinal disease The causes of duodenal obstruction and the presentation • of duodenal tumours Long-term complications of surgery Long-term complications of surgery There is very little functional di ff erence between patients who have a total gastrectomy and those who have a subtotal gastrectomy . Patients need to be given detailed nutritional advice, the substance of which is to eat small meals and often, while the jejunum or small gastric remnant adapts. Nutritional deficiencies may occur and loss of the parietal mass leads to deficiency that requires replacement routinely . vitamin B 12 Spleen Pancreas (d) (f) (b) exposure of the lesser sac; (c) splenectomy; (f) mobilisation of the oesophagus. nodes removed) resection. Site of cancer Lymph node Antrum number 1 Right cardia N2 2 Left cardia 3 Lesser curve N1 4sa Short gastric N1 4sb Left gastroepiploic N1 4d Right gastroepiploic N1 5 Suprapyloric N1 6 Infrapyloric N1 7 Left gastric artery N2 8a Anterior hepatic artery N2 9 Coeliac artery N2 10 Splenic hilum 11 Splenic artery 19 Infradiaphragmatic 20 Oesophageal hiatus 110 Lower oesophagus 111 Supradiaphragmatic The nodes in stations 12–18 are not routinely removed in a D1 or D2 gastrectomy. Lymphatic drainage of the stomach Lymphatic drainage of the stomach Understanding the lymphatic drainage of the stomach is the key to understanding radical surgery for gastric cancer. The lymphatics of the antrum drain into the right gastric lymph node superiorly and right gastroepiploic and subpyloric lymph nodes inferiorly . The lymphatics of the pylorus drain to the right gastric suprapyloric nodes superiorly and the subpyloric lymph nodes situated around the gastroduodenal artery infe riorly . The e ff erent lymphatics from suprapyloric lymph nodes converge on the para-aortic nodes around the coeliac axis, whereas the e ff erent lymphatics from the subpyloric lymph nodes pass to the main superior mesenteric lymph nodes situated around the origin of the superior mesenteric arter The lymphatic vessels related to the cardia communicate freely with those of the oesophagus. The prognosis of operable cases of carcinoma of the stomach depends on whether or not there is histological evidence of regional lymph node involvement. Retrograde (downwards) spread may occur if the upper lymphatics are blocked. In Japan, lymph node dissection is highly advanced and the Japanese Research Society for Gastric Cancer has assigned a number to each lymph node station to aid pathological staging ( Figure 67.29 ). Friedrich Ernest Krukenberg , 1870–1946, ophthalmologist, Halle, Germany , wrote a classic paper on malignant tumours of the ovary in 1896. Sister Mary Joseph (Julia Dempsey) , 1856–1939, Nursing Superintendent, St Mary’s Hospital, Rochester, MN, USA, noted the presence of umbilical nodules in many patients with adv anced gastric cancer. She drew this to the attention of Dr William Mayo, founder of the Mayo Clinic. Patients with incurable disease should not subjected to futile - radical surgery , hence the value of preoperative CT/PET and laparoscopic staging. Haematogenous metastases, involvement of the distant peritoneum, M1 nodal disease and fixation to structures that are not resectable are unequivocal features of incurable disease. Involvement of another organ per se does not imply incurability , provided it can be excised. (a) 18 2 10 1 11 9 12 8 13 16 5 3 4 6 4 Figure 67.29 Lymphatic drainage of the stomach and nodal stations by the Japanese classi /f_i cation: posterior view. Lymphatics Lymphatics The lymphatics of the stomach are of considerable importance in surgery for gastric cancer and are described in detail in that section. - - Splenic artery Vasa brevia Left gastric artery Hepatic artery Right gastric artery Duodenal cap Gastroduodenal artery Superior pancreaticoduodenal artery Left gastroepiploic Right artery gastroepiploic Gastrocolic artery (greater) omentum Figure 67.1 The arterial blood supply of the stomach. Hepatic branches Anterior nerve of Latarjet Gastric branches Crow's foot Figure 67.2 The anatomy of the anterior and posterior vagus nerves in relation to the stomach. Lymphocytic gastritis Lymphocytic gastritis This type of gastritis is rare. It is characterised by the infiltration of the gastric mucosa by T cells and is probably associated with H. pylori infection. The pattern of inflammation resembles that seen in coeliac disease or lymphocytic colitis. - MICROSCOPIC ANATOMY OF THE STOMACH AND DUODENUM MICROSCOPIC ANATOMY OF THE STOMACH AND DUODENUM The gastric surface epithelial cells are mucus producing. Mucus-secreting glands are found also in the duodenum. The specialised cells of the stomach (parietal and chief cells) are found in the gastric crypts ( Figure 67.3 ). The stomach also has numerous endocrine cells. Malignancy in gastric ulcers Malignancy in gastric ulcers In contrast to chronic duodenal ulcers, gastric ulcers are associated with malignancy . There are two clinical scenarios that should be distinguished: one in which a benign chronic gastric ulcer undergoes malignant transformation (rare) and the more common scenario in which a gastric ulcer is assessed as benign either endoscopically or on contrast radiology but biopsies reveal malignancy . In this situation, the patient has - - - Figure 67.12 Benign incisural gastric ulcer shown at gastroscopy (courtesy of Dr GNJ Tytgat, Amsterdam, The Netherlands). (a) (b) Large gastric ulcer Figure 67.13 Benign gastric ulcer shown on barium meal. (a) Radiograph; (b) diagrammatic outline. peptic ulcer. Therefore, all gastric ulcers should be regarded as being malignant, no matter how classical the features of a benign gastric ulcer. Multiple biopsies should always be taken, perhaps as many as 10 well-targeted biopsies, before an ulcer can be tentatively accepted as being benign. Even then it is important that further biopsies are taken while the ulcer is healing and when healed. Modern antisecretory agents can frequently heal the ulceration associated with gastric cancer but, clearly , are ine ff ective in treating the malignancy itself. At operation, even experienced surgeons may have di ffi culty distinguishing between the gastric cancer and a benign ulcer. Operative strategies di ff er so radically that it is essential that a confident diagnosis be made before operation. At ation for a perforated gastric ulcer, even if it is considered that the ulcer is benign, the ulcer should be excised and submitted for histological examination. Mallory–Weiss tear Mallory–Weiss tear This is a longitudinal tear at the GOJ, which is induced by repetitive and strenuous vomiting. Doubtless, many such lesions occur and do not cause bleeding. When it is a cause of haematemesis, the lesion may often be missed as it can be di ffi cult to see because it is just below the GOJ, a position that - can be di ffi cult for the inexperienced endoscopist. Occasionally these lesions continue to bleed and require surgical treatment (see also Chapter 66 ). Management Management Treating the patient involves correcting the metabolic abnormalities and dealing with the mechanical obstruction. The patient should be rehydrated with intravenous isotonic saline with potassium supplementation. Replacing the sodium chloride and water allows the kidney to correct the acid–base abnormality . The metabolic abnormalities may be less if the obstruction is due to malignancy , as the acid–base disturbance is less pronounced. The stomach should be emptied using a wide-bore tube. A large nasogastric tube may not be su ffi ciently large to deal with the contents of the stomach, and it may be necessar to pass an orogastric tube and lavage the stomach until it is completely emptied. This allows investigation with endoscopy and contrast radiology . Biopsy of the area around the pylorus is essential to exclude malignancy . Early cases may settle with conservative treatment, as oedema around the ulcer diminishes as the ulcer is healed. Traditionally , severe cases are treated surgically , usually with a gastroenterostomy rather than a p yloroplasty . Endoscopic treatment with balloon dilatation may be most useful in early cases and may have to be repeated several times. A duodenal stent insertion may be considered in patients with unresectable malignancy . A number of conditions manifest as gastric polyps. Their main importance is that they may actually represent early gastric cancer. Biopsy is essential. The most common type of gastric polyp is metaplastic. These