Exocrine function

The exocrine pancreas is essential for the digestion of fat, protein and carbohydrate. The pancreas secretes 1–2 litres of alkaline (pH 7.5–8.8) enzyme-rich juice each day. The enzymes are synthesized by the acinar cells and stored there as zymogen granules. Trypsin is the key proteolytic enzyme; it is released in an inactive form (trypsinogen) and is normally only activated within the duodenum by the brush border enzyme, enterokinase. Once trypsin has been activated, a cascade is established whereby the other proteolytic enzymes become activated in turn. Lipase and amylase are secreted as active enzymes. The alkaline medium required for the activity of pancreatic enzymes is provided by the bicarbonate secreted by the ductal epithelium.

Pancreatic secretion is stimulated by eating. Hormonal and neural (vagal) mechanisms are involved. Food entering the duodenum (notably fat and protein digestion products) releases cholecystokinin (CCK), which stimulates pancreatic enzyme secretion, while at the same time causing the gallbladder to contract and increase bile flow into the intestine. Acid in the duodenum releases the hormone secretin, which stimulates the pancreas to secrete watery alkaline juice.

Endocrine function

The islets of Langerhans are distributed throughout the pancreas. Although they account for only 2% of the weight of the gland, they receive 10% of its blood supply. Interaction between the endocrine and the exocrine pancreas is facilitated by the close proximity of islets and acini, and by a local ‘portal’ system in which blood draining from the islets enters a capillary network around neighbouring acinar cells before entering the tributaries of the portal vein. Four types of islet cell are recognized: A cells produce glucagon; B cells, insulin; D cells, somatostatin; and PP cells, pancreatic polypeptide. Glucagon and insulin have well-established physiological roles; the function of the other islet products is uncertain, but somatostatin and pancreatic polypeptidemay serve as local (paracrine) regulators, rather than as circulating (endocrine) messengers. Gastrin-producing (G) cells are not normally found in the pancreas, except in the rare Zollinger–Ellison syndrome.

Pancreatic pain

The parasympathetic nervous system has no role in the perception of pancreatic pain. Painful stimuli from the pancreas are transmitted by sympathetic fibres that travel along the arteries of supply to the coeliac ganglion, and from there to segments 5–10 of the thoracic spinal cord via the greater, lesser and least splanchnic nerves.

Acute pancreatitis

Acute pancreatitis is a common cause of emergency admission to hospital. There are 100–400 new cases per million of the population each year in the UK, and the incidence continues to rise, possibly because of an increase in gallstone disease, alcohol misuse and obesity in the population. The disease is relatively rare in children, but all adult age groups may be affected.

Gallstone pancreatitis

Gallstones are present in some 40% of patients in the UK who develop acute pancreatitis, but tiny gallstones or even microscopic crystals (so called microlithiasis) are thought to account for the majority of ‘idiopathic’ cases. Transient impaction of a gallstone within the common channel between the common bile duct and pancreatic duct causes obstruction of the pancreatic duct (Fig. 15.3) and a sequence of events within the pancreatic acinar cells resulting in intracellular activation of pancreatic enzymes, acinar cell damage and pancreatic inflammation.

Fig. 15.3 A Common channel shared by the bile duct and the pancreatic duct may allow gallstone pancreatitis. B Operative cholangiogram showing a stone in the distal common bile duct and reflux of contrast into the pancreatic duct.

Clinical features of acute pancreatitis

Constant, severe or agonizing pain in the epigastrium, with radiation through to the back, is usually prominent. Pain can also be experienced in either hypochondrium. Nausea, vomiting and retching are often marked. Clinical examination often reveals much less tenderness, guarding and rigidity than might have been expected from the patient’s history and the presence of generalized peritonism may warrant further investigation by CT to exclude other intra-abdominal pathology. Signs of systemic disturbance include tachycardia, hypotension or tachypnoea and are indicative of severe pancreatitis. Obstructive jaundice may be apparent in patients with pancreatitis due to an impacted gallstone, and if present should raise awareness of the possibility of co-existent cholangitis.

