72 T_h e pancreas ANATOMY AND PHYSIOLOGY Anatomy ANATOMY AND PHYSIOLOGY Anatomy The name ‘pancreas’ is derived from the Greek ‘pan’ (all) and ‘kreas’ (flesh). For a long time, its glandular function was not understood and it was thought to act as a cushion for the stomach. The pancreas is situated in the retroperitoneum. It is divided into a head, which occupies 30% of the gland by mass, and a body and tail, which together constitute 70%. The head lies within the curve of the duodenum, overlying the body of the second lumbar vertebra and the vena cava. The aorta and the superior mesenteric vessels lie behind the neck of the gland. Coming o ff the side of the pancreatic head and passing to the left and behind the superior mesenteric vein is the uncinate process of the pancreas. Behind the neck of the pancreas, near its upper border, the superior mesenteric vein joins the splenic Paul Langerhans , 1847–1888, Professor of Pathological Anatomy , Freiberg, Germany vein to form the portal vein ( Figures 72.1 and 72.2 ). The tip of the pancreatic tail extends up to the splenic hilum. The pancreas weighs approximately 80 /uni00A0 g. Of this, 80–90% is composed of exocrine acinar tissue, which is organised into lobules. The main pancreatic duct branches into interlobular and intralobular ducts , ductules and, finally , acini. The main duct is lined by columnar epithelium, which becomes cuboi - dal in the ductules. Acinar cells are clumped around a central lumen, which communicates with the duct system. Clusters of endocrine cells, known as islets of Langerhans, are distributed throughout the pancreas. Islets consist of di ff er ent cell types: 75% are B cells (producing insulin); 20% are A cells (producing glucagon); and the remainder are D cells (producing soma - tostatin) and a small number of pancreatic polypeptide cells. Within an islet, the B cells form an inner core surrounded by the other cells. Capillaries draining the islet cells drain into the portal vein. There are nine key processes that occur during pancreatic embr yogenesis ( Table 72.1 ). Malrotation of the ventral bud in the fifth week results in an annular pancreas, while the mode of , described the islets in 1869, in his doctoral thesis. Splenic artery Splenic Left Inferior vein kidney vena cava Spleen Aorta Portal vein Right kidney Left re nal vessels Right Inferior re nal Right mesenteric vessels ureter Left vein Superior ureter mesenteric vein Figure 72.1 The posterior relations of the pancreas. Assessment and management of pancreatitis • Diagnosis and treatment of pancreatic cancer • Pancreatoduodenal artery Head Neck Ta il Body Superior mesenteric artery Uncinate Superior mesenteric vein process Figure 72.2 Transverse section of the pancreas. Note the position of the uncinate process behind the vessels. ble ductular patterns. Between the 12th and 40th weeks of fetal life, the pancreas di ff erentiates into exocrine and endocrine elements. The primitive ducts and their ductules are respon sible for the lobular arrangement of the pancreas . Congenital anomalies of the pancreas are varied and arise during the early Summary box 72.1 Anomalies of the pancreas /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF Abraham Vater , 1704–1751, Professor of Anatomy and Botany , and later of Pathology and Therapeutics, Wittenberg, Germany . Johann Georg Wirsung , 1589–1643, Professor of Anatomy , Padua, Italy . Giovanni Domenico Santorini , 1701–1737, Professor of Anatomy and Medicine, V enice, Italy . His drawings of the accessory pancreatic duct were published after his death. Eugen von Hippel , 1866–1939, Professor of Ophthalmology , Göttingen, Germany . Arvid Lindau , 1892–1958, pathologist, Lund, Sweden, established the link between the retinal angiomatosis described by von Hippel and the cerebellar and visceral components of the syndrome. Ruggero Oddi , 1866–1913, anatomist and physiologist, Perugia, Italy . variable as a result of the primordial bud development. The dorsal duct is expressed in a variable manner in the adult, as - outlined in Figure 72.3 . Approximately 10% of patients will have a significant flow from the main duct through the acces - sory papilla. The anatomy of the main duodenal papilla, also known as the ampulla of Vater, is also variable ( Figure 72.4 ). The outlet of each duct is protected by a complex sphincter mechanism (sphincter of Oddi) ( Figure 72.5 ). (a) (b) (e) (c) (f) (g) (d) TABLE 72.1 Steps in the development of the pancreas. 1 Day 26 Dorsal pancreatic duct arises from the dorsal side of the duodenum 2 Day 32 Ventral bud arises from the base of the hepatic diverticulum 3 Day 37 Contact occurs between the two buds. Fusion by the end of week 6 4 Week 6 Ventral bud produces the head and uncinate process 5 Week 6 Ducts fuse 6 Week 6 Ventral duct and distal portion of the dorsal duct form the main duct (duct of Wirsung) 7 Week 6 Proximal dorsal duct forms the duct of Santorini 8 Month 3 Acini appear 9 Months Islets of Langerhans appear and become 3–4 biologically active Aplasia Hypoplasia Hyperplasia Hypertrophy Dysplasia a Variations and anomalies of the ducts Pancreas divisum Rotational anomalies a Annular pancreas Pancreatic gallbladder a Polycystic disease Congenital pancreatic cysts a Cystic /f_i brosis von Hippel–Lindau syndrome a Ectopic pancreatic tissue, accessory pancreas Vascular anomalies a Choledochal cysts Horseshoe pancreas a The more frequent anomalies encountered in surgical practice. ‘Normal’ pancreatic ducts 60% Suppression of the Suppression of the accessory duct main duct (Santorini) (Wirsung) Pancreas 30% 10% divisum Wirsung branch Wirsung branch Figure 72.3 Variations in the pancreatic ducts. (a) Normal. (b–d) Pro gressive suppression of the accessory duct (30%). (e–g) Progressive suppression of the main duct (10%). (f, g) Pancreas divisum. Figure 72.4 Variations in the relation of the common bile duct and main pancreatic duct at the main duodenal papilla. In (a) there is a common channel with no sphincter mechanism protecting /f_l ow between the ducts. In (b) there is a partial common channel, while in (c) there is separation of the two channels. Gallstone pancreatitis is more likely with (a) and (b) . 1 2 3 4 Figure 72.5 The complexity of the sphincter of Oddi. (1) Superior cho ledochal sphincter; (2) inferior choledochal sphincter; (3) ampullary sphincter; (4) pancreatic sphincter. Acute pancreatitis Acute pancreatitis Incidence Acute pancreatitis accounts for 3% of all cases of abdominal pain among patients admitted to hospital in the UK. The hospital admission rate for acute pancreatitis is 9.8 per year per 100 /uni00A0 000 population in the UK, although worldwide the annual incidence may range from 5 to 50 per 100 /uni00A0 000. The disease may occur at any age, with a peak in young men and older women. Summary box 72.5 Possible causes of acute pancreatitis /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF The two major causes of acute pancreatitis are biliary calculi, which occur in 50–70% of patients, and alcohol abuse, which accounts for 25% of cases. Gallstone pancreatitis is thought to be triggered by the passage of gallstones down the common bile duct. If the biliary and pancreatic ducts join to share a common channel before ending at the ampulla, then obstruc - tion of this passage may lead to reflux of bile or activated pancreatic enzymes into the pancreatic duct. Patients who have small gallstones and a wide cystic duct may be at a higher risk of passing stones . The proposed mechanisms for alcoholic pancreatitis include the e ff ects of diet, malnutrition, direct toxicity of alcohol, concomitant tobacco smoking, hyperse - cretion, duct obstruction or reflux, and hyperlipidaemia. The - remaining cases may be due to rare causes or may be idiopathic. - Among patients who undergo ERCP , 1–3% develop pan - creatitis, pr obably as a consequence of duct disruption and enzyme extravasation. Patients with sphincter of Oddi dys - function or a history of recurrent pancreatitis, and those w ho undergo sphincterotomy or balloon dilatation of the sphinc - ter, carry a higher risk of developing post-ERCP pancreatitis . Patients who have undergone upper abdominal or cardiotho - racic surgery may develop acute pancreatitis in the postoper - ative phase , as may those who have su ff ered blunt abdominal trauma. Hereditary pancreatitis is a rare familial condition associ - ated with mutations of the cationic trypsinogen gene. Patients have a tendency to su ff er acute pancreatitis while in their teens, progress to chronic pancreatitis in the next two decades and have a high risk (possib ly up to 40%) of developing pancreatic cancer by the age of 70 years. Hypertriglyceridaemia should be excluded. Occasionally , tumours at the ampulla of Vater may cause acute pancreatitis. It is important to check the serum calcium level, a fasting lipid profile, autoimmune mar kers and viral titres in patients with so-called idiopathic acute pancreatitis. It is equally important to take a detailed drug history and remem - ber the association of corticosteroids, azathioprine, asparagi - nase and valproic acid with acute pancreatitis. Statins (taken over a long time) and gliptins have been linked with pancre - atitis, but the evidence is slim. It is essential to exclude tiny gallstones. A careful search for the aetiology must be made in all cases, and no more than 20% of cases should fall into the idiopathic category . Summary box 72.6 Aetiology of acute pancreatitis /uni25CF /uni25CF /uni25CF Clinical presentation Pain is the cardinal symptom. It characteristically develops quickly , reaching maximum intensity within minutes rather than hours and persists for hours or even days. The pain is Gallstones Alcoholism Post ERCP Abdominal trauma Following biliary, upper gastrointestinal or cardiothoracic surgery Ampullary tumour Drugs (corticosteroids, azathioprine, asparaginase, valproic acid, thiazides, oestrogens) Hyperparathyroidism Hypercalcaemia Hypertriglyceridaemia Pancreas divisum Sphincter of Oddi dysfunction Autoimmune pancreatitis Hereditary pancreatitis Viral infections (mumps, coxsackie B) Malnutrition Scorpion bite Idiopathic It is essential to establish the aetiology Investigate thoroughly before labelling it as ‘idiopathic’ If due to gallstones, cholecystectomy is desirable during the same admission of analgesics. Pain is usually experienced first in the epigas trium but may be localised to either upper quadrant or felt di ff usely throughout the abdomen. There is radiation to the back in about 50% of patients, and some patients may g relief by sitting or leaning forwards. The suddenness of onset may simulate a perforated peptic ulcer, while biliary colic or acute cholecystitis can be mimicked if the pain is maximal in the right upper quadrant. Radiation to the chest can simulate myocardial infarction, pneumonia or pleuritic pain. In fact, acute pancreatitis can mimic most causes of the acute abdo men and should seldom be discounted in di ff erential diagnosis. Nausea, repeated vomiting and retching are usually marked. The retching may persist despite the stomach being kept empty by nasogastric aspiration. Hiccoughs can be trou blesome and may be due to gastric distension or irrita the diaphragm. On examination, the appearance may be that of a patient who is well or, at the other extreme, one who is gravely ill with profound shock, toxicity and confusion. Tachypnoea is com mon, tachycardia is usual and hypotension may be present. The body temperature is often normal or even subnormal, but frequently rises as inflammation develops. It is useful to reiter ate here tha t SIRS is defined by the presence of two or more of the following criteria: heart rate >90/min, core temperature <36°C or >38°C, respirations >20/min or P CO <32 /uni00A0 mmHg, 2 3 and white blood cell count <4000 or >12 /uni00A0 000/mm (see also Chapter 2 ). Mild icterus can be caused by biliary obstruction in gallstone pancreatitis, and an acute swinging pyrexia sug gests cholangitis. Bleeding into the fascial planes can produce bluish discoloration of the flanks (Grey Turner’s sign) or umbi licus (Cullen’s sign). Subcutaneous fat necr osis may produce small, red, tender nodules on the skin of the legs. Abdominal examination may reveal distension due to ileus or, more rarely , ascites with shifting dullness. A mass can develop in the epig astrium owing to inflammation. There is usually muscle guarding in the upper abdomen, although marked rigidity is unusual. A pleural e ff usion is present in 10–20% of patients. Pulmonary oedema and pneumonitis are also described and may give rise to the di ff erential diagnosis of pneumonia or myocardial infarction. The patient may be con fused and exhibit the signs of metabolic derangement together with hypoxaemia. Investigations Typically , the diagnosis is made on the basis of the clinical presentation and an elevated serum amylase level. A serum amylase level three times above normal is indicative of the disease. A normal serum amylase level does not exclude acute pancreatitis, particularly if there is delay in presentation. The serum lipase level provides a more sensitive and specific test George Grey Turner , 1877–1951, Professor of Surgery , Durham University , Durham (1927–1934), and at the Postgraduate Medical School, Hammersmith, London, UK (1934–1945). Thomas Stephen Cullen , 1870–1953, Professor of Gynecology , Johns Hopkins University , Baltimore, MD, USA. Described bluish discoloration of the perium bilical skin as a sign of ruptured ectopic pregnancy . John HC Ranson , 1938–1995, Professor of Surgery , New Y ork University School of Medicine, New Y ork, NY , USA. J ohn C Marshall , contemporary , trauma surgeon and intensivist, St Michael’s Hospital, Toronto, Canada. - abdomen have to be excluded, contrast-enhanced CT is the best single imaging investigation. ain Summary box 72.7 Investigations in acute pancreatitis should be aimed at answering three questions: /uni25CF /uni25CF - /uni25CF - Assessment of severity tion of It is important to identify those patients who will develop severe pancreatitis as they require aggressive early manage - ment and possibly transfer to a specialist unit. A severe attack may be heralded by an initial clinical impression of a very ill - patient and a worsening physiological state at 24–48 hours. Various prognostic scoring systems hav e been used, all aimed at predicting persistent organ failure, particularly respiratory , - cardiac and renal. Severity stratification assessments should be performed in patients at 24 hours, 48 hours and 7 days after admission. The Ranson and Glasgow scoring systems are specific