are associated with H. pylori infection and regress fol - lowing eradication therapy . Inflammatory polyps are also com - mon. Fundic gland polyps deserve particular attention. They are associated with use of PPIs and are also found in patients with familial adenomatous polyposis (FAP). Neither metaplas - tic nor fundic gland polyps hav e proven malignant potential; however, true adenomas do and should be removed. Metabolic effects Metabolic effects V omiting hydrochloric acid results in hypochloraemic alkalosis. Initially the sodium and potassium may be relatively normal; however, as dehydration progresses, more profound metabolic abnormalities arise, partly related to renal dysfunction. Initially , the urine has a low chloride and high bicarbonate content, reflecting the primary metabolic abnormality . With time the patient becomes progressively hyponatraemic and more profoundly dehydrated. Because of the dehydration, sodium is retained and potassium and hydrogen ions are excreted. This results in the urine becoming paradoxically acidic and hypokalaemia ensues. Alkalosis leads to a lowering in the circulating ionised calcium, and tetany can occur. Ménétrier’s disease Ménétrier’s disease This is an unusual condition characterised by gross hypertro - phy of the gastric mucosal folds, mucus production and hypo - chlorhydria. The condition is premalignant and may present with hypoproteinaemia and anaemia. There is no treatment other than a gastrectomy . The disease seems to be caused by overexpr ession of transforming growth factor alpha (TGF- α ). Like epidermal growth factor (EGF), this peptide also binds to the EGF receptor. The histological features of Ménétrier’s disease may be reproduced in transgenic mice overexpressing TGF- α . Neoadjuvant chemotherapy Neoadjuvant chemotherapy Most operable patients should have neoadjuvant chemother - apy as there is level 1 evidence of improved survival. Since the early 2000s a platinum-based triplet regime containing epirubicin (e.g. epirubicin, cisplatin and 5-fluorouracil [5-FU]; ECF) has been the standard of care. Recently epirubicin has - been re placed by docetaxel after publication of the FLOT4 trial; this was a direct comparison of ECF with FLOT (fluoro - uracil, leucovorin, oxaliplatin, docetaxel) chemotherapy that showed a significant survival advantage for FLOT (50 months versus 35 months). Unfortunately , only a minority of patients y . receive a clinically meaningful survival adv antage and mecha - nisms to predict response are urgently required to prevent the ine ff ective and harmful treatment of the majority . Evidence for the use of perioperative (before and after surgery) chemo - therapy is less r obust, as in all major trials (MRC-MAGIC and FLOT4) fewer than 50% of patients received the postopera - tive component. (b) 4 10 17 11 6 14 15 (a) the anterior view of the stomach; (b) the This is best performed through a long upper midline incision. The stomach is removed en bloc, including the tissues of the entire greater omentum and lesser omentum ( Figure 67.30 commencing the operation, the transverse colon is completely separated from the greater omentum. The dissection may then be commenced proximally or, more usually , distally . The subpyloric nodes are dissected, and the first part of the duode num is divided, usually with a surgical stapler. The hepatic nodes are dissected to clear the hepatic artery; this dissection also includes the suprapyloric nodes. The right gastric artery is divided at its origin from the hepatic artery . The lymph node dissection is contin ued to the origin of the left gastric artery , which is divided at its origin. Dissection is continued along the splenic artery , removing all nodes on the superior aspect of the pancreas and accessible nodes in the splenic hilum. Separation of the stomach from the spleen, if it is not going to be removed, allows access to the nodal tissues around the upper stomach and GOJ. The oesophagus can then be divided at an appropriate point using a combination of stay sutures and a soft non-crushing clamp, usually of the right-ang led vari ety . It is important that the resection margins are well clear of the tumour (>5 /uni00A0 cm). Frozen section should be performed if involvement of either proximal or distal resection margin is in doubt. Gastrointestinal continuity is reconstituted by means of a Roux loop. The alimentary limb of the Roux loop should be at least 50 /uni00A0 cm long to avoid bile reflux oesophagitis. The simplest means of e ff ecting the oesophagojejunostomy is to place a purse-string suture in the cut end of the oesophagus and, using a circular stapler introduced through the blind end of the Roux loop, staple the end of the oesophagus onto the side of the Roux loop. The blind open end of the Roux loop may then be closed either with sutures or with a linear stapler. Recent evidence supports long-term intestinal and nutritional benefits of construction of a jejunal pouch. The anastomosis can also be fashioned end to end. The Roux loop may be placed in either an antecolic or retrocolic position. The end to-side jejunojejunostomy is undertaken at a convenient point ( Figure 67.31 ). The di ff erentiation between a D1 and a D2 operation depends upon the tiers of nodes removed. Di ff erent tiers need to be remo ved depending on the positions of primary tumour ( Table 67.7 ). In general, a D1 r esection involves the removal of the perigastric nodes and a D2 resection involves the clearance of the major arterial trunks. In practice the majority of special ist centres will perform a radical total gastrectomy , conserving the spleen and pancreas, with D2 lymphadenectomy sparing station 10 lymph nodes. Nerves Nerves The stomach and duodenum possess both intrinsic and extrinsic nerve supplies. The intrinsic nerves exist principally in two plexuses, the myenteric plexus of Auerbach and the submucosal plexus of Meissner. Compared with the rest of the gut, the submucosal plexus of the stomach contains relatively few ganglionic cells, as does the myenteric plexus in the fundus. However, in the antrum the ganglia of the myenteric plexus are well developed. The extrinsic supply is derived mainly from the vagus nerves (cranial nerve X), fibres of which originate in the brainstem. The vagal plexus around the oesophagus condenses into bundles that pass through the oesophageal hiatus ( Figure 67.2 ), the posterior bundle being usually identifiable as a large nerve trunk. Vagal fibres are both a ff erent (sensory) and e ff erent. The e ff erent fibres are involved in the receptive relaxation of the stomach and the stimulation of gastric motility , as well as having the well-known secretory function. The sympathetic supply is derived mainly from the coeliac ganglia. Neuroendocrine tumours Neuroendocrine tumours A number of neuroendocrine neoplasms occur in the duode - num. It is a common site for primary gastrinoma (Zollinger– Ellison syndrome). Non-functioning neuroendocrine tumours (usually called carcinoid tumours) also occur but uncommonly in comparison with the ileum. OTHER GASTRIC CONDITIONS Acute gastric dilatation OTHER GASTRIC CONDITIONS Acute gastric dilatation This condition usually occurs in association with pyloroduo denal disorders or following abdominal surgery . The stomach dilates enormously . The patient may be dehydrated and have electrolyte disturbances. Failure to treat can r esult in a sudden vomit with aspiration into the lungs. Treatment is nasogastric suction with a large-bore tube, fluid replacement and treatment of the underlying condition. Operations for duodenal ulceration Operations for duodenal ulceration Procedures for the treatment of duodenal ulcers have the common aim of excluding acid from the duodenum. This is ing the secretory potential of the stomach or both. All proce - dures achieve this aim to some extent, but with varying degrees of morbidity and postoperative side e ff ects. There is now no role for acid-r educing operations in the routine management of peptic ulcer disease, but occasionally operations that involve gastrectomy have to be performed in the emergency situation. Gastrectomy-based procedures Gastrectomy in the form of either Billroth I ( Figure 67.14 ) or Billroth II/Pólya ( Figure 67.15 ) has been performed for - - - - - Figure 67.14 Billroth I gastrectomy. The lower half of the stomach is removed and the cut stomach anastomosed to the /f_i rst part of the duodenum. Figure 67.15 Billroth