Diagnosis

The key to the diagnosis of acute pancreatitis is a high index of suspicion and measurement of the serum amylase concentration. Serum lipase is an alternative and has some advantages but is rarely available in UK hospitals. The usual diagnostic cut-off for serum amylase is three times the upper reference limit but the diagnosis should be considered in any patient with a relevant history, even where there is a non-diagnostic rise in serum amylase. A high serum amylase can be seen in patients with abdominal pain due to other pathology. The most common of these is mesenteric ischaemia due either to mesenteric vascular occlusion or small bowel strangulation, and when there is diagnostic doubt, an urgent CT is indicated to clarify the diagnosis. High serum amylase levels are also seen in some patients with perforated ulcer or ruptured aneurysm but rarely above the diagnostic threshold for pancreatitis. In all cases, if the history or clinical examination is atypical for acute pancreatitis, CT should be carried out to clarify the diagnosis.

Serum amylase levels fall rapidly in acute pancreatitis and have no relationship to the severity of the attack or the resolution of the disease. Patients who present some days after the initial onset of abdominal pain may have normal or near-normal serum amylase levels and although urinary amylase or serum lipase can be helpful in such cases, the diagnosis is again best clarified by CT.

Radiology

Initial diagnosis of acute pancreatitis is based on clinical features combined with serum amylase levels. The role of radiology in initial assessment is confined to cases where there remains diagnostic doubt, as when serum amylase is non-diagnostic or where the clinical history or examination findings are atypical (for example when there is evidence of generalized peritonitis). In these cases urgent contrast-enhanced CT is mandatory. In patients with acute pancreatitis, changes will be identified ranging from mild peripancreatic oedema through to extensive pancreatic necrosis (Fig. 15.4) but more importantly at this stage, other diagnoses which require urgent operative intervention, such as mesenteric ischaemia or perforated viscus, will be excluded.

Fig. 15.4 Early CT with oedema and tail necrosis.

Differentiation between gallstone- and alcohol-associated pancreatitis

It is important to clarify the aetiology of acute pancreatitis, primarily so that further attacks can be prevented where possible. In the UK, the majority of cases are due to gallstones and these may be present even where there is a clear history of alcohol excess. Therefore, all patients with acute pancreatitis should have an abdominal ultrasound carried out. Even when no stones are identified on ultrasound, other factors may suggest a gallstone diagnosis. In particular, elevated alanine transaminase (ALT) at admission of more than twice the upper reference limit is highly suggestive of a gallstone aetiology. In patients where no cause is found, further investigation by endoscopic ultrasound may detect microlithiasis or rare causes such as a small pancreatic neoplasm. This is best performed once the acute attack has resolved.

Assessment of severity

Approximately 80% of patients with acute pancreatitis will have a self-limiting illness which resolves within 48–72 hours. In such cases the main issue is identification and treatment of the underlying cause. The major challenge faced in the management of this condition is the 20% of patients who have a severe episode of pancreatitis in whom life-threatening complications can occur. Much effort has been directed at the early recognition of severe acute pancreatitis, the aim being to ensure these patients are adequately managed and placed in an appropriate high-dependency or intensive care environment. Many systems have been proposed of which the Glasgow Prognostic Score, APACHE II score and C-reactive protein have been most widely studied. None of these however have proved sufficiently accurate to influence management decisions, particularly in the crucial first 24 hours after hospital admission. Other attempts with serum or urine markers of severity have either proved disappointing or have not yet been tested in prospective studies. When faced with a patient with acute pancreatitis, the challenge therefore is to recognize the development of a severe attack which necessitates a clear understanding of the natural history of the illness.

The most important feature of severe acute pancreatitis is the development of multiple organ dysfunction syndrome (MODS). In most patients who develop severe acute pancreatitis this is identified by the presence of hypoxia, shock or more rarely, renal dysfunction around the time of admission to hospital. A minority of patients will develop such complications over the course of the next 48 hours and in these cases the presence of SIRS (systemic inflammatory response syndrome) characterized by a tachycardia, raised white cell count and/or tachypnoea is almost always present. It is very rare for a patient without SIRS at admission to develop MODS. Where SIRS persists for more than 48 hours, the risk of further deterioration is very high and such patients need close monitoring for the development of respiratory and renal complications. It is the group of patients with early persistent SIRS or MODS who are also at greatest risk of developing septic and other local complications of acute pancreatitis.