for acute pancreatitis, and a score of 3 or more at 48 hours indicates a severe attack ( Table 72.3 ). Several other systems that are used in intensive care units can also be applied. - These include the APACHE, SAPS, SOFA, MODS and modi - fied Marshall scoring systems (the latter has the advantage of - simplicity). Regardless of the system used, persisting organ fail - ure indicates a severe attack. A serum C-reactive protein le vel >150 /uni00A0 mg/L at 48 hours after the onset of symptoms is also an indicator of severity . Patients with a body mass index over 30 are at higher risk of developing complications. A revision in 2013 of the Atlanta classification of acute pancreatitis (1992) recommends that patients with acute pancreatitis be stratified into three groups: /uni25CF Mild acute pancreatitis: /uni25CF - no organ failure; /uni25CF no local or systemic complications. /uni25CF Moderately severe acute pancreatitis: /uni25CF organ failure that resolves within 48 hours (transient organ failure); and/or /uni25CF local or systemic complications without persistent or - gan failure. /uni25CF Severe acute pancreatitis: /uni25CF persistent organ failure (>48 hours); /uni25CF single organ failure; /uni25CF multiple organ failure. - Is a diagnosis of acute pancreatitis correct? How severe is the attack? What is the aetiology? Imaging Plain erect chest and abdominal radiographs are not diagnostic of acute pancreatitis but are useful in the di ff erential diagnosis. Non-specific findings in pancreatitis include a generalised or local ileus (sentinel loop), a colon cut-o ff sign and a renal halo sign. Occasionally , calcified gallstones or pancreatic calcifi cation may be seen. A chest radiograph may show a pleural e ff usion and, in severe cases, a di ff use alveolar interstitial shadowing may suggest acute respiratory distress syndrome. Ultrasonography does not estab lish a diagnosis of acute pancreatitis. The swollen pancreas may be seen, but ultraso nography should be performed within 24 hours in all patients to detect gallstones as a potential cause , rule out acute chole cystitis as a di ff erential diagnosis and determine whether the common bile duct is dilated. CT is not necessary for all patients, particularly those deemed to have a mild attack on prognostic criteria. But a contrast-enhanced CT is indica ted in the following situations: /uni25CF If there is diagnostic uncertainty . /uni25CF In patients with severe acute pancreatitis to distinguish in terstitial from necrotising pancreatitis ( Figure 72.22 the first 72 hours, CT may underestimate the extent of necrosis. The severity of pancreatitis detected on CT may be staged according to the Balthazar criteria. /uni25CF In patients with organ failure, signs of sepsis or progressive clinical deterioration. /uni25CF When a localised complication is suspected, such as fluid collection, pseudocyst or a pseudoaneurysm. Cross-sectional MRI can yield similar information to that obtained by CT . EUS and MRCP can help in detecting stones in the common bile duct and directly assessing the pancreatic par enchyma but are not widely available. ERCP allows the identification and removal of stones in the common bile duct Emil J Balthazar , contemporary , Professor Emeritus, Department of Radiology , New Y ork University , New Y ork, NY , USA. - x - - - ). In in gallstone pancreatitis. In patients with severe acute gallstone pancreatitis and signs of ongoing biliary obstruction and chol - angitis, an urgent ERCP should be sought. The presentation is so variable that sometimes even an experienced clinician can be mistaken. While this is not desir - able, occasionally the diagnosis is only made at laparotomy . The appearances at laparotomy are characteristic ( Figure 72.23 ). disease is classi /f_i ed as severe when three or more factors are present. Ranson score On admission Age >55 years 9 White blood cell count >16 × 10 /L Blood glucose >11 /uni00A0 mmol/L (>200 /uni00A0 mg/dL) LDH >350 units/L AST >250 units/L Within 48 hours Haematocrit fall of 10% or greater Blood urea nitrogen rise >5 /uni00A0 mg/dL (1.8 /uni00A0 mmol/L) despite /f_l uids Arterial oxygen saturation (PaO ) <8 /uni00A0 kPa (60 /uni00A0 mmHg) 2 Serum calcium <8 /uni00A0 mg/dL (2.0 /uni00A0 mmol/L) Base de /f_i cit >4 /uni00A0 mmol/L Fluid sequestration >6 litres AST, aspartate aminotransferase; LDH, lactate dehydrogenase; PaO Glasgow score Within 48 hours Age >55 years 9 White blood cell count >15 × 10 /L Blood glucose >10 /uni00A0 mmol/L (no history of diabetes) LDH >600 units/L or AST >200 units/L Serum urea >16 /uni00A0 mmol/L (no response to intravenous /f_l uids) Arterial oxygen saturation (PaO ) <8 /uni00A0 kPa (60 /uni00A0 mmHg) 2 Serum calcium <2.0 /uni00A0 mmol/L Serum albumin <32 /uni00A0 g/L , arterial oxygen tension. 2 Figure 72.22 Contrast-enhanced computed tomography scan showing acute necrotising pancreatitis. Note the area of reduced enhancement in the pancreas (marked X), the peripancreatic oedema and stranding of the fatty tissues (courtesy of Dr Niall Power). Management If after initial assessment a patient is considered to have a mild attack of pancreatitis, a conservative approach is indicated with intravenous fluid administration and frequent, but non-invasive, observation. A brief period of fasting may be sensible in a patient who is nauseated and in pain, but there is little physiological justification for keeping patients on a prolonged ‘nil by mouth’ regimen. Antibiotics are not indicated. Apart from analgesics and antiemetics, no drugs or interventions are warranted, and CT scanning is unnecessary unless there is evidence of deterioration. However, if a stable patient meets the prognostic criteria for a severe attack of pancreatitis, then a more aggressive approach is required, with admission to a high-dependency or intensive care unit and invasive monitoring ( Table 72.4 ). Adequate analgesia should be administered. Aggressive fluid resuscitation is important, guided by frequent measure ment of vital signs, urine output and central venous pr Supplemental oxygen should be administered and serial arte rial blood gas analysis performed. The haematocrit, clotting profile, blood glucose and serum levels of calcium and magne sium should be closely monitored. A nasogastric tube is not essential but may be of value in patients with vomiting. Specific tr eatments such as aprotinin, somatostatin analogues, platelet-activating factor inhibitors and selective gut decontamination hav e failed to improve out come in numerous clinical trials. There are no data to support a practice of ‘resting’ the pancreas and feeding only by the parenteral or nasojejunal routes. If nutritional support is felt to be necessary , enteral nutrition (e.g. feeding via a nasogastric tube) should be used. There is some evidence to support the use of prophylactic antibiotics in patients with severe acute pancreatitis but there is no consensus. The rationale is to prevent local and other septic complications. T he regimens used include intravenous cefuroxime, or imipenem, or ciprofloxacin plus metronidazole. The duration of antibiotic prophylaxis should not exceed 14 days. Additional antibiotic use should be guided by microbio - logical cultures. If, however, there is evidence of cholangitis or concomitant respiratory or urinary infection then antibiotics should be given promptly . If gallstones are the cause of an attack of predicted or proven se vere pancreatitis, or if the patient has jaundice, chol - angitis or a dilated common bile duct, ERCP should be carried out within 72 hour s of the onset of symptoms as sphincterot - omy and clearance of the bile duct can reduce the incidence of - infective complications. In patients with cholangitis, sphincter - essure. otomy should be car ried out or a biliary stent placed to drain - the duct; however, ERCP is an invasiv e procedure and carries a small risk of worsening the pancreatitis . - Systemic complications Pancreatitis may involve all organ systems ( Table 72.5 ) and should be managed by a multidisciplinary team including - intensive care specialists. When there is organ failure, appro - priate supportive therapies may include inotropic support for haemodynamic instability , haemofiltration in the event of renal failure, ventilatory support for respirator y failure and Figure 72.23 Widespread fat necrosis of the omentum. A test tube has been /f_i lled with blood-stained peritoneal /f_l uid. This specimen was rich in amylase. Fat necroses are dull, opaque, yellow-white areas suggestive of drops of wax. They are most abundant in the vicinity of the pancreas but are widespread in the greater omentum and the mesentery. Fat necroses consist of small islands of saponi /f_i cation caused by the liberation of lipase, which splits into glycerol and fatty acids. Free fatty acids combine with calcium to form soaps (fatty necrosis) (courtesy of Dr GD Adhia, Mumbai, India). pancreatitis. Admission to HDU/ICU Analgesia Aggressive /f_l uid rehydration Supplemental oxygen Invasive monitoring of vital signs, central venous pressure, urine output, blood gases Frequent monitoring of haematological and biochemical parameters (including liver and renal function, clotting, serum calcium, blood glucose) Nasogastric drainage (only initially) Antibiotics if cholangitis suspected; prophylactic antibiotics can be considered CT scan essential if organ failure, clinical deterioration or signs of sepsis develop ERCP within 72 hours for severe gallstone pancreatitis or signs of cholangitis Supportive therapy for organ failure if it develops (inotropes, ventilatory support, haemo /f_i ltration, etc.) If nutritional support is required, consider enteral (nasogastric) feeding CT, computed tomography; ERCP , endoscopic retrograde cholangio pancreatography; HDU, high-dependency unit; ICU, intensive care unit. role during the initial period of resuscitation and stabilisation and is reserved for the patient who deteriorates following successful stabilisation. Local complications and their management Once the patient survives the acute phase and major organ failure is controlled, local complications become pre-eminent as they carry a significant mortality . A CT scan should be performed if pain persists, signs of sepsis develop, organ dysfunction worsens or there is a further spike in the serum amylase level. The management is conservative with surgery only when conservative management has failed. Definitions are important. Terms such as ‘phlegmon’, which may refer to an abscess or to an inflammatory mass in the pancreas, are best avoided. Acute peripancreatic fluid collection Acute peripancreatic fluid collection (APFC) occurs early in the course of mild pancreatitis without necrosis and is located adjacent to the pancreas. It has no encapsulating wall and is confined within normal fascial planes. The fluid is sterile and most such collections resolve. No intervention is necessary unless a large collection causes symptoms or pressure e ff ects, in which case it can be percutaneously aspirated under ultrasound ultrasound guidance is another option. Sterile and infected pancreatic necrosis The term ‘pancreatic necrosis’ refers to a di ff use or focal area of non-viable parenchyma. This can be identified by an absence of parenchymal enhancement on CT with intravenous contrast. Pancreatic necrosis is typically associated with lysis of peripancreatic fat. This may lead to an acute necrotic collection (ANC). This is typically an intra- or extrapancreatic collection containing fluid and necrotic material, with no definable wall. Gradually , over a period of over 4 weeks, this may develop a well-defined inflammatory capsule and evolve into walled-o ff necrosis (WON). Collections associated with necrotising pancreatitis are sterile to begin with but often become subsequently infected, probably because of translocation of gut bacteria. Infected necrosis is associated with a mortality rate of up to 50%. Ster - ile necrotic ma terial should not be drained or interfered with. However, if the patient shows signs of sepsis, then one should determine whether the collection is infected ( Figur e 72.24 ). Aspiration fluid with a fine needle, percutaneously under CT or ultrasound guidance, can provide the answer. If the aspirate is purulent, drainage of the infected fluid should be carried out. Internal drainage into the stomach under endoscopic ultrasound guidance should be considered first. A plastic or covered metal stent can be used to create a communication between the collection and the gastric lumen. The stent may be left in for weeks if necessary and may need to be changed if blocked. If endoscopic internal drainage is not possible, then percutaneous drainage should be considered. The tube drain inserted should have the widest bore possible. The aspirate should be sent for microbiological assessment and appropriate antibiotic therapy should be commenced as per the sensitivity report. The fluid can be quite viscous with particulate mat - ter, and the drain may need regular flushing with full aseptic TABLE 72.5 Complications of acute pancreatitis. Systemic Local ( More common in the /f_i rst week ) ( Usually develop after the /f_i rst week ) Cardiovascular Peripancreatic /f_l uid collection Shock Sterile pancreatic necrosis Arrhythmias Infected pancreatic necrosis Pulmonary Pancreatic abscess ARDS Pseudocyst Renal failure Pancreatic ascites Haematological Pleural effusion DIC Portal/splenic vein thrombosis Metabolic Pseudoaneurysm Hypocalcaemia Hyperglycaemia Hyperlipidaemia Gastrointestinal Ileus Neurological Visual disturbances Confusion, irritability Encephalopathy Miscellaneous Subcutaneous fat necrosis Arthralgia ARDS, acute respiratory distr ess syndrome; DIC, disseminated intra- vascular coagulation. Figure 72.24 Infected pancreatic necrosis. Note the areas of reduced enhancement in the pancreas and the peripancreatic /f_l uid collection with pockets of gas within it (arrow). This resolved after percutaneous drainage and antibiotic therapy. of progressively wider drains is necessary . Pancreatic necrosectomy should be considered if sepsis worsens despite conservative measures. This is a challenging operation that carries a high morbidity and mortality; it is best carried out in a specialist unit and is necessary only in a very small proportion of patients. The surgical approach may be through a midline laparotomy , especially if the area involved is around the pancreatic head. The duodenocolic and gastro colic ligaments should be divided and the lesser sac opened. Thorough debridement of the dead tissue around the pancreas should be carried out. If the body and