II. Two-thirds of the stomach is removed, the duodenal stump is closed and the stomach anastomosed to the jejunum. operations remove the gastric antrum, hence reducing acid. The Pólya gastrectomy diverts the gastric secretions away from the duodenum. There is no elective role for these procedures in the treatment of duodenal ulcer, but the safer Pólya procedure is occasionally needed in the management of complex ulcer disease presenting as an emergency . Gastrojejunostomy Gastrojejunostomy ( Figure 67.16 ) was developed as an opera tion for duodenal ulcer, in which role it was very unsuccessful. Although reflux of alkali into the stomach allowed healing in some cases, the exposure of jejunal m ucosa to acid resulted in stomal ulceration. Gastroenterostomy , however, remains a commonly performed operation, usually to bypass malignant obstruction due to tumours in the distal stomach, duodenum or pancreas. This is performed through opening the lesser sac and performing an anastomosis between the most dependent part of the antrum and the first jejunal loop. An isoperistaltic anastomosis is most commonly performed. Vagotomy-based procedures The principle of the operation is that section of the vagus nerves, which are critically involved in the secretion of gastric acid, reduces the maximal acid output by approximately 50%. Truncal vagotomy (cutting the vagal verves at the lower oesophagus) was first introduced in the mid-twentieth century and, for many years, combined with a gastric drain age procedure, was the mainstay of treatment of duodenal ulceration ( Figure 67.17 ). Because the vagal nerves are motor to the stomach, denervation of the antr opyloroduodenal segment results in gastric stasis in a substantial proportion of patients on whom truncal vagotomy alone is performed. The most popular drainage procedure was the Heineke–Mikulicz pyloroplasty ( Figure 67.18 ). It is simple to perform and involves longitudinal division of the pyloric ring. The incision is closed transversely . Gastrojejunostomy ( Figure 67.16 an alternative drainage procedure to pyloroplasty . In highly selective vagotomy , only the parietal cell mass of the stomach is denervated ( Figure 67.19 ). Operations for gastric ulcer Operations for gastric ulcer In contrast to surgery for duodenal ulcer, where the princi pal objective is to reduce duodenal exposure to gastric acid, in gastric ulcer surgery the ulcer is usually excised so that malignancy can then be confidently excluded. The standard operation is the Billroth I ( Figure 67.14 ) but as with duodenal ulceration such surgery is now performed only for complica tions of gastric ulcer. Other forms of gastritis Other forms of gastritis Eosinophilic gastritis appears to have an allergic basis and is treated with steroids and cromoglycate. Granulomatous gastri - tis is seen rarely in Crohn’s disease and also may be associated with tuberculosis. Acquired immunodeficiency syndrome (AIDS) gastritis is secondary to infection with cryptosporid - iosis. Phlegmonous gastritis is a rare bacterial infection of the stomach found in patients with se vere intercurrent illness. It is usually an agonal event. Although the name ‘peptic’ ulcer suggests an association with pepsin, this is essentially unimportant as, in the absence of acid, peptic ulcers do not occur. Nearly all peptic ulcers can be healed by using PPIs, which can render a patient virtually achlorhydric. Common sites for peptic ulcers are the first part of the duo denum and the lesser curve of the stomach, but they also occur on the stoma following gastric surgery , in the oesophagus and even in a Meckel’s diverticulum, which contains ectopic gastric epithelium. In general, the ulcer occurs at a junction between di ff erent types of epithelia, in the epithelium least resistant to acid damage. In the past, much distinction has been made between acute and chronic peptic ulcers, but this di ff erence can sometimes be di ffi cult to determine clinically . It is probably best to consider that there is a spectrum of disease from the superficial gas tric and duodenal ulceration, frequently seen at endoscopy , to deep chronic penetrating ulcers. This does not minimise the importance of acute stress ulceration. These ulcers can both perforate and bleed. For many y ears, the cause of peptic ulceration remained an enigma. When comparing groups of patients with duode nal and prepyloric peptic ulcers with normal subjects, gastric acid levels ar e higher, but the overlap is considerable. Patients with gastric ulceration have rela tively normal levels of gastric acid secretion. It is clear that acid is important as peptic ulcer ation occurs in the presence of very high acid levels, such as those found in patients with a gastrinoma (Zollinger–Ellison syndrome), and ulcers heal in the absence of acid. In patients with a gastrinoma it may be the only aetiological factor, but this is not the case in the majority of patients. Summary box 67.4 Peptic ulceration /uni25CF /uni25CF /uni25CF /uni25CF H. pylori /uni25CF /uni25CF /uni25CF Johann Friedrich Meckel (the younger), 1781–1833, Professor of Anatomy and Surgery , Halle, Germany , described the diverticulum in 1809. Robin Milton Zollinger , 1903–1992, Professor of Surgery , Iowa State University , Columbus, OH, USA. Edwin Homer Ellison , 1918–1970, Professor of Surgery , Marquette University , Milwaukee, WI, USA. consumption of NSAIDs are the most important factors in the development of peptic ulceration. Cigarette smoking predis - poses to peptic ulceration and increases the relapse rate after treatment. Most peptic ulcers are caused by H. pylori or NSAIDs and changes in epidemiology mirror changes in these principal aetiological factors Duodenal ulcers are more common than gastric ulcers, but the symptoms are indistinguishable Gastric ulcers may be malignant and an ulcerated gastric cancer may mimic a benign ulcer Gastric antisecretory agents and eradication therapy are the mainstays of treatment, and elective surgery is very rarely performed The long-term complications of peptic ulcer surgery may be dif /f_i cult to treat The common complications of peptic ulcers are perforation, bleeding and stenosis The treatment of the perforated peptic ulcer is primarily surgical, although some patients may be managed conservatively Other peptic ulcers Other peptic ulcers A prepyloric gastric ulcer was in the past di ffi cult to treat, a problem overcome with the introduction of PPIs. Pyloric chan nel ulcers are similar to duodenal ulcers. Both prepyloric and pyloric ulcers may be malignant and biopsy is essential. Stomal ulcers occur after a gastroenterostomy (now most commonly found after bariatric surgery; see Chapter 68 ) or a gastrectom of the Billroth II type. The ulcer is usually found on the jejunal side of the stoma. Other treatment modalities Other treatment modalities Because of the failure of radical surgery to cure advanced gastric cancer, there has been an interest in the use of radio therapy and chemotherapy . Palliative radiotherapy The routine use of radiotherapy is controversial as the results of clinical trials are inconclusive. There are a number of radiosensitive tissues in the region of the gastric bed, which limits the dose that can be given. Radiotherapy has a role in the palliative treatment of painful bony metastases. - Palliative chemotherapy There are a number of regimes, but the best results are currently obtained using either platinum-containing triplet combina - tions or FLOT . Second-line treatment using combinations that Middle Cardia Cardia and oesophagus N1 N1 N1 N1 N1 N1 N1 N1 N1 N1 N1 N1 N1 N1 N1 N1 N2 N2 N1 N2 N2 N1 N2 N2 N2 N2 N2 N2 N2 N2 N2 N2 N2 N2 N2 N2 N2 N2 N2 N2 N2 N1 N2 N2 Figure 67.31 Oesophagojejunostomy Roux-en-Y . for advanced disease is palliative. Newer biological agents such as trastuzumab (Herceptin) o ff er potential advantages to survival in the minority of patients (<20%) with HER2 -positive gastric cancer. However, the absolute survival advantages are small (~4 months) and the cost of treatment is high. Never theless trastuzumab has been approved for use in metastatic HER2 -positive gastric cancer in the UK and European Union. Outlook after surgical treatment Outlook after surgical treatment The outlook after surgical treatment varies considerably between the West and Japan. In Japan, approximately 75% of patients will have a curative resection and, of these, the overall 5-year survival rate is 50–70%. In contrast, in the