Contrast enhanced CT is used in some institutions to identify severe acute pancreatitis, as the presence of pancreatic necrosis or extensive fluid collections identifies a group at high risk of further complications. However it is increasingly recognized that the main determinant of outcome is early systemic organ dysfunction and the role of early CT is now mainly confined to cases of diagnostic doubt.

Management

Most attacks of acute pancreatitis will settle with conservative management involving intravenous fluids, analgesia and gradual re-introduction of diet when nausea and vomiting have settled. All patients with SIRS or early systemic organ dysfunction should be managed in a high-dependency or intensive care environment where adequate monitoring and specialist care is available.

Complications

Pancreatic pseudocyst

A pancreatic pseudocyst is a collection of pancreatic secretions and inflammatory exudate enclosed in a wall of fibrous or granulation tissue. It differs from a true cyst in that the collection has no epithelial lining and is surrounded by inflammatory tissue. Pseudocysts form most commonly in the lesser sac or in the adjacent retroperitoneum, and by consensus are differentiated from acute fluid collections in that they persist for 4 or more weeks from the onset of acute pancreatitis (Fig. 15.5). Small pseudocysts are usually asymptomatic and resolve spontaneously. In about 10% of patients, larger collections persist and can pose problems.

Fig. 15.5 Axial CT with a large retrogastric postacute inflammatory collection approximately 8 weeks after initial presentation.

Pseudocysts typically do not declare themselves for some weeks after the episode of pancreatitis. Persistent or intermittent abdominal discomfort and mild to moderate hyperamylasaemia usually signal their presence, and larger collections may compress neighbouring structures to cause vomiting and obstructive jaundice. Some cysts become so large that they are palpable and, in some cases, visible.

The presence of a pseudocyst is not in itself an indication for surgical treatment. Approximately 50% of asymptomatic pseudocysts will resolve up to 12 weeks following the onset of acute pancreatitis. Treatment is indicated only if the pseudocyst is enlarging or symptomatic, and aims to prevent infection of the contents, haemorrhage or rupture. Simple percutaneous drainage carries a high risk of recurrence and some form of internal drainage is usually preferred. The conventional surgical approach consists of drainage of the pseudocyst into the stomach (pseudocyst-gastrostomy), a Roux loop of jejunum (pseudocyst-jejunostomy), or duodenum (pseudocyst-duodenostomy); whichever appears most appropriate (Fig. 15.6). As the tissues holding the sutures must be firm, it is desirable to avoid surgery until at least 6 weeks after the onset of the acute attack to allow the walls of the pseudocyst to ‘mature’. Endoscopic cyst-gastrostomy or cyst-duodenostomy offers an alternative to surgery, and is now usually carried out under endoscopic ultrasound guidance. Laparoscopic cystgastrostomy or cyst-enterostomy is also described but the relative roles of conventional surgical, laparoscopic and endoscopic drainage have yet to be determined. The selection of the appropriate procedure is often determined by the clinical presentation, anatomical features of the fluid collection, the extent of necrosis present and of course, local expertise. A multidisciplinary approach is mandatory.

Fig. 15.6 Treatment of pancreatic pseudocyst.

A Transgastric cyst gastrostomy. B Roux cyst jejunostomy.

Gastrointestinal bleeding

Severe acute pancreatitis may be complicated by bleeding from gastritis, erosions or duodenal ulceration, and prophylactic PPI therapy is advisable. Bleeding which occurs following treatment of infected pancreatic necrosis is usually a consequence of erosion of a retroperitoneal vessel, often the splenic artery or a major branch of this vessel. Control is best achieved by mesenteric angiography with embolization where possible but surgical control may be necessary. Mortality from such bleeding remains high, particularly where surgical intervention is required. In patients with pseudocysts, bleeding may occur into the cyst causing sudden pain and often collapse. This is due to rupture of a false aneurysm within the wall of the pseudocyst and again is best managed by mesenteric embolization where possible. Overt evidence of gastrointestinal bleeding in a patient with infected pancreatic necrosis or pancreatic pseudocyst commonly indicates a communication between the retroperitoneal collections and the lumen of the GI tract (commonly stomach or colon) and urgent mesenteric angiography (or CT angiography if the patient is sufficiently stable) (Fig. 15.7) rather than endoscopy is the appropriate course of action.