tail of the gland are primarily involved ( Figur e 72.25 ), a retroperitoneal approach through a left flank incision may be more appropriate. The tissues are inevitably friable, and one should be careful not to precipitate excessive bleeding or inadvertently breach the bowel wall. Blunt dissection is preferable to sharp dissection. A feeding jejunostomy may be a useful adjunct to the procedure. If gallstones are the precipitating factor of the pancreatitis, a cholecystectomy should be included. Some prefer a minimally invasive approach to a formal laparotomy . A rigid laparoscope is inserted into the peripancreatic area through a retroperi toneal approach, and vigorous irrigation and suction is com bined with a gradual nibbling away of the necrotic debris. Once a necrosectomy has been completed, further necrotic tissue may form. There are several possible ways of dealing with this (listed below), none of whic h has been proved to be /uni00A0 more e ff ective than the others. The last two approaches make greater logistic demands as one is committed to a re-exploration every 48–72 hours. /uni25CF Closed continuous lavage. Tube drains are left in and the raw area flushed (Beger) ( Figure 72.26 ). /uni25CF Closed drainage. The incision is closed, but the cavity is packed with gauze-filled Penrose drains and closed suc tion drains. The Penrose drains are brought out through the flank and slowly pulled out and removed after 7 days. /uni25CF Open packing. The incision is left open, and the cavity is packed with the intention of returning to the operat ing room at regular intervals and repacking until there is a clean granulating cavity . /uni25CF Closure and relaparotomy . The incision is closed with drains with the intention of performing a series of planned relaparotomies every 48–72 hours until the raw area granulates (Bradley). There is a subgroup of patients who respond initially to percutaneous treatment but then develop recurrent sepsis that requires repeated insertion of drains and fail to thriv e. Necro sectomy should be considered in these patients, but it can be a di ffi cult judgement call. Patients with peripancreatic sepsis are ill for long periods of time and may require management in an intensive care unit. Nutritional support is essential. The parenteral and nasojeju nal appr oaches are more popular (on the assumption that they Hans Günter Beger , b. 1936, Emeritus Professor of Surgery , Ulm, Germany . Charles Bingham Penrose , 1862–1925, Professor of Gynecology , University of Pennsylvania, Philadelphia, PA, USA. Edward Bradley III , contemporary , Emeritus Professor of Surgery , Florida State University College of Medicine, FL, USA. - - - - - rest the pancreas), although there is little evidence to show that nasogastric feeding, if tolerated, is harmful in any way . Pancreatic abscess This is a circumscribed intra-abdominal collection of pus, usually in proximity to the pancreas. It may be an ANC or a WON that has become infected. The principles of diagnosis and management are as outlined above for infected pancreatic necrosis. Endoscopic internal drainage or, failing that, percu - - taneous drainage with the widest possible drains is the treat - ment, along with appropriate antibiotics and supportive care. Repeated scans may be required depending on the progress of the patient, and drains may need to be flushed, repositioned or reinserted. V ery occasionally , open drainage of the abscess - may be necessary . Figure 72.25 Necrotic body and tail of the pancreas removed as an intact specimen rather than piecemeal. The patient had suffered severe necrotising gallstone pancreatitis complicated by persistent pancreatic sepsis. Necrosectomy was carried out through a left /f_l ank retroperitoneal approach. Figure 72.26 Continuous postoperative closed lavage of the lesser sac as advised by Beger. Lavage is carried out through several double-lumen and single-lumen catheters. Each time, 1 litre of saline is infused through and then drained over a period of hours, and the process is repeated. This is a chronic, generalised, peritoneal, enzyme-rich e ff usion usually associated with pancreatic duct disruption. Paracente sis will reveal turbid fluid with a high amylase level. Adequate drainage with wide-bore drains placed under imaging guidance is essential. Measures that can be taken to suppress pancreatic secretion include parenteral or nasojejunal feeding and administration of octreotide. An ERCP may demonstrate duct disruption and allow placement of a pancr eatic stent. Pancreatic effusion This is an encapsulated collection of fluid in the pleural cavity , arising as a consequence of acute pancreatitis. Concomitant pancreatic ascites may be present or there may be a commu nication with an intra-abdominal collection. Percutaneous drainage under imaging guidance is necessary . Haemorrhage Bleeding may occur into the gut, the retroperitoneum or peri toneal cavity . Possible causes include bleeding into a pseudocyst cavity , di ff use bleeding from a large raw surface or a pseudoan eurysm. The last is a false aneurysm of a major peripancreatic vessel confined as a clot by the surrounding tissues and often associa ted with infection. Recurrent bleeding is common, often culminating in fatal haemor rhage. CT , angiography or magnetic resonance angiography helps to make the diagnosis. Treatment involves embolisation or surgery . Portal or splenic vein thrombosis This may develop silently and is identified on a CT scan. A marked rise in the platelet count should raise suspicions. In the context of acute pancreatitis, treatment is usually conservative. The patient should be screened for procoagulant tendencies. If varices or other manifestations of portal hypertension develop, they will require treatment, such as endoscopic injection or banding, β -blockade, etc. Thrombocytosis may mandate the use of aspirin or other antiplatelet drugs for a period. Systemic anticoagulation, if instituted early in the process, may achieve recanalisation of the vein but it is not routinely used as it carries considerable risks in a patient with ongoing pancreatitis. Pseudocyst A pseudocyst is a collection of amylase-rich fluid enclosed in a well-defined wall of fibrous or granulation tissue. Pseudocysts typically arise following an attack of mild acute pancreatitis, lie outside the pancreas and represent an APFC that has not resolved and matured. Formation of a pseudocyst requires 4 /uni00A0 weeks or more from the onset of acute pancreatitis. The term ‘pseudocyst’ is often used more loosely to include sterile WON that has failed to resolve or a collection that has developed in the context of chronic pancreatitis or after pancreatic trauma. ( Figure 72.27 ; see also Figure 72.10 ). More than half have a communication with the main pancreatic duct. Pseudocysts are often single but are occasionally multiple. It is important to di ff erentiate a pseudocyst from an APFC; the clinical scenario and radiological appearances should allow that distinction to be made. Occasionally , a cystic neo plasm may be confused with a chronic pseudocyst. EUS and The fluid should be sent for measurement of carcinoembryonic antigen (CEA) le vels, amylase levels and cytology . Fluid from a - pseudocyst typically has a low CEA level, and levels above 400 /uni00A0 ng/mL are suggestive of a mucinous neoplasm. Pseudo - cyst fluid usually has a high amylase level, but that is not diag - nostic as a tumour that communicates with the duct system may yield similar findings. Cytology typically reveals inflam - matory cells in pseudocyst fluid. If there is no access to EUS, not then percutaneous FNA is acceptable (just aspiration, percutaneous insertion of a drain). ERCP and MRCP may demonstrate communication of the cyst with the pancreatic duct system, demonstrate ductal anomalies or diagnose chronic pancreatitis, and thus help in planning treatment. - Pseudocysts usually resolve spontaneously , but compli - cations can develop ( Table 72.6 ) . Pseudocysts that are thick walled or large (>6 /uni00A0 cm in diameter), have lasted for a long time (over 12 weeks) or have arisen in the context of chronic pan - creatitis are less likely to resolve spontaneously . Therapeutic - intervention is advised only if the pseudocyst causes symptoms, complications develop or distinction has to be made between a - pseudocyst and a tumour. There are three possible approaches to draining a pseudo - cyst: percutaneous , endoscopic and surgical. Percutaneous drainage to the exterior under radiological guidance should be avoided. It carries a very high likelihood of recurr ence. Moreover, it is not advisable unless one is absolutely certain that the cyst is not neoplastic and that it has no communication with the pancreatic duct (or else a pancreaticocutaneous fistula will develop). A percutaneous transgastric cystgastrostomy can be performed under imaging guidance, and a double-pigtail drain placed with one end in the cyst cavity and the other end in the gastric lumen. In experienced hands, recurrence rates are no more than 15%. Endoscopic drainage usually involves - Figure 72.27 Barium meal. Pseudocyst displacing the stomach (cour tesy of Professor VK Kapoor, Lucknow, India). puncture of the cyst through the stomach or duodenal wall under endoscopic ultrasound guidance, and placement of a tube drain with one end in the cyst cavity and the other end in the gastric lumen. The success rates depend on operator expertise. Occasionally , ERCP and placement of a pancreatic stent across the ampulla may help to drain a pseudocyst that is in communication with the duct. Surgical drainage involves internally draining the cyst into the gastric or jejunal lumen ( Figure 72.28 ). Recurrence rates should be no more than 5%, and this still remains the standard against which the evolving radiological and endoscopic approaches are measured. The approach is conventionally through an open incision but lapa roscopic cystgastrostomy is also feasible. Pseudocysts that have developed complications are best managed surgically . There is a small group of patients who, having su ff ered an attack of necr otising pancreatitis with duct disruption, go on to su ff er repeated complications in the form of recurrent fluid collections, pseudocysts, pleural e ff usions or pancrea tic ascites. V ery often disruption of the main pancreatic duct in the neck, body or tail is compounded by a stricture or a stone in the head that cannot be treated endoscopically . In such patients, some form of surgical resection and/or a drainage procedure – even though it may be technically challenging – may be the only way to achieve lasting resolution. Summary box 72.8 Distinguishing a pseudocyst from a cystic neoplasm /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF William Wayne Babcock , 1872–1963, surgeon, Philadelphia, PA, USA. pseudocyst. Process Outcomes Infection Abscess Systemic sepsis Rupture Into the gut Gastrointestinal bleeding Internal /f_i stula Into the peritoneum Peritonitis Enlargement Pressure effects Obstructive jaundice from biliary compression Bowel obstruction Pain Erosion into a vessel Haemorrhage into the cyst Haemoperitoneum History Appearance on CT and ultrasonography FNA of /f_l uid, preferably under endoscopic ultrasound guidance: CEA (high level in mucinous tumours) Amylase (level usually high in pseudocysts but occasionally in tumours) Cytology Figure 72.28 Cystgastrostomy for the pancreatic pseudocyst shown in Figure 72.10 . The anterior wall of the stomach has been opened and the edges drawn back, held by Babcock’s forceps. An opening has been made through the posterior wall of the stomach into the pseudocyst and the tips of the dissecting forceps are in the cavity of the pseudocyst, which is lined by slough and granulation tissue. The tip of a nasogastric tube is visible. A running stitch will next be placed along the edges of this opening, suturing the full thickness of the posterior gastric wall to the capsule of the pseudocyst. Annular pancreas Annular pancreas This is the result of failure of complete rotation of the ventral pancreatic bud during development, so that a ring of pancre - atic tissue surrounds the second or third part of the duodenum. It is most often seen in association with congenital duodenal stenosis or atresia and is therefore more prevalent in children with Down syndrome. Duodenal obstruction typically causes vomiting in the neonate (see Chapter 18 ). The usual treat - - ment is bypass (duodenoduodenostomy). The diagnosis may be made in later life as a cause of pancreatitis, in which case resection of the head of the pancreas should be considered. CARCINOMA OF THE PANCREAS CARCINOMA OF THE PANCREAS Pancreatic cancer is the seventh leading cause of cancer deaths in men and women worldwide. In the USA it follows lung cancer and colorectal cancer as the third most common cause of cancer death. In the UK, it is the tenth most common cancer and its incidence has increased slightly over the last 10 years. Nearly 85% of patients present with unresectable or metastatic disease. Even among those who undergo surgery , 5-year survival is around 20%. There is no simple screening test. Patients with an increased inherited risk of pancreatic cancer ( Table 72.8 ) should be referred to specialist units for screening and counselling. CONGENITAL ABNORMALITIES Cystic fibrosis CONGENITAL ABNORMALITIES Cystic fibrosis This is inherited as an autosomal recessive condition. It occurs most frequently among white people, in whom it is the most common inherited disorder (incidence of 1:2000 live births in the UK). Cystic fibrosis (CF) develops when there is a mutation in the CFTR (cystic fibrosis transmembrane conductance regulator) gene on chromosome 7. This gene creates a cell membrane protein that helps to control the movement of chloride across the cell membrane. CF is a multisystem disorder of exocrine glands that a ff ects the lungs, intestines, pancreas and liver and is characterised by elevated sodium and chloride ion concentrations in sweat. The mother may notice that the child is salty w hen kissed. Most of the organ damage is due to blockage of narrow passages by thickened secretions. Chronic pulmonary disease arises from plugging of bronchi and bronchioles. CF is the most common cause of chronic lung disease among childr in resource-rich countries. Cor pulmonale may develop later. At birth, the meconium may set in a sticky mass and produce intestinal obstruction (meconium ileus) (see Chapter 18 Secretions precipitate in the lumen of the pancreatic duct causing blockage, which results in duct ectasia and fatty replacement of exocrine acinar