West most series show that only 25–50% of patients undergoing surgery will have a curative operation and the 5-year survival rate in such patients is only about 25–30%, although in some series it approaches Japanese levels. A combination of di ff erences in staging and a higher standard of surgery in Japan probably accounts for the di ff erences. Staging is clearly crucial when survival figures are being compared and, therefore, stage for stage the outcome seems better in patients who are adequately staged pathologically . This phenomenon is termed ‘stage migration’. PHYSIOLOGY OF THE STOMACH AND DUODENUM PHYSIOLOGY OF THE STOMACH AND DUODENUM The stomach mechanically breaks down ingested food and, together with the actions of acid and pepsin, forms chyme that passes into the duodenum. In contrast with the acidic environ ment of the stomach, the environment of the duodenum is alkaline, owing to secretion of bicarbonate ions from both the pancreas and the duodenum. This neutralises the acid chyme and adjusts the luminal osmolarity to approximately that of plasma. Endocrine cells in the duoden um produce cholecys tokinin, which stimulates the pancreas to produce trypsin and the gallbladder to contract. Secretin is also produced by the endocrine cells of the duodenum. This hormone inhibits gastric acid secr etion and promotes production of bicarbonate by the pancreas. Johann Conrad Brunner , 1653–1729, Professor of Anatomy , Heidelberg, Germany , and later Strasburg, France. Anatomy and physiology of the stomach /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF - The stomach acts as a reservoir for food and commences the process of digestion Gastric acid is produced by a proton pump in the parietal cells, which in turn is controlled by histamine acting on H 2 receptors The histamine is produced by the endocrine gastric ECL cells in response to a number of factors, particularly gastrin and vagus nerve stimulation PPIs abolish gastric acid production, whereas H -receptor 2 antagonists only markedly reduce it The gastric mucous layer is essential to the integrity of the gastric mucosa Palliative surgery Palliative surgery In patients with significant symptoms of either obstruction or bleeding, palliative resection is appropriate. A palliative gastrectomy need not be radical as it is su ffi cient to remove the tumour and reconstruct the gastrointestinal tract. Sometimes it is impossible to resect an obstructing tumour in the distal stomach and other palliative procedures need to be consid - ered. A high gastroenterostomy is a poor operation that very frequently does not allow the stomach to empty adequately and may produce the additional problem of bile reflux. A Roux - loop with a wide anastomosis between the stomach and jeju - num may be a better option, although ev en this may not allow the stomach to empty well. For inoperable tumours situated in the cardia, palliative intubation or stenting can be used (see Chapter 66 ). Parietal cells Parietal cells These are found in the body (acid-secreting portion) of the stomach and line the gastric crypts, being more abundant Leopold Auerbach , 1828–1897, Professor of Neuropathology , Breslau, Germany (now Wroc ł aw , Poland). George Meissner , 1829–1905, Professor of Pathology , Gottingen, Germany . . André Latarjet , 1877–1947, anatomist, Lyon, France Guiseppe Grassi , 1913–1980, surgeon, San Giovanni Hospital, Rome, Italy . ‘Criminal’ nerve of Grassi Coeliac branch Posterior nerve Gastric branches Crow's foot Figure 67.3 The histological appearance of a gastric gland. The mucus-secreting cells are seen at the mucosal surface, the eosino philic parietal cells super /f_i cially in the glands and the basophilic chief cells in the deepest layer. hydrogen ions that form hydrochloric acid. The hydrogen ions are actively secreted by a hydrogen–potassium-ATPase proton pump, which exchanges intraluminal potassium for hydrogen ions. The potassium ions enter the lumen of the crypts passively , but the hydrogen ions are pumped against an immense concentration gradient (1 000 000:1). Proton + + pump inhibitors (PPIs) act by blocking the H /K ATPase and thereby significantly reduce gastric acid secretion (see Gastric acid secretion ). Pathology Pathology Gastric ulcers have similar features to duodenal ulcers but tend to be larger. Fibrosis may result in an ‘hourglass’ deformity of the stomach. Chronic ulcers may erode posteriorly into the pancreas, major vessels such as the splenic artery or rarely into other organs such as the transverse colon. Chronic gastric the incisura angularis; Figures 67.12 and 67.13 ) than on the greater curve and, even when high on the lesser curve, they tend to be at the boundary between the acid-secr eting and the non-acid-secr eting epithelia. With atrophy of parietal cell mass, non-acid-secreting epithelium migrates up the lesser curvature. Pathology The most useful clinicopathological classification of gastric cancer is the Laurén classification. In this system there are principally two forms of gastric cancer: intestinal gastric cancer and di ff use gastric cancer (often with signet ring cells). In intestinal gastric cancer, the tumour resembles a carcinoma elsewhere in the tubular gastrointestinal tract and forms poly - poid tumours or ulcers; it probably arises in areas of intestinal metaplasia. In contrast, di ff use gastric cancer infiltrates deeply into the stomach without forming obvious mass lesions but spreads widely in the gastric wall. Not sur prisingly , this has a much worse prognosis. A small proportion of gastric cancers are of mixed morphology . Gastric cancer can be divided into early gastric cancer and advanced gastric cancer. Early gastric cancer is defined as cancer limited to the mucosa and submucosa with or without lymph node involvement (T1, any N); it can be protruding, superficial or excava ted as described in the Japanese classifi - cation ( Figures 67.25 and 67.26 ). This type of cancer is emi - nently curable with 5-year survival rates in the region of 90%. In Japan, approximately one-third of gastric cancers diag - nosed are in this stage. However, early g astric cancer diagnosis in the UK is relatively uncommon as dyspeptic patients are not always referred for endoscopy at an appropriate stage . Advanced gastric cancer involves the muscularis. Its mac - roscopic appearances have been classified by Borrmann into four types ( Figures 67.27 and 67.28 ). Types III and IV are commonly incurable. Pattern of relapse following surgical treatment Pattern of relapse following surgical treatment The most common site of relapse following radical gastrec tomy is the gastric bed, representing inadequate extirpation of the primary tumour. Widespread nodal intraperitoneal metastases, distant nodal metastases and liver metastases are all common. Dissemination to the lung and bones usually only occurs after liver metastases are already established. Peptides and neuropeptides in the stomach and duod Peptides and neuropeptides in the stomach and duodenum As with most of the gastrointestinal tract, the endocrine cells of the stomach produce peptide hormones and neurotrans mitters. Previously , nerves and endocrine cells were considered distinct in terms of their products. However, it is increasingly realised that there is enormous over lap within these systems. Many peptides recognised as hormones may also be produced by neurones, hence the term neuropeptides. The term ‘messen ger’ can be used to describe all such products. There are three conventional modes of action that overlap. 1 Endocrine . The messenger is secreted into the circula tion, where it a ff ects tissues that may be remote from the site of origin. 2 Paracrine . Messengers are produced locally and have Ivan Petrovitch Pavlov , 1849–1936, Professor of Physiology , St Petersburg, Russia. act in this way . 