Fig. 15.7 Late CT with splenic artery pseudoaneurysm.

Prognosis

Most patients with acute pancreatitis suffer a self-limiting illness and can be expected to make a full recovery. Further treatment is directed at preventing further attacks by definitive management of gallstones or advising against further alcohol abuse. Unfortunately, many patients are unwilling or unable to abstain from drinking, and suffer further attacks of acute pancreatitis with progression to chronic pancreatitis.

Patients with severe acute pancreatitis may be expected to have a more protracted illness and may require many months of hospital care. Overall mortality for such patients is in the region of 10–20%, usually as a consequence of multiple organ failure. Death within the first two weeks of acute pancreatitis accounts for approximately 50% of all mortality in this condition and is more common in patients with extensive necrosis and in the elderly. Late deaths are usually due to complications arising from infected pancreatic necrosis, with mesenteric ischaemia or severe retroperitoneal bleeding being common terminal events. Following recovery from severe acute pancreatitis, return to normal activities can be expected but full recovery can take many months, requiring nutritional support, management of persistent or recurrent sepsis and definitive management of wound or gastrointestinal complications.

Aetiology

Chronic pancreatitis is a relatively rare disease but its incidence may be increasing with the growing problem of alcohol misuse. Although alcohol is by far the most common aetiological factor, being implicated in some 60–80% of cases, the factors that predispose some patients to develop chronic pancreatitis are poorly understood, however cigarette smoking appears to be an important co-factor. The risk of chronic pancreatitis appears to increase when alcohol consumption is greater than 50 g of alcohol (or 5 standard drinks) per day.

Hereditary pancreatitis is a rare form of chronic pancreatitis with onset in early adult life and is due to one of a variety of identified mutations of the trypsinogen gene. In addition, many cases of idiopathic chronic pancreatitis are now believed to be associated with other gene mutations, such as that of the cystic fibrosis gene, CFTR. In some cases however, the cause remains unknown. Even where there is evidence of alcohol aetiology, there may be complex genetic factors which predispose to the development of chronic pancreatitis.

Pathophysiology

The secretion of an unduly viscid pancreatic juice may allow protein plugs to form in the duct system, and these plugs subsequently calcify to form duct stones. Impaired flow of pancreatic juice then leads to inflammation, stricture formation in the duct system, and progressive replacement of the gland by fibrous tissue. Loss of acinar tissue is eventually reflected by steatorrhoea and, in time, loss of islet tissue may lead to diabetes mellitus.

Clinical features

Pain is the outstanding feature in most cases. It is characteristically epigastric with marked radiation through to the back, and is often eased by leaning forward or getting down on all fours. In some cases, the pain is precipitated by eating, or the patient learns to avoid certain foods, notably fatty ones. The application of heat sometimes brings relief, and permanent discoloration of the skin may reflect the continued use of heat pads or hot water bottles. The progressive use of powerful opioid analgesics can result in drug dependency.

Weight loss is usual and reflects a combination of inadequate intake, a poor diet and malabsorption. Steatorrhoea is common, the bowel motion being pale, bulky, offensive, floating on water, and difficult to flush. Diabetes mellitus develops in about one-third of patients, but islet function is often preserved for some years following the onset of exocrine insufficiency.

Other less common manifestations of chronic pancreatitis include transient or intermittent obstructive jaundice, duodenal obstruction and splenic vein thrombosis (leading to splenomegaly, hypersplenism and gastric and oesophageal varices). Many patients also have other comorbidity related to cigarette and alcohol consumption which, particularly when combined with nutritional failure, can make management challenging.