tissue. Pancreatic exocrine insu ffi ciency leads to fat malabsorption. Steatorrhoea is usually present from birth, resulting in stools that are bulky , oily and o ff ensive. The islets of Langerhans usually appear normal, but diabetes mellitus can occur in older patients. The liver may become cirrhotic as a result of bile duct plugging, and signs of portal hypertension may appear. Infertility is common owing to the absence of the vas deferens in men and thick cervical mucus in women. Outside the newborn period, the earliest clinical signs of CF are poor growth, poor appetite, rancid greasy stools, abdominal distension, chronic respiratory disease and finger clubbing. The appearance of secondary sexual characteris tics may be delayed. The diagnosis can be made by prenatal genetic testing, by the newborn blood spot (heel prick) test done on newborns in the UK and by the sweat test. Levels of sodium and chloride ions in the sweat above 90 /uni00A0 mmol/L confirm the diagnosis. Treatment is aimed at control of the secondary conse quences of the disease. Pulmonary function is preserved with aggressive physiotherapy and antibiotics. Malabsorption is treated by administration of oral pancrea tic enzyme prepa rations. The diet should be low in fat but contain added salt to replace the high losses in the sweat. With early diagnosis John Langdon Haydon Down (sometimes given as Haydon-Down), 1828–1896, physician, The London Hospital, London, and Superintendent, Earlswood Asylum for Idiots, Redhill, UK, described this syndrome in 1866. Johann Friedrich Meckel (the younger), 1781–1833, Professor of Anatomy and Surgery , Halle, Germany , described the embryological origin of the eponymous diverticulum in 1809. now expect to survive to their mid-thirties. Those with end- - stage lung disease ma y be considered for lung transplanta - tion. Heterozygous carriers of the various gene muta tions are asymptomatic but can be identified by DNA analysis. There is a suggestion that such patients may develop pancreatitis later in life . Chronic pancreatitis Chronic pancreatitis Chronic pancreatitis is a progressive inflammatory disease in which there is irreversible destruction of pancreatic tissue. Its clinical course is characterised by severe pain and, in the later stages, exocrine and endocrine pancreatic insu ffi ciency . In the early stages of its evolution, it is frequently complicated by attacks of acute pancreatitis, which are responsible for the recurrent pain that may be the only clinical symptom. The incidence of chronic pancreatitis in several European, North American and Japanese studies ranges from 2 to 10 new cases per 100 /uni00A0 000 population per year, with a prevalence of around 13 cases per 100 /uni00A0 000, although there are suspicions that the prevalence is actually higher. In certain parts of the world, such 100 /uni00A0 000). The disease occurs more frequently in men (male to-female ratio of 4:1) and the mean age of onset is about 40 years. Aetiology and pathology High alcohol consumption is the most frequent cause of chronic pancreatitis, accounting for 60–70% of cases, but only 5–10% of people with alcoholism develop chronic pancreatitis. The exact mechanism of how alcohol causes chronic inflammation in these patients is unclear; genetic and metabolic factors may be at play . Other causes include pancreatic duct obstruction resulting from stricture formation after trauma, after acute pancreatitis or even occlusion of the duct by pancrea tic cancer. Congenital abnormalities, such as pancreas divisum and annular pancreas, if associated with papillary stenosis, are rare causes of chronic pancreatitis. Hereditary pancreatitis, CF , infantile malnutrition and a large unexplained idiopathic group make up the remainder. Normally , if trypsinogen becomes prematurely activated within the pancreas , it is inhibited by SPINK1 and is destroyed. Hereditary pancreatitis is an autosomal dominant disorder with an 80% penetrance; it is associated with a gain-of function mutation in the cationic trypsinogen gene ( PRSS1 chromosome 7, which leads to production of a degradation- resistant form of trypsin. A loss-of-function mutation in SPINK1 also predisposes to idiopathic pancreatitis. Some patients with idiopathic chronic pancreatitis have mutations in the CFTR gene. Idiopathic chronic pancreatitis accounts for approximately 30% of cases and has been subdivided into early-onset and late-onset forms. The importance of hereditary pancreatitis and pancreatitis occurring at a young age is that there is a markedly increased risk of developing pancreatic cancer, particularly if the patient smokes tobacco. Hyperlipidaemia and hypercalcaemia can lead to chronic pancreatitis. Tropical pancreatitis is a form of idiopathic pancreatitis that begins at a young age and is associated with a high inci dence of diabetes mellitus and stone formation. This has been described in resource-poor countries in Asia, Africa and cen tral America. Malnutrition, ingestion of cyanogenic glycosides in cassav a and exposure to hydrocarbons released by kerosene or para ffi n lamps have been pr oposed as possible mechanisms for tropical pancreatitis. Autoimmune pancreatitis has been described relatively recently . Features include di ff use enlargement of the pancreas and di ff use and irregular narrowing of the main pancreatic duct. It may occur in associa tion with other autoimmune dis eases, as a multisystem disorder, or may a ff ect the pancreas alone. There may be changes in the biliary tree (autoimmune c holangiopathy) as well. The changes may be confused with neoplasia. Autoantibodies may be present and levels of the immunoglobulin subtype IgG4 are elevated. At the onset of the disease when symptoms have developed, the pancreas may appear normal. Later, the pancreas enlarges and becomes hard as a result of fibrosis. The ducts become distorted and dilated with areas of both stricture formation and ectasia. Calcified stones weighing from a few milligrams - occluded with a gelatinous proteinaceous fluid and debris and inflammatory cysts may form. Histologically , the lesions a ff ect the lobules, producing ductular metaplasia and atrophy of acini, hyperplasia of duct epithelium and interlobular fibrosis. Clinical features Pain is the outstanding symptom in the majority of patients. The site of pain depends to some extent on the main focus of the disease. If the disease is mainly in the head of the pancreas then epigastric and right subcostal pain is common, whereas if it is limited to the left side of the pancreas left subcostal and back pain are the presenting symptoms. In some patients, the pain is more di ff use. Radiation to the shoulder can occur. Nausea is common during attacks and vomiting may occur. The pain is often dull and gnawing. Severe flare-ups of pain may be superimposed on background discomfort. All the complications of acute pancreatitis can occur with chronic pancreatitis. Weight loss is common because the patient does not feel like eating. The pain prevents sleep and time o ff work is frequent. T he number of hospital admissions for acute exacerbations is a pointer towards the severity of the disease. Analgesic use and abuse are frequent. This, too, gives an indi - - cation of the severity of the disability . The patient’s lifestyle ) on is gradually destroyed by pain, analgesic dependence, weight loss and inability to work. Loss of exocrine function leads to steatorrhoea in more than 30% of patients with chronic pan - creatitis. Loss of endocrine function and the development of diabetes are not uncommon, and the incidence increases as the disease progresses. Complications frequently bring the patient to the attention of the surgeon. Infection is not infrequent, possibly related to the diabetes mellitus. Investigations Only in the early stages of the disease will there be a rise in serum amylase. Tests of pancreatic function merely confirm the presence of pancreatic insu ffi ciency or that more than 70% of the gland has been destroyed. - Pancreatic calcifications may be seen on abdominal radio- graphs ( Figure 72.18 ). CT or MRI scan will show the outline - of the gland, the main area of damage and the possibilities for surgical correction ( Figure 72.29 ; see also Figure 72.7 ). Calcification is seen very well on CT but not on MRI. An MRCP will identify the presence of biliary obstruction and the state of the pancreatic duct ( Figure 72.30 ). The use of intravenous secretin during the study may demonstrate a pancreatic duct stricture not apparent on standard MRCP , but a normal-looking pancreas on CT or MRI does not rule - out chronic pancreatitis. ERCP is the most accurate way of elucidating the anatomy of the duct and, in conjunction with the whole organ morphology , can help to determine the type of operation required, if operative intervention is indicated. Histologically proven chronic pancreatitis can, however, occur in the setting of normal findings on pancreatography . Sonographic findings characteristic of chronic pancreatitis include the presence of stones, visible side branches, cysts, lobularity , an irregular main pancreatic duct, hyperechoic foci and strands, dilatation of the main pancreatic duct and hyperechoic margins of the main pancreatic duct. The of chronic pancreatitis. Treatment Most patients can be managed with medical measures. There is no single therapeutic agent that has been shown to relieve symptoms ( Summary box 72.9 ) . Endoscopic, radiological or surgical interventions are indi cated mainly to relieve obstruction of the pancreatic duct, bile duct or the duodenum, or in dealing with complications (e.g. pseudocyst, abscess, fistula, ascites or variceal haemorrhage). Decompressing an obstructed pancreatic duct can provide pain relief in some patients (the assumption is that ductal hypertension causes the pain). Endoscopic pancr eatic sphincterotomy might be bene ficial in patients with papillary stenosis and a high sphincter Charles Frederick Frey , b. 1929, Professor of Surgery , University of California, Davis, CA, USA. Medical treatment of chronic pancreatitis /uni25CF /uni25CF - /uni25CF /uni25CF /uni25CF /uni25CF - /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF pressure /uni00A0 and pancreatic ductal pressure. Patients with a dom - inant pancreatic duct stricture and upstream dilatation may benefit by placement of a stent across the stricture. The stent should be left in for no more than 4–6 weeks as it will block. The complication rate is high and less than two-thirds of patients experience pain r elief, but those who do get relief may benefit from a surgical bypass. Pancreatic duct stones may be extracted at ERCP; this may sometimes be combined with extracorpo - real shock wave lithotripsy . Pseudocysts may be drained inter - nally under endoscopic ultrasound guidance. Percutaneous or transgastric drainage of pseudocysts under ultrasound or CT guidance may be performed. The role of surgery is to overcome obstruction and remove mass lesions. Some patients ha ve a mass in the head of the pancreas, for which either a pancreatoduodenectomy or a Beger procedure (duodenum-preserving resection of the pan - creatic head) is appropriate. If the duct is markedly dilated, then a longitudinal pancreatojejunostomy or Frey procedure can be of value ( Figure 72.31 ). The natural evolution of the disease may not be altered significantly , but around half the patients get long-term pain relief. The rare patient with disease limited to the tail will be cured by a distal pancreatectomy . Patients with intractable pain and di ff use disease may plead for a total pancreatectomy in the expectation that removing the Figure 72.29 Computed tomography scan in a patient with chronic pancreatitis. A stone (arrow) is obstructing the main pancreatic duct in the body of the gland. The duct is markedly dilated upstream of the obstruction. Figure 72.30 Magnetic resonance cholangiopancreatography in a patient with chronic pancreatitis, showing a stricture of the pancreatic duct in the body of the gland (arrow), with dilatation upstream. Treat the addiction Help the patient to stop alcohol consumption and tobacco smoking Involve a dependency counsellor or a psychologist Alleviate abdominal pain Eliminate obstructive factors (duodenum, bile duct, pancreatic duct) Escalate analgesia in a stepwise fashion Refer to a pain management specialist For intractable pain, consider CT/EUS-guided coeliac axis block Nutritional and pharmacological measures Diet: low in fat and high in protein and carbohydrates Pancreatic enzyme supplementation with meals Correct malabsorption of the fat-soluble vitamins and vitamin B12 Micronutrient therapy with methionine, vitamins C and E, selenium (may reduce pain and slow disease progression) Steroids (only in autoimmune pancreatitis, for relief of symptoms) Medium-chain triglycerides in patients with severe fat malabsorption (they are directly absorbed by the small intestine without the need for digestion) Reducing gastric secretions may help Treat diabetes mellitus keep in mind that pancreatic function and quality of life are significantly impaired after this procedure, and the operative mortality rate is not trivial. Moreover, there is no guarantee of pain relief (approximately a third of patients get resolution, a third show some benefit and a third see no benefit at all). Total pancreatectomy and islet autotransplantation have been reported in selected patients, but it is di ffi cult to demonstrate any overall benefit. Prognosis Chronic pancreatitis is a di ffi cult condition to manage. Patients often su ff er a gradual decline in their professional, social and personal lives. The pain may abate after a surgical or percuta neous intervention but tends to return over a period of time. In a proportion of patients, the inflammation may gradually burn out over a period of years , with disappearance of the pain, leaving only the exocrine and endocrine insu ffi ciencies. Development of pancreatic cancer is a risk in those who have had the disease for more than 20 years. New symptoms or a change in the pattern of symptoms should be investigated and malignancy excluded. Sphincter of Oddi dysfunction Sphincter of Oddi dyskinesia or dysfunction (SOD) is a clinical syndrome in which pain, biochemical abnormalities and dilatation of the bile duct and/or pancreatic duct are attributed to abnormal function of the sphincter of Oddi. The true incidence of SOD is unknown. Females are more commonly a ff ected than males. SOD may result from stenosis of the sphincter or from dysmotility . Scarring or stenosis of the sphincter can result from passage of stones, pancreatitis