3 Neurocrine (classical neurotransmitter). Messengers are produced by the neurone via the synaptic knob and pass across the synaptic cleft to the target. Many peptide hormones act on the intrinsic nerve plexus of the gut (see Gastroduodenal motor activity ) and influence motility . Similarly , neuropeptides may influence the structure gas - and function of the m ucosa. Some of these peptides, neuro - peptides and neurotransmitters are listed in Table 67.1 . The stomach is vital to regulation of appetite and weight control through a combination of mechanical and hormonal mecha - nisms (see Chapter 68 ). Portal gastropathy Portal gastropathy Portal gastropathy refers to changes in the gastric mucosa as a result of portal hypertension. The mucosa is friable and may exude blood, even in the absence of well-developed visible varices. The treatment is as for portal hypertension. Portal hypertension and portal gastropathy Portal hypertension and portal gastropathy The management of bleeding gastric varices is very challeng ing. Fortunately , most bleeding from varices is oesophageal and is much more amenable to sclerotherapy , banding and balloon tamponade. Gastric varices may also be injected, although this is technically more di ffi cult. Banding can also be used, ag ain with di ffi culty . The gastric balloon of the Sengstaken– Blakemore tube can be used to arrest the haemorrhage from the fundus of the stomach or GOJ ( Figure 67.24 ). Intravenous infusion of octreotide (somatostatin analogue) or terlipressin (Glypressin), a vasopressin analogue, reduces portal pressure in patients with varices and is of value in arresting haemorrhage. Acute surgery on bleeding varices should be avoided, if possible, because of high operative mortality; it has been superseded in most centres by transjugular intrahepatic porto systemic shunt (TIPSS) insertion (see Chapter 69 ). Postoperative complications of gastrectomy Postoperative complications of gastrectomy Radical gastrectomy is complex major surgery and predict - ably there is a large number of potential complications of the operation. Leakage of the oesophagojejunostomy can often be managed conservatively as the Roux-en-Y reconstruction means that it is mainly saliva and ingested food that leaks. Some patients may establish a fistula from the w ound or drain site and others may need radiologically or surgically placed drains. It is unusual to detect a major anastomotic leak in - the absence of clinical signs and the use of postoperative water-soluble contrast swallows is no longer routine in most centres. Leakage from the duodenal stump is usually due to a degree of distal obstruction and care must be taken to avoid kinking when perf orming the Roux-en-Y anastomosis. Para- duodenal collections can be drained radiologically , which may convert the collection into an external fistula. Biliary peritonitis - requires a laparotomy and peritoneal toilet. In this circum - stance it is best to leave a Foley catheter in the duodenum to establish a controlled duodenal fistula. If it is established that there is no distal obstruction, or if any such obstruction is man - aged, then the fistula will close with time. The presence of septic collections along with a radical vas - cular dissection may lead to catastrophic secondary haemor - rhage from the exposed or divided blood vessels. This situation may be very di ffi cult to manage, whether or not reoperation or interventional radiology is employed. (c) Spleen Pancreas (e) Figure 67.30 Radical total gastrectomy: (a) dissection of omentum off the transverse colon; (d) division and oversewing of the duodenum; (e) dissection of the left gastric artery nodes (group 17); Reflux gastritis Reflux gastritis This is caused by enterogastric reflux. Its histological features are distinct from other types of gastritis. Although commonly seen after gastric surgery , it is occasionally found in patients with no previous surgical intervention or those who have had Pierre Eugène Ménétrier , 1859–1935, pathologist, Paris, France. Burrill Bernard Crohn , 1884–1983, gastroenterologist, Mount Sinai Hospital, New Y ork, NY , USA, described regional ileitis in 1932 along with Leon Ginzburg and Gordon Oppenheimer. useful in treatment and as a temporising measure to avoid - revisional surgery that should be reserved for severe cases . - Sequelae of peptic ulcer surgery Sequelae of peptic ulcer surgery There are a number of sequelae of peptic ulcer surgery , which include recurrent ulceration, small stomach syndrome, bilious Eugen (Jeno) Alexander Pólya , 1876–1944, surgeon, St Stephen’s Hospital, Budapest, Hungary . Walther Hermann Heineke , 1834–1901, surgeon, Erlangen, Germany . Johann von Mikulicz-Radecki , 1850–1905, Professor of Surgery , Breslau, Germany (now Wroc ł aw , Poland). transformation. These sequelae principally follow from the more destructive operations that are now seldom performed. Howe ver, a substantial number of patients have side e ff ects from operations undertaken in the past. Approximately 30% of patients can expect to su ff er a degree of dysfunction follow - ing peptic ulcer surgery ( Table 67.2 ); in about 5% of such patients, the symptoms will be intractable. - - ) is - - TABLE 67.2 Operative mortality, side effects and incidence of recurrence following duodenal ulcer operations. Recurrent Operation Operative Signi /f_i cant ulceration mortality (%) side effects (%) (%) Gastrectomy 1–2 20–40 1–4 Gastroenterostomy <1 10–20 50 alone Truncal vagotomy <1 10–20 2–7 and drainage Selective vagotomy <1 10–20 5–10 and drainage Highly selective <0.2 <5 2–10 vagotomy Truncal vagotomy 1 10–20 1 and antrectomy Figure 67.16 Gastroenterostomy. The jejunum is anastomosed to the posterior, dependent, wall of the stomach. Recurrent ulceration and gastrocolic fistula As with other peptic ulcers, recurrent ulcers may present with complications, particularly bleeding and perforation. In this respect, the complication of gastrojejunal–colic fistula requires particular mention. In this rare condition, an anastomotic ulcer in the gastrojejunostomy penetrates into the transverse colon. Patients su ff er from diarrhoea that is severe and follows every meal. They have foul breath and may vomit formed faeces. Severe weight loss and dehydration are rapid in onset; for this reason the condition may be mistaken for malignancy . The major factor producing the nutritional disturbance is the severe contamination of the jejunum with colonic bacteria. A number of imaging techniques can be used to detect the fistula, most commonly CT with oral contrast or indeed a barium enema. Endoscopy may not convincingly demonstrate the fistula and, in about one-half of such cases, the barium meal will not reveal the problem. The treatment of gastrocolic fistula consists of first correcting the dehydration and malnutrition and then performing revisional surgery . Small stomach syndrome Early satiety follows most ulcer operations to some degree, including highly selective vagotomy . In this latter circumstance, although there is no anatomical disturbance of the stomach there is loss of receptive relaxation. Fortunately , this problem does tend to get better with time and revisional surgery is not necessary . Bile vomiting Bile vomiting can occur after any form of vagotomy with drainage or gastrectomy . Commonly , the patient presents with vomiting a mixture of food and bile or sometimes some bile alone after a meal. Often eating will precipitate abdominal pain and reflux symptoms are common. Bile-chelating agents can be tried but are usually ine ff ective. In intractable cases, revisional surgery may be indicated. The nature of that revi - sional surgery depends very much on the original operation. Following gastrectomy , Roux-en-Y diversion is probably the best treatment. In patients with a gastroenterostom y , this can Figure 67.17 Truncal vagotomy: (a) division of the anterior vagus; (a) (a) (i) (ii) (ii) (i) Figure 67.18 Heineke–Mikulicz pyloroplasty in which (a) a full-thickness longitudinal incision traversing the pylorus is retracted by stay sutures (i) and closed transversely with full-thickness sutures (ii). (b) Completed transverse closure. (b) mobilisation of the oesophagus; (c) division of the posterior vagus. (b) (b) be taken down and, in most circumstances, a small pyloroplasty can be performed. In patients with a pyloroplasty , reconstruc tion of the pylorus has been attempted but, in general terms, the results of this operation have been rather poor. Antrectomy and Roux-en-Y reconstruction may be the better option. Early and late dumping Although considered together because the symptoms are similar, early and late dumping have di ff erent aetiologies A common feature, however, is early rapid gastric emptying. Many patients have both early and late dumping. Early dumping Early dumping consists of abdominal and vasomotor symptoms that are found in about 10% of patients following gastrectomy or vagotomy and drainage. It also a ff ects a small percentage of patients following highly selective vagotomy owing to the loss of receptive relaxation