Investigations and diagnosis

The initial investigation for suspected chronic pancreatitis is CT. This may reveal the speckled calcification typical of chronic pancreatitis or may show evidence of inflammatory changes or pancreatic duct dilatation or pseudocyst formation (Fig. 15.8). MRCP is of value to reveal the architecture of the pancreatic duct, particularly if surgery or endoscopic therapy is contemplated. When investigating these patients, it must be borne in mind that cancer of the pancreas may block the duct system and cause pancreatitis, and that the two conditions can co-exist. Endoscopic ultrasound is increasingly utilized where diagnostic uncertainty exists, allowing pancreatic fine needle biopsy where appropriate.

Fig. 15.8 Axial CT showing extensive calcification and cyst formation within the pancreatic head, duodenal wall thickening and narrowing of the superior mesenteric veins with extensive venous collaterals.

Pancreatic endocrine function is assessed by measurement of random blood glucose levels, supplemented if necessary by a glucose tolerance test. Exocrine function can be measured in a multitude of ways, but insufficiency may not be detectable until 90% of the pancreatic parenchyma is destroyed. If necessary, faecal fat excretion can be measured over 3–5 days while the patient’s fat intake is controlled at 100 g/day (normal individuals excrete less than 5 g/day). Faecal elastase is a more convenient method of assessment of exocrine pancreatic function but is less accurate. Where assays of exocrine function are not readily available, a trial of oral pancreatic supplements may be attempted.

Management

The diagnosis of chronic pancreatitis is not in itself an indication for treatment. Considerable clinical judgment is needed to determine the need for, and timing of, intervention. In most cases, pain is the most important indication for surgery but complications resulting from biliary obstruction or gastric outlet obstruction may also necessitate intervention. Many patients have complex problems and need a multidisciplinary approach to treatment.

Surgical treatment

This is indicated if pain is intractable; when neighbouring structures, such as the common bile duct, duodenum, portal or splenic vein, are sufficiently compressed to produce symptoms; when pseudocysts or abscesses develop; when endoscopic therapy has failed; or when cancer cannot be excluded.

In general, the objective is to relieve pain or compression, while at the same time conserving as much healthy pancreatic tissue and function as possible. Surgery involves drainage of the obstructed pancreatic duct into a Roux loop of jejunum, usually combined with some form of duodenum preserving pancreatic head resection. The two most commonly performed procedures are those described by Beger and Frey (Fig. 15.9), the difference between them being the greater extent of pancreatic parenchymal excision and need for formal division of the pancreatic neck in the Beger procedure. No one procedure has been proven to be superior. Approximately 70% of patients remain pain-free or substantially improved when assessed 5 years after surgery for chronic pancreatitis. As with all aspects of chronic pancreatitis treatment, the results of surgery are better in patients who manage to abstain from alcohol.

Fig. 15.9 Longitudinal pancreaticojejunostomy

Aetiology

Ductal adenocarcinoma of the pancreas is the 10th (male)/11th (female) most common cancer in the UK, but the fifth commonest cause of cancer related death. There are about 7600 new cases in the UK per annum (or 20/day), and the incidence has been consistent over the last 40 years, with a lifetime risk of about 1 in 95. Male and females are equally affected. Only 15–20% are resectable, and in these there is only 20% 5-year survival. As with most tumours there is an increasing incidence with age but 20% of patients are less than 60 years of age. Whilst the aetiology is unknown, there is an association with tobacco smoking (20–30% thought to be smoking related), race (African–Americans > Hispanics or Caucasians), diabetes, chronic pancreatitis (particularly hereditary pancreatitis) and familial pancreatic cancer.

Pathology

Pancreatic ductal adenocarcinoma (PDAC)

The majority of adenocarcinomas arise from ductal rather than acinar tissue, 60% arising in the head of the gland. The histology (Fig. 15.10) is characterized by groups of infiltrating carcinoma cells often some (histological) distance apart, interspersed by a fibrous stroma, with involvement of nerves, vessels, lymphatics and lymph nodes, at a relatively early phase. Metastatic spread is most commonly to the liver and lung; 80% of patients present with either locoregional or metastatic dissemination.

Fig. 15.10 Histology of pancreatic cancer with small groups of epithelial cells attempting to form glands, interspersed with fibrous stoma.