or prior endoscopic sphincterotomies. is characterised by biliary pain, which may be accompanied by abnormally raised liver enzymes and/or dilatation of the bile duct and/or evidence of delayed emptying on biliary scintigraphy . It may be a cause of persistent postcholecystec - tomy symptoms. A predominance of pancreatic problems, especially recurrent episodes of acute pancreatitis, is known as pancreatic-type SOD. Each type of SOD is further divided into types I, II and III ( Table 72.7 ). T his classification helps to predict the underlying pathology and the likelihood of success - ful treatment. Type I disease is thought to result from a fixed stenosis and responds best to therapy . An episodic dysmotility is the presumed underlying abnormality in the other types and - often does not respond as w ell to treatment. Biliary-type SOD should be considered and excluded /uni00A0 in patients with the postcholecystectomy syndrome. Pancreatic- type SOD should be excluded in patients with recurrent acute pancreatitis of une xplained aetiology . The role of SOD in chronic pancreatitis is unclear. A careful history is essential. CT and MRCP can demonstrate dilatation of the biliary and pancreatic ducts. MRCP with intravenous secretin injection can particularly demonstrate pancreatic duct dilatation due to raised sphincter pressures. EUS may achieve the same end. Quantitative cholescintigraphy (hepatobiliary iminodiacetic acid [HIDA] scan) may demonstrate delayed biliary transit. ERCP with manometry is indicated to confirm the diagnosis if the pain is disabling, non-invasive investigations have not shown structural abnormalities and conservative therapy has Figure 72.31 Pancreatojejunostomy. The pancreatic duct is opened longitudinally and a loop of jejunum is sutured to the duct. In the Frey procedure, the super /f_i cial part of the head of the pancreas is removed to achieve drainage. TABLE 72.7 Milwaukee classi /f_i cation of sphincter of Oddi (SOD) dysfunction. Biliary-type SOD Type I: Typical biliary-type pain Liver enzymes (AST, ALT or ALP) >2 times normal limit documented on at least two occasions during episodes of pain Dilated CBD >12 /uni00A0 mm in diameter a Prolonged biliary drainage time (>45 min) Type II: Biliary-type pain, and One or two of the above criteria Type III: Biliary-type pain only Pancreatic-type SOD Type I: Pancreatic-type pain Amylase and/or lipase >2 times upper normal limit on at least two occasions during episodes of pain Dilated pancreatic duct (head >6 /uni00A0 mm, body >5 /uni00A0 mm) a Prolonged pancreatic drainage time (>9 min) Type II: Pancreatic-type pain, and one or two of the above criteria Type III: Pancreatic-type pain only AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP , alkaline phosphatase; CBD, common bile duct. a Dif /f_i cult to measure and often eschewed in clinical practice. is the manometric criterion used to diagnose SOD. Endoscopic sphincterotomy is the treatment of choice for type I SOD. The question of whether dual sphincterotomies (biliary and pancreatic) should be carried out remains unan swered. There is howe ver a particularly high risk of post-ERCP pancreatitis (30% or more), though placement of a pancreatic stent at the time of the procedure appear s to reduce this risk. For patients with type II SOD, manometry should be done before considering sphincterotomy , and the results of sphincterotomy are less consistent. Patients with type III SOD are even more di ffi cult, with response rates to sphincterotomy ranging from 8% to 65%. Medical therapy should be tried before proceed ing to manometry . Proton pump inhibitors, spasmolytic drugs, calcium blockers (nifedipine) and psychotropic agents have all been tried with varying degrees of success. Injection of botu linum toxin (w hich can cause a chemical sphincterotomy for up to 3 months) or placement of a pancreatic stent (these are usually removed after 6 weeks) do not provide lasting relief but can be used to identify patients who may benefit from a sphincterotom y . In a small subgroup of patients who have experienced sig nificant but short-lived relief with sphincterotomy or stenting, surgical transduodenal sphincteroplasty may be considered but the long-term results are often poor. In exceptional cir cumstances, w here the pancreatic head is badly scarred after repeated stenting and numerous attacks of pancreatitis and sphincteroplasty has failed or is unlikely to succeed, one should consider surgical resection of the pancreatic head. Clinical features Clinical features Jaundice secondary to obstruction of the distal bile duct is the most common symptom that draws attention to ampul - - lary and pancreatic head tumours. It is characteristically painless jaundice but may be associated with nausea and epigastric discomfort. Pruritus, dark urine and pale stools - with steatorrhoea are common accompaniments of jaundice. - In the absence of jaundice, symptoms are often non-specific, ). namely vague discomfort, anorexia and weight loss, and are frequently dismissed by both patient and doctor. Upper abdominal symptoms in a patient recently diagnosed with diabetes, especially in one above 50 years of age with no todu - family history or obesity , should raise suspicion. Occasionally , a patient will present with an unexplained attack of pancre - atitis; all such patients should have follow-up imaging of the pancreas. Tumours of the body and tail of the gland often gr ow silently and present at an advanced unresectable stage. Back pain is a worrying symptom, raising the possibility of retroperitoneal infiltration. On examination, there may be evidence of jaundice, weight loss, a palpable liver and a palpable gallbladder. Courvoisier first drew attention to the association of an enlarged gallblad der and a pancreatic tumour in 1890, when he noted that, when the common duct is obstructed by a stone, distension of the gallbladder (which is likely to be chronically inflamed) is rare; when the duct is obstructed in some other way , such as a neoplasm, distension of the normal gallbladder is common. Other signs of intra-abdominal malignancy should be looked for with care, such as a palpable mass, ascites, supraclavicular nodes and tumour deposits in the pelvis; when present, they indicate a grim prognosis. (b) Figure 72.33 (a) Carcinoma of the ampulla as seen at endoscopy. (b) Appearance of the same tumour (arrow) on endoscopic ultra /uni00A0 sonography (courtesy of Dr Peter Fairclough). Ectopic pancreas Ectopic pancreas Islands of ectopic pancreatic tissue can be found in the submu - cosa in parts of the stomach, duodenum or small intestine (including Meckel’s diverticulum), the gallbladder, adjoining - the pancreas, in the hilum of the spleen and within the liver. Ectopic pancreas may also be found in the wall of an alimen - tary tract duplication cyst. Endoscopic ultrasonography Endoscopic ultrasonography Endoscopic ultrasonography (EUS) is performed using a special endoscope that has a high-frequency ultrasonic transducer at its tip. When the endoscope is in the lumen of the stomach or duodenum, the pancreas and its surrounding vasculature and lymph nodes can be assessed ( Figure 72.20 This is particularly useful in identifying small tumours that may not show up well on CT or MRI, and in demonstrat - ing the relationship of a pancreatic tumour to major vessels nearby . EUS can clarify the relationship of a neuroendocrine tion tumour to the main pancreatic duct (important if enuclea is being considered). ). Figure 72.19 Adenocarcinoma cells identi /f_i ed in pancreatic juice collected at the time of endoscopic retrograde cholangiopancreatog raphy (courtesy of Professor Roger Feakins). (a) (b) Figure 72.20 (a) Carcinoma of the pancreatic head as seen with endoscopic ultrasonography (EUS). (b) Aspiration biopsy carried out under EUS guidance: needle seen entering the tumour (courtesy of Dr Peter Fairclough). Transduodenal or transgastric fine-needle aspiration (FNA) or Trucut biopsy performed under endoscopic ultrasound guid ance avoids spillage of tumour cells into the peritoneal cavity . FURTHER READING FURTHER READING Braganza JM, Lee SH, McCloy RF , McMahon MJ. Chronic pancreati - tis. Lancet 2011; 377 : 1184–97. Conroy T , Hammel P , Hebbar M et al . FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med 2018; 379 : 2395–406. Jarnagin W . Blumgart’s surgery of the liver, biliary tract and pancreas , 6th - edn. Philadelphia, PA: Elsevier, 2016. Leppäniemi A, Tolonen M, Tarasconi A et al. WSES guidelines for the management of severe acute pancreatitis. World J Emerg Surg 2019; 14 : 27. Mizrahi JD, Surana R, Valle JW , Shro ff RT . Pancreatic cancer. Lancet 2020; 395 : 2008–20. National Institute for Health and Care Excellence. Pancreatitis . NICE Clinical Guideline 104. London: NICE, 2020. Available from - https://www .nice.org.uk/guidance/ng104. - The European Study Group on Cystic Tumours of the Pancreas. European evidence-based guidelines on pancreatic cystic neoplasms. Gut 2018; 67 : 789–804. INJURIES TO THE PANCREAS External injury INJURIES TO THE PANCREAS External injury Presentation and management The pancreas is not frequently damaged in blunt abdominal trauma but when it occurs it is often associated with injuries to other viscera, especially the liver, the spleen and the duode num. Occasionally , a forceful blow to the epigastrium (such as from the steering wheel in a car accident) may crush the body of the pancreas against the vertebral column. Penetrating trauma to the upper abdomen or the back carries a higher chance of pancreatic injury . P ancreatic injuries may range from a contusion or laceration of the parenchyma without duct disruption to major parenchymal destruction with duct disrup tion (sometimes complete transection) and, rarely , massive destruction of the pancreatic head. The most important factor that determines treatment is whether the pancreatic duct has been disrupted. Blunt pancreatic trauma usually presents with epigastric pain, whic h may be minor at first, with the progressive devel opment of more sev ere pain due to the sequelae of leakage of pancreatic fluid into the surrounding tissues. The clinical pre sentation can be quite deceptive; careful serial assessments and a high index of suspicion are required. A rise in serum amylase occurs in most cases. A CT scan of the pancreas will delineate the damage that has occurred to the pancreas ( Figur e 72.21 If there is doubt about duct disruption, an urgent ERCP should be sought. MRCP may also provide the answer, but the images can be di ffi cult to interpret. Support with intrave nous fluids and a ‘nil by mouth’ regimen should be instituted while these investigations are performed. There is no need to rush to a laparotomy if the patient is haemodynamically stable, without peritonitis . It is preferable to manage conservatively at first, investigate and, once the extent of the damage has been ascertained, undertake appropriate action. Operation is indicated if there is disruption of the main pancreatic duct; in almost all other cases, the patient will recover with conservative management. In penetrating injuries, especially if other organs are injured and the patient’s condition is unstable, there is a greater need to perform an urgent surgical exploration. Assessment of pancreatic damage and duct disruption a t the time of surgery can be di ffi cult because the bruising associated with the retro peritoneal damage prevents clear visualisation of the pancreas. A patient and thorough examination of the gland should be carried out. Haemostasis and closed drainage are adequate for minor parenchymal injuries. If the gland is transected in the body or tail, a distal pancreatectomy should be performed, with or without splenectomy . If damage is purely confined to the head of the pancreas, haemostasis and external drainage - - are normally e ff ective. In the emergency setting, in an unsta - ble patient with concomitant injuries, a surgeon unaccustomed - to pancreatic surgery should refrain from trying to ascertain whether the duct in the pancreatic head is intact or embarking - on a major resection. However, if there is severe injury to the pancreatic head and duodenum, then a pancreatoduodenec - tomy may be necessary . ). Summary box 72.3 - External injury to the pancreas /uni25CF /uni25CF /uni25CF /uni25CF Prognosis The most common cause of death in the immediate period is bleeding, usually from associated injuries. Once the acute phase has passed, the morbidity related to the pancreatic injury itself is treatable, with a complete return to normal activity - being the usual outcome. Persistent drain output occurs in up to a third of patients (see Pancreatic fistula ). Sometimes, in the aftermath of trauma that has been treated conservatively , duct stricturing develops, leading to recur rent episodes of pancreatitis. The appropriate treatment in such cases is resection of the tail of the pancreas distal to the site of duct disruption. Figure 72.21 Computed tomography scan showing a pancreatic transection due to a bicycle handlebar injury. A distal pancreatectomy was performed. Other organs are likely to be injured It is important to ascertain if the pancreatic duct has been disrupted CT and ERCP are the most useful tests Surgery is indicated if the main pancreatic duct is disrupted is intact, the cyst can be aspirated percutaneously in the first instance; it may not be necessary to undertake a cyst gastros tomy . If the cyst develops in the presence of complete disrup tion of the pancreas, there is no alternative but to undertake a distal resection or, occasionally , a pancreatojejunostomy with a Roux-en-Y loop. In a patient who pr esents with a peri pancreatic cyst and a history of previous blunt abdominal trauma, do not assume that it is a post-traumatic pseudocyst. The possibility of a cystic neoplasm should be considered and excluded. INVESTIGATIONS Estimation of pancreatic enzymes in INVESTIGATIONS Estimation of pancreatic enzymes in body fluids Investigations of the pancreas are listed in Table 72.2 . When the pancreas is damaged, enzymes such as amylase, lipase, trypsin, elastase and chymotrypsin are released into the serum. Measurement of serum amylase is the most widely used test of pancreatic damage (serum lipase is more sensitive and specific but is not widely av ailable). The serum amylase rises within a few hours of pancreatic damage and declines over the next 4–8 days. A markedly elevated serum level is highly suspi - cious but not diagnostic of acute pancreatitis. Urinary amylase and amylase–creatinine clearance ratios add little to diagnostic accuracy . If confirmation of