of the stomach. The small bowel is filled with foodstu ff s from the stomach, which have a high osmotic load that leads to the sequestration of fluid from the circulation into the gastrointestinal tract. This can be observed by the rise in the packed cell volume while the symptoms are present. All of the symptoms shown in Table 67.3 can be related to this e ff ect on the gut and the circulation. The principal treatment is dietary manipulation. Small, regular meals based on fat and protein are best. Avoiding fluids with a high carbohydrate content also helps. Fortunately , the César Roux , 1857–1934, Professor of Surgery and Gynecology , Lausanne, Switzerland. syndrome tends to improve with time; however, a group of patients have intractable dumping. The somatostatin analogue octreotide given before meals is useful in some individuals and the long-acting preparation may also be useful; however, it does not help diarrhoea, which many patients with dumping also su ff er. Revisional surgery may be occasionally required. In patients with a gastroenterostomy , the drainage may be taken down or, in the case of a pyloroplasty , repaired. Alterna tively , antrectomy with Roux-en-Y reconstruction is often e ff ective, although the procedure is of greater magnitude; following gastrectomy , it is the revisional procedure of choice ( Figure 67.20 ). - 6–8 cm 7 cm Figure 67.19 Highly selective vagotomy. The anterior and posterior vagus nerves are preserved but all branches to the fundus and body of the stomach are divided. Early Late Incidence 5–10% 5% Relation to Almost immediate Second hour meals after meal Durations of 30–40 minutes 30–40 minutes attack Relief Lying down Food Aggravated More food Exercise by Precipitating Food, especially carbohydrate As early factor rich and wet dumping Tremor, Major Epigastric fullness, sweating, faintness, symptoms light-headedness, tachycardia, prostration colic, sometimes diarrhoea Stomach Gastrojejunal anastomosis Duodenum 50-cm limb of proximal jejunum Jejunojejunal anastomosis Figure 67.20 Roux-en-Y reconstruction following Billroth I gastrectomy. Note the length of the proximal jejunal limb required to minimise bilious re /f_l ux. This is due to reactive hypoglycaemia. The carbohydrate load in the small bowel causes a rise in the plasma glucose, which, in turn, causes insulin levels to rise, causing a secondary hypoglycaemia. This can be easily demonstrated by serial measurements of blood glucose in a patient following a test meal. The treatment is essentially the same as for early dump ing. Octreotide is very e ff ective in dealing with this problem. Postvagotomy diarrhoea This can be the most devastating symptom to a ffl ict patients having peptic ulcer surgery . Most patients will have some loose ness of bowel action (with the exception of highly selective vagotomy), but it may be intractable in approximately 5%. The cause is uncertain but is related to rapid gastric emptying, denervation of the upper g astrointestinal tract and an exag gerated gastrointestinal peptide response. Many patients with severe diarrhoea do not have other symptoms of dumping and likewise some patients with dumping do not experience significant diar rhoea. In general, patients should be managed as for early dumping and antidiarrhoeal preparations may be of value. Octreotide is not e ff ective and the results of revisional surgery are unpredictable. Malignant transformation Partial gastrectomy or vagotomy and drainage are indepen dent risk factors for development of gastric cancer as bile reflux gastritis, intestinal metaplasia and gastric cancer are linked. The lag phase between operation and the development of malignancy is at least 10 years. Highly selective vagotom does not seem to be associated with an increased long-term incidence of gastric cancer. Nutritional consequences Nutritional disorders are more common after gastrectomy than after vagotomy and drainage. Weight loss is common after gastrectomy and patients may never return to their original weight. Taking more frequent small meals is often useful. Henry Hamilton Bailey , 1894–1961, surgeon, The Royal Northern Hospital, London, UK. vagotomy and drainage. Reduced iron absorption is proba - deficiency occurs bly the most important factor. Vitamin B 12 after total gastrectomy; however, it may be years before meg - aloblastic anaemia is clinically apparent. Vitamin B supple - 12 mentation after total gastrectomy is essential. Rarely , vitamin B deficiency may occur after lesser forms of gastrectomy . In 12 - such patients the cause is probably a combination of reduced intrinsic factor production and bacterial colonisation, which results in vitamin B being metabolised in the gut, preventing 12 absorption. Bone disease is seen principally after gastrectomy and - mainly in women. The condition is essentially indistinguish - able from the osteoporosis commonly seen in postmenopausal women. It is only the frequency and magnitude of the disorder that distinguish it. Treatment is with dietary supplementation, - calcium and vitamin D, and e xercise. Gallstones Following truncal vagotomy , the biliary tree is denervated, leading to cholestasis and gallstone formation. Symptomatic patients require cholecystectomy; however, this may induce or worsen other postpeptic ulcer surgery syndromes such as bilious vomiting and postvagotomy diarrhoea. - Figure 67.21 A sketch of Mr Hamilton Bailey watching for abdominal movement on respiration. In the case of a classically presenting perfo rated ulcer, the abdominal movement is restricted or absent. Site Site The proximal stomach is now the most common site for gastric cancer in the West. Because the lower oesophagus is also a very common site of adenocarcinoma approximately 60% of all malignancies in the upper gastrointestinal tract occur in proximity to the GOJ (see Chapter 66 ). Adenocarcinoma at this site has doubled in incidence in the UK over the last 30 years. This high prevalence of proximal gastric cancer is not seen in Japan, where distal cancer still predominates, as it does in most of the rest of the world. Spread of carcinoma of the stomach Spread of carcinoma of the stomach Gastric cancer is an excellent example of the various distant metastases that are uncommon in the absence of lymph node metastases. The intestinal and di ff use types of gastric cancer spread di ff erently . The di ff use type spreads via the submucosal and subserosal lymphatic plexus and penetrates the gastric wall at an early stage. Direct spread The tumour penetrates the muscularis, serosa and ultimately adjacent organs such as the pancreas, colon and liver. Lymphatic spread This is by both permeation and emboli to the a ff ected tiers (see Lymphatic drainage of the stomach ) of nodes. This may be extensive, the tumour even appearing in the supra - clavicular nodes (Troisier’s sign). Unlike malignancies such as breast cancer, nodal involvement does not imply systemic dissemination. Blood-borne metastases This occurs first to the liver and subsequently to other organs, including lung and bone. This is uncommon in the absence of - nodal disease. Transperitoneal spread This is a common mode of spread once the tumour has reached the serosa of the stomach and indicates incurability . Tumours can manifest anywhere in the peritoneal cavity and (c) Mucosa Submucosa Type 1 Muscularis Serosa Type 2 Type 3 Type 4 Figure 67.27 Borrmann classi /f_i cation of advanced gastric cancer: type 1, polypoid; type 2, ulcerating; type 3, in /f_i ltrating/ulcerating; type 4, in /f_i ltrating/linitis plastica. Figure 67.26 Early gastric cancer: (a) type I; (b) type IIa; (c) type III (courtesy of Dr GNJ Tytgat, Amsterdam, The Netherlands). (a) (b) (d) (c) Figure 67.28 Advanced gastric cancer: (a) type I; (b) type II; (c) type III; (d) type IV (linitis plastica) (courtesy of Dr GNJ Tytgat, Amsterdam, The Netherlands). Tx Primary tumour cannot be assessed T0 No evidence of primary tumour Tis Carcinoma in situ : intraepithelial tumour without invasion of the lamina propria, high-grade dysplasia T1 Tumour involves lamina propria, muscularis mucosae or submucosa T1a Tumour invades lamina propria or muscularis mucosae T1b Tumour invades submucosa T2 Tumour invades muscularis propria T3 Tumour involves subserosa T4 Tumour perforates serosa (visceral peritoneum) or invades adjacent structures T4a Tumour perforates serosa T4b Tumour invades adjacent structures Nx Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in 