Mucinous cystic neoplasm

Mucinous cystic tumours of the pancreas predominate in the body and tail of the pancreas and have a strong female predilection. They are multiloculated tumours with a characteristic smooth glistening surface, a dense fibrous wall and occasional calcification (Fig. 15.11). They arise from oversecretion of the mucus by the hyperplastic columnar lining of the ducts and therefore contain thickened viscous material, which can also be haemorrhagic. These tumours should be considered potentially malignant but are classified histologically as benign, borderline, or malignant based on degree of dysplastic changes.

Fig. 15.11 Distal pancreatectomy / splenectomy specimen (transected) with mucinous cystic neoplasm (MCN showing cystic and solid components).

Solid pseudopapillary tumour of the pancreas

Solid pseudopapillary tumour, otherwise known as solid-cystic tumour, or Frantz tumour of the pancreas, is an unusual form of pancreatic carcinoma (Fig. 15.12). Its natural history differs from the more common pancreatic adenocarcinoma in that it is almost always in female patients (10:1), often at a young age (20–30 years), is more indolent, and carries a better prognosis. Pathologically, the tumour is usually well circumscribed with regions of necrosis, haemorrhage, and cystic degeneration. Metastatic disease can occur, usually involving the liver, and resection is the preferred treatment.

Fig. 15.12 Solid pseudopapillary tumour of the pancreatic head.

Curative management

Surgical resection currently offers the only potential for cure in pancreatic tumours. Tumours localised to the pancreatic parenchyma, or with limited involvement of the peripancreatic fat or lymph nodes may be considered for resection. Many adenocarcinomas of the body and tail are unresectable at diagnosis, but when identified early may be removed by distal pancreatectomy and splenectomy.

For tumours sited in the head of the pancreas the standard operation is a pancreaticoduodenectomy (Whipple’s procedure) (Fig. 15.14), which entails block resection of the head of the pancreas, the distal half of the stomach, the duodenum, gallbladder and common bile duct. Reconstruction is achieved by anastomoses of the pancreatic tail remnant to the jejunum (or stomach) and anastomosing the common hepatic duct and the stomach to the jejunum. The procedure used to carry a prohibitively high operative mortality, but in specialist hands this should now be less than 5%. Attempts to improve prognosis through escalating the radicality of resection by removing all of the pancreas or by extending the lymphadenectomy have proved disappointing. A standard pancreaticoduodenectomy combined with adjuvant chemotherapy, remains the standard of care, and is associated with a median survival of 24 months, although long-term cure remains a rarity. The prospects for patients with cancer of the periampullary region, distal common bile duct or duodenum are less gloomy, with 5-year survival rates ranging from 20% to 40%.

Fig. 15.14 Classic pancreaticoduodenectomy (Kausch–Whipple).

Palliative treatment

Only about 15–20% of patients are candidates for resection through a combination of advanced stage or co-morbidity. The objective is the optimization of quality of life through relief of obstructive symptoms (jaundice or duodenal obstruction), pruritus, and pain control. Effective preoperative staging has reduced the number of patients found to have inoperable disease at exploratory laparotomy, although when this occurs a double (biliary and gastric) bypass is appropriate.

Where inoperability is confirmed at the pretreatment planning meeting, surgical bypass can be avoided by achieving biliary drainage endoscopically at ERCP, or radiologically by percutaneous transhepatic cholangiography (PTC), along with brush cytology for histological confirmation. This is particularly important if surgery is not contemplated, as a number of benign lesions (e.g. autoimmune pancreatitis, chronic pancreatitis) can masquerade as malignancy and, as discussed above, a number of pancreatic mass lesions may have a significantly better prognosis than pancreatic ductal adenocarcinoma. In those with negative brush cytology at the time of biliary drainage, cytology may be obtained by EUS-FNA. This is of importance in that quality of life can be improved through palliative chemotherapy and most oncologists will not proceed without histological evidence of malignancy.

Patients often benefit from proactive nutritional support with the addition of pancreatic exocrine supplements to alleviate steatorrhoea, dietary advice and antiemetics. Dexamethasone can be of benefit, but close glucose control is needed. Pain is often a late manifestation, but can often be effective controlled through an analgesic ladder or occasionally coeliac plexus block or thoracoscopic splanchnicectomy.