the diagnosis is required, com - puted tomography (CT) of the pancreas is of greater value. Summary box 72.2 Causes of raised serum amylase level other than acute pancreatitis /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF Upper gastrointestinal tract perforation Mesenteric infarction Torsion of an intra-abdominal viscus Retroperitoneal haematoma Ectopic pregnancy Macroamylasaemia Renal failure Salivary gland in /f_l ammation Iatrogenic injury Iatrogenic injury This can occur in several ways: /uni25CF Injury to the tail of the pancreas during splenectomy , resulting in a pancreatic fistula. /uni25CF Injury to the pancreatic head and the accessory pancreatic duct (Santorini), which is the main duct in 7% of patients, during Billroth II gastrectomy . A pancreatogram per formed by cannulating the duct at the time of discovery of such an injury will demonstrate whether it is safe to ligate and divide the duct. If no alternative drainage duct can be demonstrated, then the duct should be reanastomosed to the duodenum or alternatively r esection of the pancreatic head should be considered. /uni25CF Enucleation of islet cell tumours of the pancreas can result in fistulae. /uni25CF Duodenal or ampullary bleeding following sphincteroto my . This injury may require duodenotomy to control the bleeding. Imaging investigations Imaging investigations Ultrasonography Ultrasonography is the initial investigation of choice in patients with jaundice to determine whether or not the bile duct is dilated, the coexistence of gallstones or gross disease within the liver such as metastases. It may also define the presence or absence of a mass in the pancreas ( Figure 72.6 ). However, obesity and overlying bowel gas often make interpretation of the pancreas itself unsatisfactory . Computed tomography Most significant pathologies within the pancreas can be diagnosed on high-quality CT scans, with three-dimensional reconstruction if necessary . A specific pancreatic protocol should be followed. An initial unenhanced CT scan is essential to determine the presence of calcification within the pancreas and gallbladder ( Figure 72.7 ). Then, following rapid injection of intravenous contrast, scanning is performed in the arterial and venous phases. The stomach and duodenum should be outlined with water and distended to define the duodenal loop. Pancreatic carcinomas of 1–2 /uni00A0 cm in size can usually be demon - strated ( Figure 72.8 ). Endocrine tumours are also well imaged on CT ( Figure 72.9 ). In patients with pancreatitis, necrotic areas within the gland can be identified by the absence of contrast enhancement on CT . Inflammatory collections and pseudocysts can be seen ( Figure 72.10 ). CT-guided drainage is helpful in the treatment of pancreatic collections, cysts and pseudocysts, and facilitates percutaneous fine-needle or Trucut biopsy . Magnetic resonance imaging With magnetic resonance imaging (MRI) the pancreas can be clearly identified, and the anatomy of the bile duct and the pancreatic duct, together with fluid collections, can be defined. Magnetic resonance cholangiography and pancreatography (MRCP) has largely replaced diagnostic endoscopic cholangi - ography and pancreatography (ERCP) as it is non-invasive and less expensive ( Figure 72.11 ). Using the technique in conjunc - tion with intravenous injection of secretin, emptying of the pancreatic duct can be demonstrated to show the absence or obstruction. presence of Figure 72.6 Ultrasound scan showing a mass in the head of the pan creas (marked by an arrow) and a dilated pancreatic duct in the body of the gland (courtesy of Dr Alison McLean). (b) Figure 72.7 (a) Unenhanced computed tomography scan of a man with chronic pancreatitis, showing a focus of calci /f_i cation (marked by an arrow) in the head of the pancreas and a cyst adjacent to that. Oral contrast has been administered. (b) The same area after injection of intravenous contrast. 3 1 4 2 Stomach Pseudocyst Figure 72.8 Contrast-enhanced computed tomography scan of a patient with a carcinoma of the pancreatic head. The main bulk of the tumour lies inferior to the section shown here. The dilated bile duct (1) and main pancreatic duct (2) can be seen, with tumour in /f_i ltration around them. There is a thrombus in the superior mesenteric vein (3). The gallbladder is distended (4). Figure 72.9 Computed tomography scan showing a hypervascular insulinoma (arrow) adjacent to the splenic vein. Local excision of the tumour resulted in normoglycaemia. Figure 72.10 Computed tomography scan of a large pseudocyst in relation to the body and tail of the pancreas. Figure 72.11 Magnetic resonance cholangiopancreatography in a patient with obstructive jaundice. A dilated common bile duct was seen on ultrasonography, but no pancreatic mass lesion was visible on computed tomography. The bile duct and the main pancreatic duct are seen very well, with a stone visible in the lower part of the bile duct and another in the neck of the gallbladder. (a) (b) Contrast in duodenal loop Catheter Figure 72.12 Endoscopic retrograde cholangiopancreatography. /uni00A0 (a) Normal pancreatic duct with /f_i lling of the duct of Santorini from the duct of Wirsung. (b) Diagrammatic outline of (a) . cholangiopancreatography ERCP is performed using a side-viewing fibreoptic duo denoscope. The ampulla of Vater is intubated, and contrast is injected into the biliary and pancreatic ducts to display /uni00A0 the anatomy radiologically ( Figure 72.12 ). In pancreatic carci noma, the main pancreatic duct may be narrowed or completely obstructed at the site of the tumour ( Figure 72.13 ), or the distal bile duct may be narrowed. Concurrent narrowing of both ducts results in the so-called double duct sign ( Figure 72.14 Changes seen in chronic pancreatitis include the presence of pancreatic duct strictures, dilatation of the main pancre atic duct with stones, abnormalities of pancreatic duct side branches, communication of the pancreatic duct with cysts and bile duct strictures ( Figures 72.15–72.17 ). A plain radiograph 2 1 ( Figure 72.18 ). In addition to imaging, bile or pancreatic fluid and brushings from duct strictures can yield cells that confirm - the suspected diagnosis of carcinoma ( Figure 72.19 ). Brush cytology taken from malignant strictures at the time of ERCP yields a positive diagnosis in 40–50% of patients. ERCP also - allows the placement of biliary and pancreatic stents. ). - (b) Figure 72.13 Endoscopic retrograde cholangiopancreatography: pancreatic carcinoma. Irregular stricture of the main pancreatic duct (arrow) with dilatation distal to the obstruction. Figure 72.14 Endoscopic retrograde cholangiopancreatography depicting a malignant stricture in the lower part of the common bile duct (1) and in the main pancreatic duct (2), an appearance referred to as the double duct sign (courtesy of Dr George Webster). Figure 72.15 Endoscopic retrograde cholangiopancreatography: chronic pancreatitis. Most of the opacities lie within the duct system and are stones. Gross dilatation of ducts in the body and tail are due to obstruction by stones in the head of the pancreas. (a) Partially /f_i lled cyst Dilated CBD Stricture Small cyst Dilated PD Figure 72.16 (a) Endoscopic retrograde cholangiopancreatography: relapsing acute pancreatitis. Normal biliary tree. Pancreatogram shows stricture of the main duct in the body with distal dilatation and cyst formation. (b) Diagrammatic outline of (a) . CBD, common bile duct; PD, pancreatic duct. (b) Dilated chain of lakes Stricture Catheter Figure 72.17 (a) Endoscopic retrograde cholangiopancreatography: chronic pancreatitis. Long stricture of the pancreatic duct in the head; distal pancreatic duct shows sacculation with intervening short stric tures, ‘chain of lakes’. (b) Diagrammatic outline of (a) . Figure 72.18 Plain abdominal radiograph: chronic pancreatitis. Multiple opacities can be seen in the region of the head and tail of the pancreas. Introduction Introduction No content extracted automatically. Investigations Investigations In a jaundiced patient, the usual blood tests and ultrasound scan should be performed. Ultrasonography will determine if the bile duct is dilated. If it is, and there is a genuine suspicion Ludwig Courvoisier , 1843–1918, surgeon, Basel, Switzerland, was one of the first surgeons to remove stones from the common bile duct. a contrast-enhanced CT scan ( Figure 72.8 ). In the majority of instances, this should establish if there is a tumour in the it is resectable. The presence of hepatic or pancr eas and if peritoneal metastases, lymph node metastases distant from the pancreatic head or encasement of the superior mesenteric, hepatic or coeliac artery by tumour are clear contraindications to surgical resection. Tumour size, continuous invasion of the duodenum, stomach or colon and lymph node metastases within the operative field are not contraindications. If the tumour abuts or minimally invades the portal or superior mesenteric vein, this is not a contraindication to surgery (as part of the vein can be resected if necessary); however, complete encasement and occlusion of the vein and any degree of arterial involvement remain contraindications to surgical resection. MRI and magnetic resonance angiography can provide information comparable to CT . ERCP and biliary stenting should be carried out if there is any suggestion of cholangitis, if there is diagnostic doubt or if there is likely to be a delay between diagnosis and surgery in a deeply jaundiced patient with distressing pruritus . It relieves the jaundice and can also provide a brush cytology or biopsy specimen to confirm the diagnosis ( Figures 72.13, 72.14 and 72.19 ). Otherwise, preoperative ERCP and biliary stenting is not routine in patients with resectable disease as it is associ - ated with a higher incidence of infective complications after surgery . The prothrombin time should be checked, and clotting abnormalities should be corrected with vitamin K or fresh- frozen plasma prior to ERCP . If a stent is placed in a pa tient who may undergo resection, it should be a plastic stent or a cov - er ed metal stent, as these can be easily removed during surgery . EUS is useful if CT fails to demonstrate a tumour, if tissue diagnosis is required prior to surgery (e.g. a mass has devel - oped on a background of chronic pancreatitis and a distinc - tion needs to be made between inflammation and neoplasia), if vascular invasion needs to be confirmed or if separating cys - tic tumours from pseudocysts ( Figure 72.33 ; see also Figure 72.20 ). T ransduodenal or transgastric FNA or Trucut biopsy performed under endoscopic ultrasound guidance avoids spill - age of tumour cells into the peritoneal cavity . Percutaneous transperitoneal biopsy of potentially resectab le pancreatic - tumours should be avoided as far as possible. Histological con - firmation of malignancy is desirable but not essential, particu - lar ly if the imaging clearly demonstrates a resectable tumour. The lack of a tissue diagnosis should not delay appropriate sur - gical therapy . In patients judged to have unresectable disease, tissue diagnosis should be obtained prior to starting palliative therapy . A CT scan of the chest and a fluorodeoxyglucose– positron emission tomography (FDG-PET) scan are routinely used to complete the staging. Diagnostic laparoscopy prior to an attempt at resection can spare a proportion of patients an unnecessary laparot - omy by identifying small peritoneal and liver metastases . It can be combined with laparoscopic ultrasonography . The tumour marker carbohydrate antigen 19-9 (CA19-9) is not highly specific or sensitive, but a baseline level should be identifying recurrence. Learning objectives Learning objectives To understand: The anatomy and physiology of the pancreas • Investigations of the pancreas • Congenital abnormalities of the pancreas • Management Management At presentation, more than 85% of patients with ductal adeno carcinoma are unsuitable for resection because of advanced disease. If imaging shows that the tumour is potentially resect able, the patient should be considered for surgical resection, as that o ff ers the only (albeit small) chance of a cure. Every patient with pancreatic cancer should ideally be discussed in a multidisciplinary forum. Comorbidities should be taken carefully into account. Biological rather than chronological age should be the consideration. In patients with locally advanced or metastatic disease the primary objective should be to relieve symptoms, improve quality of life and extend survival, rather than achieve a cure. Patients will broadly fall into four categories. 1 Resectable: these patients should be o ff ered surgery , to be followed by adjuvant chemotherapy . Some centres have begun to suggest that neoadjuvant chemotherapy be used prior to resection, but the evidence is not strong. 2 Borderline resectable (usually because of significant venous occlusion or arterial abutment): these patients may be o ff ered neoadjuvant chemotherapy with/without chemoradiotherapy , to be followed by surgical resection if the disease has been downstaged. Adjuvant therapy should follow . 3 Locally advanced and unresectable: o ff er systemic chemo therapy . Surgery may subsequently be possible in a small cohort who get downstaged. 