1 or 2 regional lymph nodes N2 Metastasis in 3–6 regional lymph nodes N3 Metastasis in 7 or more regional lymph nodes N3a Metastasis in 7–15 regional lymph nodes N3b Metastasis in 16 or more regional lymph nodes M0 No distant metastasis M1 Distant metastasis Involvement of non-regional intra-abdominal lymph nodes such as retropancreatic, mesenteric and para-aortic groups is considered to be distant metastasis (M1) Involvement of the liver or the presence of peritoneal seedlings is also staged as M1 Staging IA T1 IB T1 T2 IIA T1 T2 T3 IIB T1 T2 T3 T4a IIIA T2 T3 T4a IIIB T3 T4a T4b T4a IIIC T4b Any T IV N0 M0 N1 M0 N0 M0 N2 M0 N1 M0 N0 M0 N3 M0 N2 M0 N1 M0 N0 M0 N3 M0 N2 M0 N1 M0 N3 M0 N2 M0 N0–1 M0 N3 M0 N2–3 M0 Any N M1 may be palpated either abdominally or rectally as a tumour ‘shelf ’. The ovaries may sometimes be the sole site of transcoe lomic spread (Krukenberg’s tumours). Tumour may spread via the abdominal cavity to the umbilicus (Sister Joseph’s nodule). Transperitoneal spread of gastric cancer can be detected most e ff ectively by laparoscopy and cytology . Staging Staging The International Union Against Cancer (UICC) staging system is shown in Table 67.6 . Important changes have been made in the seventh and eighth editions of the TNM staging system that are worthy of discussion. In an attempt to reflect the current evidence base and to improve outcome prediction for individual patients, all gastric tumours whose epicentre is within 5 /uni00A0 cm of the GOJ and extend into the oesophagus are now classified according to the oesophageal system. Tumours whose epicentre is within 5 /uni00A0 cm of the GOJ but do not extend into the oesophagus, and all other gastric cancers, are staged using the revised gastric staging system. In addition, any tumour that perforates the serosa is now classified as T4 disease. Stress gastritis Stress gastritis This is a common sequel of serious illness or injury and is characterised by a reduction in the blood supply to the gastric mucosa. Although common, this is not usually recognised unless stress ulceration and bleeding supervene, in which case treatment can be di ffi cult. Prevention is much easier than treating it, hence routine use of H antagonists with or 2 without barrier agents, such as sucralfate, in patients who are on intensive care. These measures have been shown to reduce the incidence of bleeding from stress ulceration. Stress ulceration Stress ulceration This commonly occurs in patients with major injury or illness who have undergone major surgery or who have major - comorbidity . Many such patients are found in intensive care - units. The incidence has reduced in recent years owing to the widespread use of prophylactic acid inhibition and nasogastric or oral administration of sucralfate. Endoscopic means of treating stress ulceration may be ine ff ective and operation may be required. The principles of management are the same as for a chronic ulcer. Subtotal gastrectomy Subtotal gastrectomy For tumours in the distal stomach, it is unnecessary to remove the whole stomach. However, the operation is very similar to that of a total gastrectomy except that the proximal stomach Frederick Eugene Basil Foley , 1891–1966, urologist, St Paul Ramsey Medical Center, St Paul, MN, USA. gastric arteries. Following the resection, the simplest form of reconstruction is to close the stomach from the lesser curve, near the GOJ, with either sutures or staples and then ). In perform an anastomosis of the greater curve to the jejunum. Although this can be performed as in a Billroth II/Pólya-type gastrectomy , this reconstruction may result in quite marked enterogastric reflux and bile reflux oesophagitis; the preferred - reconstruction is to use a Roux loop. The molecular pathology of gastric cancer The molecular pathology of gastric cancer Understanding of the molecular pathology of gastric cancer has been revolutionised by the application of next-generation sequencing platforms to the disease. The Cancer Genome Atlas (TCGA) group described four molecular subtypes of gastric cancer: Epstein–Barr virus positive, microsatellite unstable, genomically stable and chromosomal instability . Recognition of these subgroups and their underlying common gene mutations and driver events is leading to the development of targeted therapies, including immunotherapies. Similar genetic classifications are now available for other tumours of the gastrointestinal tract, meaning that novel treatments can be applied across tumour types. A range of mutations in genes related to genome integ rity (e.g. BRCA2, TP53, ARID1A ), chromatin remodelling (e.g. SMARCA1, CHD3, CHD4 ) and cell–cell adhesion and motility (e.g. RHOA, CDH1 ) have been described in gastric cancer. In addition, cell signalling pathways commonly mutated in other solid organ tumours are also often found perturbed in gastric Michael Anthony Epstein , b. 1921, Professor of Pathology , University of Bristol, Bristol, UK. Yvonne Barr , 1931–2016, virologist who emigrated to Australia. Epstein and Barr discovered this virus in 1964. Charles Emile Troisier , 1844–1919, Professor of Pathology , Paris, France. specific small-molecule inhibitors. Unsurprisingly gastric can - cer exhibits a range of mutations in receptor tyrosine kinases and PI3K/MAPK signalling (see Chapter 11 ). The rapid dev elopment of sequencing technologies, includ - ing single-cell platforms and the dev elopment of real-time sequencing, o ff ers the promise of precision therapy for gastric cancer in the future, b ut currently treatment is still based on surgery with or without conventional chemo/radiotherapy . Mucosa Type I Submucosa Muscularis Type IIa Type IIb Type IIc Type III Cancer Figure 67.25 Japanese classi /f_i cation of early gastric cancer: type I, protruding; type II, super /f_i cial, a, elevated, b, /f_l at, c, depressed; type III, ulcerated. Treatment of peptic ulceration Treatment of peptic ulceration The vast majority of uncomplicated peptic ulcers are treated medically . Surgical treatment of uncomplicated peptic ulcer - ation has decreased markedly and is now seldom performed. Surgical treatment was aimed principally at reducing gastric acid secretion and, in the case of gastric ulceration, removing the diseased mucosa. When originally devised, medical treat - ment also aimed to r educe gastric acid secretion, initially using the highly successful H -receptor antagonist and, subsequently , 2 PPIs. This has now largely given way to H. pylori eradication therapy . Medical treatment It is reasonable to suggest modifications to the patient’s life - style, particularly the cessation of cigarette smoking; however, pharmacological measures form the mainstay of treatment. H -receptor antagonists and proton pump 2 inhibitors H -antagonists revolutionised the management of peptic 2 ulceration. Most duodenal ulcers and gastric ulcers can be healed by a few weeks of treatment. There remained, however, tional doses of H -receptor antagonists. This is largely now 2 irrelevant as PPIs can e ff ectively render a patient achlorhydric and all benign ulcers will heal using these drugs, the majority within 2 weeks. Symptom relief is rapid, most patients being asymptomatic within a few days. Like H -antagonists, PPIs are 2 safe and relatively devoid of serious side e ff ects. The problem with all gastric antisecretory agents is that, following cessation of therapy , relapse is almost universal. Eradication therapy Eradication therapy is now routinely given to patients with peptic ulceration. If H. pylori is the principal aetiological factor (essentially in patient not taking NSAIDs) then complete eradication of the organism will cure the disease. Reinfection as an adult is uncommon. Eradication therapy is therefore the mainstay of treatment for peptic ulceration. It is extremely economical by comparison with prolonged courses of anti- secretory agents or surgery . It is also considerably safer than surgical treatment. There are some patients with peptic ulcers in whom erad ication therapy may not be appropriate, and this includes patients with NSAID-associated ulcers. Such patients should avoid these drugs if possible; if not, they should be co- prescribed with a potent antisecr etory agent. Similarly , patients with stomal ulceration are not e ff ectively treated with eradication therapy and require prolonged prescription of antisecretory agents. Patients with Zollinger–Ellison syndrome should be treated in the long term with