4 Metastatic: o ff er systemic chemotherapy If a cystic tumour is encountered, no matter how large, surgical resection should be considered as it carries a reason able chance of cure. Tumours of the ampulla have a good prognosis and should, if at all possible, be resected. Some of the rare tumours and the neuroendocrine lesions should also be resected if at all possible. Surgical resection The standard resection for a tumour of the pancreatic head or the ampulla is a pylorus-preserving pancreatoduodenectomy (PPPD). This involves removal of the duodenum and the pancreatic head, including the distal part of the bile duct. The original pancreatoduodenectomy as proposed by Whipple included resection of the gastric antrum. Preserving the antrum and the pylorus is thought to result in a more physiological outcome with no di ff erence in survival or recurrence rates. The Whipple procedure is now reserved for situations in which the entire duodenum has to be removed (e.g. in FAP) or in which the tumour encroaches on the first part of the duodenum or the distal stomach and a PPPD would not achieve a clear resection margin. Total pancreatectomy is warranted only in situations Allen Oldfather Whipple , 1881–1963, Director of Surgical Services, The Presbyterian Hospital, and Professor of Surgery , Columbia University , New Y ork, NY , USA, began to perform two-stage pancreatoduodenectomies in 1934 and shortened the procedure into a one-stage process in 1940. (1861–1912) and Walter Kausch (1867–1928) had performed the operation before him, but Whipple was the surgeon who established pancreatoduodenectomy as an operation. IPMN) or the body and tail of the gland are too inflamed or too friable to achieve a safe anastomosis with the bowel. The PPPD procedure includes a local lymphadenectomy . Extended lymphadenectomy has not been shown to be beneficial in impr oving survival and is associated with increased morbidity . - If the tumour is adherent to the portal or superior mesenteric vein but can still be removed by including a patch or a short - segment of vein in the resection, with an appropriate recon - struction of the vessel, then that should be done. This is not associated with an increase in the morbidity or mortality of the procedure and the outcomes are similar. Arterial resections are not r ecommended unless carried out within the context of a trial. If performed outside a trial, they should be preceded by multidisciplinary discussion and careful counselling of the patient, and be carried out in a specialist unit. For tumours of the body and tail, distal pancreatectomy with splenectomy is the standard. Infiltration of the splenic artery or vein by the tumour is not a contraindication to resec - tion. When resecting the pancreatic tail for a benign lesion, one may attempt to preserv e the spleen if possible. When removing the spleen, prior vaccinations against pneumococci, meningo - cocci and Haemophilus influenzae B should be administered, and subsequent antibiotic prophylaxis given (see Chapter 70 ). While the majority of pancreatic resections continue to be performed via an open approach, minimally invasive approaches – laparoscopic and robotic – are feasible and may yield comparable results. Minimally in vasive pancreatic resec - tions are technically challenging, pose additional demands on - operating room time and equipment and involve a significant learning curve for the surgeon and the entire team. They should be restricted to specialist centres and surgeons who hav e experience in doing them. Distal pancreatectomy , especially for smaller tumours, lends itself more easily to the laparoscopic or robotic approach than a pancreatic head resection. Robotic - surgery may carry greater ergonomic benefit for the surgeon (see Chapter 10 ). Pancreatoduodenectomy The patient’s coagulation screen should be checked preopera - tively and adequate hydration ensured. The patient should be aware of the diagnosis, the gravity of the operation and the risks involved. The operation has three distinct phases: /uni25CF exploration and assessment; /uni25CF resection; /uni25CF reconstruction. A cholecystectomy is performed. The bile duct and hepatic artery are exposed, removing the lymphatic tissue in this area. Exposure of the hepatic artery enables division of the gastro - duodenal arter y and visualisation of the portal vein. The distal part of the gastric antrum is mobilised. The duodenum and right colon are mobilised from the retroperitoneal tissues. The superior mesenteric vein is exposed inferior to the pancreatic Alessandro Codivilla neck. Careful dissection into the plane between the vein and the pancreatic substance ( Figure 72.2 ) will reveal whether the tumour is adherent to the vein. At this juncture, a decision has to be made whether to proceed to the next phase of resection or not. If resection is to be performed, the fourth part of the duodenum is dissected and freed from the ligament of Treitz so that the upper jejunum can be brought into the supracolic compartment. The jejunum is divided 20–30 /uni00A0 cm downstream from the duodenojejunal flexure, and the mesentery of the proximal jejunum is detached. The first part of the duode num is divided. The neck of the pancreas is divided, and then the uncinate process is separated from the superior mesenteric vein and artery working up towards the upper bile duct, which is divided, releasing the specimen ( Figure 72.34 ). Retroperi toneal lymph nodes within the operative field are completely removed with the specimen. Reconstruction is carried out as in Figure 72.35 . The pancreatic stump, the divided bile duct Wenzel Treitz , 1819–1872, Professor of Anatomy and Pathology , at Kraków , Poland, and later at Prague, Czech Republic. that order. Some surgeons prefer to anastomose the pancreas to the posterior wall of the stomach instead; others pr efer to create a separate Roux loop of the jejunum and anastomose the pancreas to that. The operation should take between 3 and 6 hours. Blood loss should be low and transfusion is often not necessary . Patients are usually nursed in a high-dependency area for the first 24–48 hours after surgery . Prolonged naso - gastric drainage is unnecessary and early feeding can be com - menced. Enhanced recovery after surgery (ERAS) protocols should be applied to pancreatic resections as with other types of gastrointestinal surgery . Resection for pancreatic cancer should be carried out in specialist units. There is a clear cor relation between higher caseload volume and lower hospital mortality and morbid - ity . PPPD should carry a mortality of no more than 3–5%. The morbidity remains high, with some 30–40% of patients developing a complication in the postoperative period. These complica tions are usually infective, but a leak from the anasto - mosis between the pancreas and the bowel is known to occur in at least 10% of patients, and this may give rise to the major complication of a postoperative pancreatic fistula (POPF). Octreotide may be administer ed in the perioperative period to suppress secretion and reduce the likelihood of a leak, but the evidence for its e ffi cacy is still debatable. Following surgi - cal resection, the pathological tumour–node–metastasis stage should be documented. Adjuvant therapy At the beginning of this century , the reported 5-year survival following resection of a pancreatic adenocarcinoma ranged from 7% to 25% (around 10% for most centres). The median survival was 11–20 months. Considering that, at best, 15% of patients had resectable disease to begin with, this meant only two or three out of 100 patients with this disease could expect to survive to 5 years. Moreover, recurrences could and did show up even beyond the 5-year cut-o ff . The high recurrence rate following resection inevitably led to the consideration of adjuvant treatments to improve outcome. Starting with the large multicentre European study (ESPAC-1) in 2004, which showed an improvement in median survival after adjuvant chemotherapy with 5-fluorouracil (5-FU) but no advantage with adjuvant radiotherapy , there have been several further studies that have looked at gemcitabine alone, gemcitabine with capecitabine and most recently modified fluorouracil plus leucovorin, oxaliplatin and irinotecan (mFOLFIRINOX). The latter has been associated with disease-free survival of over 21 months and median overall survival of over 54 months. Most patients with resected ductal adenocarcinoma are now o ff ered - 6 months of adjuvant chemotherapy with mFOLFIRINOX. Those with a poor functional status or a contraindication to mFOLFIRINOX are o ff ered gemcitabine with/without capecitabine. Some centres continue to o ff er chemoradio - - therapy , particularly in patients with involved (R1) resection margins, and further trials of adjuvant chemoradiation are in progress. Pancreatic duct Body and tail of pancreas Superior mesenteric artery and vein Jejunum Figure 72.34 Resection of the head of the pancreas in a pylorus- preserving pancreatoduodenectomy. Liver Stomach Bile duct Choledocho jejunostomy Pancreato jejunostomy Pylorus Duodenu Jejunum Figure 72.35 Reconstruction after a pylorus-preserving pancreatodu odenectomy. m (c) It should be emphasised, however, that these depressing sta tistics apply to ductal adenocarcinomas. Patients with resected ampullary tumours have a 5-year survival of 40%, and cystic tumours and neuroendocrine tumours can often be cured by surgical resection. Palliation The median survival of patients with unresectable, locally advanced, non-metastatic pancreatic cancer is 6–10 months and, in patients with metastatic disease, it is 2–6 months. If unresectable disease is found in the course of a laparot omy that was commenced with the intent to resect, a choled - ochoenterostomy and a gastroenterostomy should be carried out to relieve (or pre-empt) jaundice and duodenal obstruction. The bile duct may be anastomosed to the duodenum or to a loop of jejunum. It is preferable to use the bile duct rather than the gallbladder. Cholecystojejunostom y is easier to perform, but the bile must then drain through the cystic duct, which is narrow and, if inserted low into the bile duct, is vulnerable to occlusion by tumour growth. A coeliac plexus block can also be administered. A transduodenal Trucut biopsy of the tumour should be obtained. - In patients found to have unresectable disease on imag - - ing, jaundice is relieved by stenting at ERCP ( Figure 72.36a ). Mesh metal stent in bile duct Tu mour Endoscope Endoscope Pancreatic tumour Stent in essing duodenum compr duodenum approach Mesh metal stent in bile duct Tu mour Figure 72.36 Approaches to biliary and duodenal stenting. (a) Endoscopic retrograde cholangiography and placement of a biliary stent; (b) percutaneous transhepatic cholangiography followed by cannulation of the biliary system and percutaneous placement of a biliary stent (mesh metal in this instance); (c) endoscopic placement of a duodenal stent (mesh metal). Plastic stents are cheaper but tend to occlude faster and, if the patient is likely to have a longer life expectancy , a metal stent can be used. If the patient is not a suitable candidate for endoscopic biliary stenting, a percutaneous transhepatic stent can be placed ( Figure 72.36b ). Obstruction of the duodenum occurs in approximately 15% of cases. If this occurs early in the course of the disease, surgical bypass by gastrojejunostomy is appropriate but, if it is late in the course of the disease, then the use of expanding metal stents inserted endoscopically is preferable, as many of these patients have prolonged delayed gastric emptying following surgery ( Figure 72.36c ). If both bil iary and duodenal metal stents are to be placed endoscopically , the biliary one should be placed first. If no operative procedure is undertaken, an EUS-guided or percutaneous biopsy of the tumour should be performed before consideration of chemotherap y or chemoradiation. Lymphomas of the pancreas are rare and constitute less than 3% of all pancr eatic cancers. These respond to chemoradio therapy and surgical resection is not indicated. For patients with ductal adenocarcinoma who have locally advanced or metastatic disease, mFOLFIRINOX or alternatively gemcit abine plus albumin-bound paclitaxel particles (nab-paclitaxel) should be consider ed if the functional status is good. However, the 2–5 months’ increase in median survival with these regi mens has to be o ff set against the higher toxicity and cost. No long-term cures hav e been described with chemotherapy or radiotherapy . There is no role for sur gical resection if metastases are present at the time of the initial presentation. In a very small proportion of patients who have been deemed unresectable owing to major vascular in volvement and do not have met astatic disease, attempts have been made to downstage the tumour with one of the newer combination chemotherapy regimens, sometimes with chemoradiation added in, to try to render them resectable. Such neoadjuvant therapies are only very occasionally successful and should ideally be considered within a clinical trial. Steatorrhoea is treated with enzyme supplementation. Dia betes mellitus, if it develops, is treated with oral hypoglycae mics or insulin as appropriate, and pain with either analgesics or an appropriate nerve block. Palliation of pancreatic cancer /uni25CF /uni25CF /uni25CF /uni25CF - /uni25CF /uni25CF /uni25CF /uni25CF - /uni25CF /uni25CF - - Relieve jaundice and treat biliary sepsis Surgical biliary bypass Stent placed at ERCP or percutaneous transhepatic cholangiography Improve gastric emptying Surgical gastroenterostomy Duodenal stent Pain relief Stepwise escalation of analgesia Coeliac plexus block Transthoracic splanchnicectomy Symptom relief and quality of life Encourage normal activities Enzyme replacement for steatorrhoea Treat diabetes Consider chemotherapy Outcomes and follow-up of acute pancreatitis Outcomes and follow-up of acute pancreatitis The overall mortality from acute pancreatitis has remained at 10–15% over the past 20 years. There is a clear responsibility before the patient is discharged to determine the aetiology of - the attack of pancreatitis and the causes listed in Summary box 72.5 must be looked for and excluded. Failure to remove a predisposing factor could lead to a second attack of pancre - atitis, which could be fatal. A proportion of patients in the idiopathic group who su ff er repeated attacks may prov e to have biliary microlithiasis, which can be identified only by bile sampling at ERCP or by EUS. In a patient who has gallstone pancreatitis, the gallbladder and gallstones should be removed as soon as the patient is fit to undergo surgery and, preferably , before discharge from hospital. PANCREATITIS PANCREATITIS Pancreatitis is inflammation of the pancreatic parenchyma. For clinical purposes, it is useful to divide pancreatitis into acute, which presents as an emergency , and chronic, which is a prolonged and frequently lifelong disorder resulting from the development of fibrosis within the pancreas. It is possible that acute and chronic pancreatitis are di ff erent phases of the same process. - Acute pancreatitis is defined as an acute condition pre - senting with abdominal pain, a threefold or greater rise in the serum levels of the pancreatic enzymes amylase or lipase and/or characteristic findings of pancreatic inflammation on contrast-enhanced CT . Acute pancreatitis may recur . The underlying mechanism of injury in pancreatitis is thought to be premature activation of pancreatic enzymes - within the pancreas, leading to a process of autodigestion. Anything that injures the acinar cells and impairs the secr e - - tion of zymogen granules or damages the duct epithelium, and thus delays enzymatic secretion, can trigger acute pancreati - tis. Once cellular injury has been initiated, the inflammatory process can lead to pancr eatic oedema, haemorrhage and, eventually , necrosis. As inflammatory mediator s are released - into the circulation, systemic complications can arise, such as haemodynamic instability , bacteraemia (due to translocation of gut flora), acute respiratory distress syndrome and pleural e ff usions, gastrointestinal haemorrhage, renal failure and dis - seminated intravascular coagulation (DIC). Acute pancreatitis may be categorised as mild (interstitial oedematous pancreatitis) or severe (necrotising pancreatitis). The former is characterised by interstitial oedema of the g land and minimal organ dysfunction. The majority of patients will have a mild attack of pancreatitis, the mortality from which is around 1%. Severe acute pancreatitis is seen in 5–10% of patients and is characterised by pancreatic necrosis, a severe In those who have a severe attack of pancreatitis, the mortality varies from 20% to 50%. Acute pancreatitis has an early phase that usually lasts a week. It is characterised by a systemic inflammatory response syndrome (SIRS), which – if severe – can lead to transient or persistent organ failure (deemed persistent if it lasts for over 48 hours). About one-third of deaths occur in the early phase of the attack, from multiple organ failure. The late phase is seen typically in those who su ff er a severe attack and can run from weeks to months. It is characterised by persistent systemic signs of inflammation and/or local complications, particularly fluid collections and peripancreatic sepsis. Deaths occurring after the first week of onset are often due to septic complications. Chronic pancreatitis is defined as a continuing inflamma tory disease of the pancreas characterised by irreversible mor phological change typically causing pain and/or permanent loss of function. Many patients with chronic pancreatitis have painful exacerbations, but the condition may be completely painless. Pancreas divisum Pancreas divisum Pancreas divisum occurs when the embryological ventral and dorsal parts of the pancreas fail to fuse ( Figure 72.3 ). The dorsal pancreatic duct becomes the main pancreatic duct and drains most of the pancreas through the minor or accessory papilla. The incidence of pancreas divisum ranges from 5% in autopsy series to 10% in some ERCP and MRCP series. Pancreas divisum found incidentally in an asymptomatic person does not warrant intervention; however, the incidence of pancreas divisum ranges from 25% to 50% in patients with recurrent acute pancreatitis, chronic pancreatitis and pancre - atic pain. The minor papilla is substantially smaller than the major papilla, thus large volumes of secretions flowing through a narrow papilla leads to incomplete drainage, which may in turn cause obstructiv e pain or pancreatitis. Certainly , pancreas divisum should be excluded in patients with idio - en pathic recurrent pancreatitis. The diagnosis can be arrived at by MRCP , EUS or ERCP , augmented by injection of secretin if necessary . There may be changes indicative of obstruction ). or chronic inflammation in the dorsal duct system. Endoscopic sphincterotomy and stenting of the minor papilla may relieve the symptoms. Surgical intervention can take the form of sphincteroplasty , pancreatojejunostomy or even resection of the pancreatic head. Pancreatic function tests Pancreatic function tests Pancreatic exocrine function can be assessed by directly measuring pancreatic secretion in response to a standardised stimulus. The stimulus to secretion can be physiological, e.g. ingestion of a test meal, as in the Lundh test, or pharmacolog - ical, e.g. intravenous injection of a hormone such as secretin triple-lumen tube so that the gastric and duodenal juices can be aspirated, and a non-absorbable marker such as polyethylene glycol is used to assess the completeness of the aspiration. The nitroblue tetrazolium–para-aminobenzoic acid (NBT–PABA) test provides an indirect measure of pancreatic function. The substance is administered orally and degraded in the gut by a pancreatic enzyme, and the breakdown product (PABA) is absorbed by the intestine and excreted in the urine; its urinary level is measured. The pancreolauryl test works on a similar principle. These tests are cheap and easy to perform but are non-specific, especially following gastrectomy and in conditions that may alter gastrointestinal transit and intestinal absorptive capacity . They are rarely used now in the clinical setting. Measurement of the enzyme elastase in stool is simple, specific and now used widely . A low level of faecal elastase indicates exocrine insu ffi ciency . Pancreatic fistula Pancreatic fistula Pancreatic fistula usually follows operative trauma to the gland or occurs as a complication of acute or chronic pancre atitis. It is important to define the site of the fistula and the epithelial structure with which it communicates (e.g. exter nally to skin or internally to bowel). If there is uncertainty about whether the fluid issuing from a drain site or a wound is pancreatic juice, measurement of the amylase content will be diagnostic. Management includes correction of metabolic and elec trolyte disturbances and adequate drainage of the fistula into a stoma bag with pr otection of the skin. Investigation of the cause of the fistula is required as the underlying cause must be treated before the fistula will close . Frequently , the cause is related to obstruction within the pancreatic duct, which can be overcome by endoscopic insertion of a stent or catheter into the pancreatic duct. While waiting for closure of the fistula, the patient should be given parenteral or nasojejunal nutritional support (as opposed to nasogastric or oral feeding; the rationale is that parenteral or nasojejunal feeding reduces the volume of pancreatic secretion). The use of octreotide will also suppress pancreatic secretion. César Roux , 1857–1934, Professor of Surgery and Gynaecology , Lausanne, Switzerland. Christian Albert Theodor Billroth , 1829–1894, Professor of Surgery , Vienna, Austria. - Management of pancreatic fistulae - /uni25CF - /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF /uni25CF - Tests Measure amylase level in /f_l uid Determine the anatomy of the /f_i stula Check if the main pancreatic duct is blocked or disrupted Measures Correct /f_l uid and electrolyte imbalances Protect the skin Drain adequately Parenteral or nasojejunal feeding Octreotide to suppress secretion Relieve pancreatic duct obstruction if possible (ERCP and stent) Treat underlying cause Pathology Pathology More than 85% of pancreatic cancers are ductal adeno carcinomas. The remaining tumours constitute a variety of pathologies with individual characteristics. Endocrine tumours of the pancreas are rare. These are cover ed in Chapter 57 Ductal adenocarcinomas arise most commonly in the head of the gland. They are solid, scirrhous tumours, characterised by neoplastic tubular glands within a markedly desmoplas tic fibrous stroma. Fibrosis is also a c haracteristic of chronic pancreatitis, and histological di ff erentiation between tumour Henry T Lynch , 1928–2019, Professor of Preventative Medicine, Creighton University , Omaha, NE, USA. John Law Augustine Peutz , 1886–1970, Chief Specialist for Internal Medicine, St John’s Hospital, The Hague, The Netherlands. Harold Joseph Jeghers , 1904–1990, Professor of Internal Medicine, The New Jersey College of Medicine and Dentistry , Jersey City , NJ, USA. - - - - - and pancreatitis can cause diagnostic di ffi culties. Ductal ade - nocarcinomas infiltrate locally , typically along nerve sheaths, along lymphatics and into blood vessels. Liver and peritoneal metastases are common. Proliferative lesions in the pancreatic ducts can precede invasive ductal adenocarcinoma. These ar e termed pancreatic intraepithelial neoplasia or PanIN, and can demonstrate a range of structural complexity and cellular atypia. Cystic tumours of the pancreas may be serous or mucinous. Serous cystadenomas are typically found in older women and are large aggregations of multiple small cysts, almost like bub - ble wrap. They are benign. Mucinous tumours, on the other hand, have the potential for malignant transformation. They include mucinous cystic neoplasms (MCNs) and intraductal papillary mucinous neoplasms (IPMNs). MCNs are seen in - perimenopausal women, show up as multilocular thick-walled cysts in the pancreatic body or tail and, histologically , contain an ovarian-type stroma. IPMNs are more common in the . pancreatic head and in older men, but an IPMN arising from a branch duct can be di ffi cult to distinguish from an MCN. IPMNs arising within the main duct are often multifocal and - have a greater tendency to prove malignant. Thick mucus seen extruding from the ampulla at ERCP is diagnostic of a main duct IPMN. Mucinous tumours can be confused with pseudo - pancreatic cancer. Demographic factors Age (peak incidence 65–75 years) Male gender Black ethnicity Environment/lifestyle Cigarette smoking Genetic factors and medical conditions Family history Two /f_i rst-degree relatives with pancreatic cancer: relative risk increases 18- to 57-fold Germline BRCA2 mutations in some rare high-risk families Hereditary pancreatitis (50- to 70-fold increased risk) Chronic pancreatitis (5- to 15-fold increased risk) Lynch syndrome (HNPCC) Ataxia telangiectasia Peutz–Jeghers syndrome Familial breast–ovarian cancer syndrome Familial atypical multiple mole melanoma Familial adenomatous polyposis – risk of ampullary/duodenal carcinoma Diabetes mellitus Obesity HNPCC, hereditary non-polyposis color ectal cancer. cysts ( Summary box 72.8 and Figure 72.32 ) . Occasionally , lymphoepithelial cysts, lymphangiomas, dermoid cysts and intestinal duplication cysts can show up in the pancreas. Solid pseudopapillary neoplasms are rare, slowly progressive but malignant lesions seen in women of childbearing age, and manifest as large, part-solid, part-cystic tumours. Tumours arising from the ampulla or from the distal com mon bile duct can present as a mass in the head of the pan creas and constitute around a third of all tumours in that area. Adenomas of the ampulla of Vater are diagnosed at endoscopy as polypoid submucosal masses covered by a smooth epithe lium. They can harbour foci of invasive carcinoma; the larger the adenoma, the greater the risk. Biopsies taken at endoscopy may not always include the malignant focus. Endoscopic sur veillance, endoscopic resection or even surgical transduode nal ampullar y excision should be considered ( Figure 72.33 Patients with familial adenomatous polyposis (FAP) can present with multiple duodenal polyps. Malignant transformation in a duodenal polyp is a significant cause of mortality in these patients, mandating endoscopic follow-up and pancrea odenectomy in selected patients with high-grade dysplasia within the polyp. Ampullary adenocarcinomas often present early with biliary obstruction. Their natural history is distinctly more favourable than that of pancreatic ductal adenocar cinoma. Ampullary carcinomas are relativ ely small when diagnosed, which may account for their better prognosis. Occasionally , other malig - nant neoplasms can arise at the ampulla, such as carcinoid tumours and high-grade neuroendocrine carcinomas. - Investigate with MRCP and EUS+FNA Send fluid for CEA, cytology (CEA ≥192 ng/mL indicates mucinous neoplasm) IPMN or MCN Relative indications for surgery: Un /f_i t for surgery No indication for surgery Absolute indications for surgery: • Growth rate ≥5 mm/year • Carcinoma or high-grade dysplasia • Serum CA19-9 >37 U/L on cytology • Main pancreatic duct dilated • Solid mass 5–9.9 mm • Jaundice (tumour related) • Cyst diameter >40 mm • Enhancing mural nodules ≥5 mm • New-onset diabetes mellitus • Main pancreatic duct dilated ≥10 mm • Acute pancreatitis • Enhancing mural nodules <5 mm Surgery Acceptable surgical risk with 1 or 2 indications or high surgical risk but >2 indications Surgery Figure 72.32 Management algorithm for cystic neoplasms of the pancreas. CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic anti gen; EUS, endoscopic ultrasonography; FNA, /f_i ne-needle aspiration; IPMN, intraductal papillary mucinous neoplasm; MCN, mucinous cystic neoplasm; MRCP , magnetic resonance cholangiography and pancreatography; NET, neuroendocrine tumour. (Adapted fr Study Group on Cystic Tumours of the Pancreas. European evidence-based guidelines on pancreatic cystic neoplasms. Solid pseudopapillary Cystic NET Serous cystic neoplasm neoplasm Other benign cyst Consider surgery Consider surgery Manage conservatively High surgical risk with 1 indication Monitor at 6 and 12 months Monitor 6-monthly and then annually with: with: • Clinical evaluation • Clinical evaluation • Serum CA19-9 • Serum CA19-9 • MRCP/EUS • MRCP/EUS om The European Gut 2018; 67 : 789–804.) Physiology Physiology In response to a meal, the pancreas secretes digestive enzymes in an alkaline (pH /uni00A0 8.4) bicarbonate-rich fluid. Spontaneous secretion is minimal; the hormone secretin, which is released from the duodenal mucosa, evokes a bicarbonate-rich fluid. Cholecystokinin (CCK) (synonym: pancreozymin) is released from the duodenal mucosa in response to food. CCK is responsible for enzyme release. Vagal stimulation increases the Camillo Golgi , 1844–1926, Professor of Anatomy and Histology at Pavia, and later at Siena, Italy , developed silver staining of neural tissue and received the Nobel Prize in 1906 (with Ramón y Cajal). Göran Lundh , 1926–1999, surgeon, Södersjukhuset, Stockholm, Sweden. (per gram of tissue) in the pancreas than in any other tissue, with the possible exception of the lactating mammary gland. About 90% of this protein is exported from the acinar cells as a variety of digestive enzymes. Approximately 6–20 /uni00A0 g of diges - tive enzymes enters the duodenum each day . Nascent proteins are synthesised as preproteins and undergo modification in a sequence of steps. The proteins move from the rough endo - thelial endoplasmic reticulum to the Golgi complex, where lysosomes and mature zymogen storage granules containing proteases are stored, and then to the ductal surface of the cell, fr om which they are extruded by exocytosis. During this phase, the proteolytic enzymes are in an inactive form, which is important in preventing pancreatitis. TABLE 72.2 Investigation of the pancreas. Serum enzyme levels Pancreatic function tests Morphology Ultrasonography Computed tomography Magnetic resonance imaging Endoscopic retrograde cholangiopancreatography Endoscopic ultrasonography Plain radiography Chest Upper abdomen pancreas pancreas This sometimes accompanies congenital disease of the kidneys and liver and occurs as part of the von Hippel–Lindau syndrome.