PPIs unless the tumour can be adequately managed by surgery . Ulcers that fail to heal The introduction of antisecretory agents and e ff ective treat ments for H. pylori have revolutionised the management of peptic ulcers. Despite these advances, peptic ulceration fails to heal in a small minority of patients. Endoscopic re-evaluation should be regarded as mandatory to confirm healing of all gastric ulcers. Furthermore, endoscopy permits the di ff erenti ation between a refractory ulcer and persistent symptoms despite ulcer healing. The most common cause of failed healing is persistent H. pylori infection. Biopsies should be repeated at the time of endoscopy as false-negative results with breath tests may be expected soon after eradication therapy and serum antibody titres may not fall for 6 months after successful eradi cation. Failure of eradication is usually due to poor compliance or bacterial resistance and bacteriological culture will guide further attempts at H. pylori eradication. The ingestion of NSAIDs should once again be addressed. A diagnosis of Zollinger–Ellison syndrome (described in detail in Zollinger– Ellison syndrome ) should be suspected in H. pylori -negative, non-NSAID-related peptic ulceration and serum gastrin levels should be measured. V ery rarely a recently described auto immune immunoglobulin G4-related (IgG4) phenomenon is the cause of resistant and recurrent gastric ulceration. Trichobezoar and phytobezoar Trichobezoar and phytobezoar Trichobezoar (hair balls) ( Figure 67.34 ) are unusual and are virtually exclusively found in young psychiatric patients. It is caused by the ingestion of hair, which remains undigested in the stomach. The hair ball can lead to ulceration and gastro intestinal bleeding, perforation or obstruction. The diagnosis is made easily at endoscopy . Treatment consists of removal of the bezoar, which may requir e open surgical treatment. Phytobezoars are made of vegetable matter and are found principally in patients who have gastric stasis, usually following gastric surgery . - - y - - Figure 67.34 Trichobezoar of the stomach in a girl aged 15 years. Tumours Tumours ly All gastric neoplasms may present with chronic or acute upper - gastrointestinal bleeding. Bleeding is not normally torrential but can be unremitting. Treatment is that of the underlying tumour as discussed in Gastric cancer . Figure 67.23 Endoscopic view of actively bleeding Dieulafoy lesion in the gastric fundus. Ultrasonography Ultrasonography Standard ultrasonography can be used to investigate the stomach but used conventionally it is less sensitive than other modalities. In contrast, endoluminal ultrasonography and laparoscopic ultrasonography are probably the most sensitive techniques available in preoperative local staging of gastric cancer. In endoluminal ultrasonography , the transducer is usually attached to the distal tip of the instrument. Five layers ( Figure 67.5 ) of the gastric wall may be identified on endolu minal ultrasonography and the depth of invasion of a tumour can be assessed (90% accuracy for the ‘T’ component of the staging). Enlarged lymph nodes can also be identified and the accuracy of the technique is about 80% in this situation. Laparoscopic ultrasonography is also a v ery sensitive imaging modality , to a large measure because of the laparoscopy itself (see Laparoscopy ). Ultrasonography can be used to assess gastric emptying. Swallowed contrast that is designed to be easily seen using an ultrasound transducer is used. Emptying of the contrast is followed directly . The accuracy of the technique is similar to that of radioisotope gastric emptying studies (see Gastric emptying studies ). Volvulus of the stomach Volvulus of the stomach Rotation of the stomach usually occurs around the axis and between its two fixed points, i.e. the cardia and the pylorus. In theory , rotation can occur in the horizontal (organoaxial) or vertical (mesenteroaxial) direction, but the former is more common. V olvulus is usually associated with a large diaphrag - matic defect around the oesophagus (paraoesophageal herni - ation) ( Figure 67.35 ). Commonly the transverse colon moves upwards to lie under the left diaphragm, taking the stomach with - it. The stomach and colon may both enter the chest through the eventration of the diaphragm. The condition is commonly chronic, the patient presenting with di ffi culty in ea ting. An acute presentation with ischaemia may occur. Endoscopically , it can be extremely di ffi cult to identify the anatomy , and this is one situation in which the contrast radiograph is superior. If symptomatic, surgical treatment is required increasingly by a laparoscopic approach. If there is a hernia, the sac and its contents (usually the stomach) should be reduced. The defect in the diaphragm should be closed, if necessary , with a mesh. It is advisable to separate the stomach from the transverse colon and to perform an anterior gastropexy to fix the stomach to the anterior abdominal wall. Figure 67.35 Barium meal showing organoaxial volvulus of the stom ach associated with eventration of the diaphragm. Zollinger–Ellison syndrome Zollinger–Ellison syndrome This syndrome is mentioned here because the gastrin - producing endocrine tumour is often found in the duodenal loop, although it also occurs in the pancreas, especially the head. It is a cause of persistent peptic ulceration. Before the development of potent gastric antisecretory agents, the condi - tion was recognised by sometimes fulminant peptic ulceration - that did not respond to gastric surgery short of total gastrec - tomy . The advent of PPIs such as omepraz ole has rendered this extreme endocrine condition fully controllable, but also - less easily recognised. Gastrinomas may be either sporadic or associated with the autosomal dominantly inherited multiple endocrine neopla - sia (MEN) type I (in which a parathyr oid adenoma is almost invariable). The tumours are most commonly f ound in the ‘gastrinoma triangle’, which is defined by the junction of the cystic duct and common bile duct superiorly , the junction of the second and third parts of the duodenum inferiorly and the junction of the neck and body of the pancreas medially (essentially the superior mesenteric artery). Many are found - in the duodenal loop, presumably arising in the G cells found in Brunner’s glands. It is extremely important that the duode - nal wall is carefully inspected endoscopically and at operation. ects into the medial wall of the duodenum. Even malignant sporadic gastrinomas may have a very indolent course. The palliative resection of liver metastases may be beneficial and, as for other gut endocrine tumours, liver transplantation is practised in some centres with reason ab le long-term results. However, a minority of tumours found to the left of the superior mesenteric artery (outside the ‘trian gle’) seem to have a worse prognosis, with more having liver metastases at presentation. In MEN type I, the tumours ma be multiple and the condition is incurable. Even in this situ ation, surgical treatment should be employed to remo ve any obvious tumours and associated lymphatic metastases, as good palliation may be achieved (see Chapter 57 ). suspected peptic ulcer suspected peptic ulcer Gastroduodenoscopy oper - In the stomach, any abnormal lesion should be biopsied, and in the case of a suspected benign gastric ulcer numerous biopsies must be taken in order to exclude, as far as possible, the pres - ence of a malignancy . Commonly , biopsies of the antrum will be taken to see whether there is histological evidence of gastri - tis and a Campylobacter -like organism (CLO) test performed to determine the presence of H. pylori . A ‘U’ manoeuvre should be carried out to inspect the incisura, lesser curve - and gastro-oesophageal junction (GOJ), given the increasing incidence of cancer at the GOJ (see Chapter 66 ). Similarly , if a stoma is present, for instance after gastroenterostomy or Billroth II gastrectomy , it is important to enter both a ff erent y and e ff erent loops. Almost all stomal ulcers will be close to the junction between the jejunal and gastric mucosa. Attention should be given to the pylorus to note whether there is any prepyloric or pyloric channel ulceration, and also whether it is deformed, which is often the case with chronic duodenal ulceration. In the duodenum, care must be taken to view all of the first part and the endoscope advanced into the second part.