Non-functioning PET

Many non- functional PETs are already metastatic by the time of diagnosis with the liver being the most common site of metastasis. Regional lymph node spread is also common, and PET may have a 5-year survival as low as 30%. Presentation is related to the mass effect of the tumour – symptoms are therefore often non-specific. Surgery with curative intent is the mainstay of treatment for localized or locoregional disease (Fig. 15.15). Non-functioning tumours should also be resected if sporadic and if > 2 cm in MEN1 or > 2–3 cm in VHL. Debulking surgery as well as other forms of local treatment like transarterial chemo-embolization or radiofrequency ablation can improve prognosis, even in patients with liver metastases. Systemic therapies have also been better defined and include radionuclide therapy against somatostatin receptors or MIBG and chemotherapy especially for poorly differentiated tumours. Cytotoxic therapy with compounds like streptozotocin, 5-fluorouracil or doxorubicin can achieve modest outcome.

Fig. 15.15 Distal pancreatectomy / splenectomy specimen with non-functioning PET.

Functioning PET

The functioning tumours and syndromes are named according to the hormones they produce: insulinoma, gastrinoma (most gastrinomas are found in the duodenum), VIPoma, glucagonoma, and somatostatinoma. The first two (insulinomas and gastrinomas) are the most frequent functioning pancreatic tumours. Unlike the non-functional tumours, presentation of functional PETs is more specific and related to the secretion of biologically active peptides like insulin, gastrin, glucagon, somatostatin, vasoactive intestinal polypeptide (VIP). The non-functional tumours also express and secrete peptides like neurotensin or chromogranin A, which are not active.

Insulinomas

Insulinomas arise from the beta cells within the pancreas and secrete excessive insulin. Insulinomas are benign in approximately 90% and solitary in 95% of sporadic cases. Beta cells should secrete insulin in response to an increase in blood sugar but the secretion of insulin by insulinomas is not properly regulated by glucose and the tumours continue to secrete insulin causing glucose levels to fall further than normal. As a result patients present with symptoms of low blood glucose (hypoglycaemia), which may be improved by eating. The diagnosis of an insulinoma is usually made biochemically: blood glucose £ 2.2 mmol/L (40 mg/dL), associated with an insulin level ≥ 6 µU/mL (36 pmol/L), C-peptide levels ≥ 200 pmol/L, proinsulin levels ≥ 5 pmol/L. Further controlled testing includes the 72-hour fast, which is the criterion standard for establishing the diagnosis of insulinoma, as 98% of patients with insulinomas will develop symptomatic hypoglycaemia within 72 hours. Localization of the tumour is most commonly achieved with contrast enhanced CT and endoscopic ultrasound. The definitive treatment is surgery.

Gastrinomas

For gastrinomas (Zollinger–Ellison syndrome), two measurements are critical: fasting serum gastrin (1000 pg/ml) and basal gastric acid output. Fasting serum gastrin (FSG) alone is not enough because of its lack of specificity, making it impossible to distinguish hypergastrinaemia caused by a gastrinoma from that caused by achlorhydric states (i.e. type 1 gastric NETs, use of PPIs, pernicious anaemia, atrophic gastritis). For these measures, a washout period from PPI treatment of 1–4 weeks is recommended. The 2006 European Neuroendocrine Tumour Society guidelines had cut-off values of greater than 10-fold elevation for FSG and gastric pH £ 2. Over 90% of gastrinomas are found in the ‘gastrinoma triangle’ bounded by the third part of the duodenum, the neck of the pancreas and the portahepatis. Gastrinomas are multiple in 20–40% of patients and often extra-pancreatic, with 20% found in the duodenum. Gastrinomas are frequently malignant with metastatic spread occurring to the liver and local lymph nodes. They tend to be small: 38% of pancreatic and all duodenal tumours are less than 1 cm in diameter at diagnosis. One-third of cases are associated with MEN type I in which multiplicity is the rule and there is a tendency to recurrence. Most gastrinomas are small lesions and therefore, localizing the tumour may be difficult. Investigations to localize the tumour include CT scan, octreotide scan, MRI and endoscopic ultrasonography.

Multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1 is characterized by hyperplasia and/or neoplasm of the parathyroid glands, enteropancreatic NETs, and pituitary adenomas. The gene for type 1 MEN has been localized to chromosome band 11q13. It is a tumour suppressor gene that encodes menin, a nuclear protein. Some patients do not present with all these tumours, so it has been agreed that diagnosis is made when a patient presents with two of these concomitantly. To diagnose familial MEN-1 syndrome, a first-degree relative has to manifest at least one of the tumours previously mentioned. Hyperparathyroidism occurs in about 90% of patients; endocrine pancreatic tumours in 60% of patients, usually they are small and non-functional, and the most common hormonally active ones are insulinomas or gastrinomas. In contrast to sporadic insulinoma these are multiple in 90% of MEN 1 patients. Pituitary adenomas are present in 40% of patients, and in 60% of the patients, skin manifestations can also be present. Biochemical screening for pancreatic NETs, in the presence of suspected MEN 1 syndrome, should include gastrin, insulin/pro-insulin, PP, glucagon, and CgA, which together have a sensitivity of approximately 70% that can be increased if α- and β-HCG subunits, VIP, postprandial gastrin, and PP measurements are added. It is recommended that carriers of MEN-1 mutation are screened biochemically every 1–3 years for hyperparathyroidism, prolactinoma, gastrinoma, insulinoma, and other enteropancreatic tumours. MEN 2 is not associated with pancreatic endocrine tumours.

Circulatory filtration

The cut surface of the spleen reveals areas of red and white pulp surrounded by fibrous trabeculae. The red pulp is a loose honeycomb of reticular tissue that contains the splenic sinusoids, lined by macrophages, and blood vessels pass into the pulp along the trabeculae. As erythrocytes age, the normal lifespan being about 120 days, the cell membrane becomes less flexible and because erythrocytes are required to deform to pass through the sinusoids, senescent cells being trapped within the spleen and therefore removed from the circulating population of cells. Following phagocytosis iron is split from the haem portion, and stored as haemosiderin before being transported to the bone marrow bound to transferrin to be incorporated into a new population of erythrocytes.

Erythrocytes move in and out of the pulp tissue, so that 1% of the body’s red cells and 20–30% of its platelets are sequestrated at any given moment. Unlike in some mammals (e.g. dogs), in humans the spleen is not a site of significant blood pooling except in pathological conditions with splenomegaly, where the spleen may contain more than a litre of blood. Following splenectomy, there is an increased number of mis-shapen red cells in the peripheral blood, some containing nuclear remnants (Howell-Jolly bodies) and others containing clumps of iron (siderocytes).

Immunological function

The spleen is an important site for promoting both cell-mediated and humoral immunity. The spleen represents the largest aggregation (∼︀25%) of lymphoid tissue in the body forming the white pulp, which consists of lymphoid follicles (Malpighian bodies) and lymphatic tissue, containing lymphocytes, macrophages and plasma cells, these cells having migrated from the bone marrow and 30–50% of them are thymus-dependent. Antigens entering the spleen are engulfed by macrophages, promoting antigen presentation, with subsequent antibody production in the germinal centres. Following splenectomy, immunological responses are impaired.

Haemopoiesis

In utero in the second and third trimester the spleen is an important source of erythrocyte and granulocyte production for the fetus. Although at birth this function usually ceases, in some disease processes with a high turnover of erythrocytes the spleen may continue to contribute to this process (extramedullary haemopoiesis).

Preoperative preparation

As many of the indications (Table 15.4) are for haematological conditions, preparation requires multidisciplinary management to ensure preoperative optimization of full blood count and coagulation status, and usually involves a further course of steroids or administration of blood products. Vaccines are best administered two weeks before surgery.

Table 15.4 Indications for splenectomy.

Open technique

For an elective splenectomy, access is usually gained via a left subcostal incision. Rarely, a thoracoabdominal incision is necessary to remove a large spleen. A normal-sized non-adherent spleen is approached by initial division of the diaphragmatic attachments and the lienorenal ligament allowing the spleen to be folded forward, improving access to the organ. Division of the short gastric vessels exposes the splenic hilum and the vessels divided either between ligatures or using a vascular stapling device, taking care to avoid injury to the tail of the pancreas. Division of the remaining peritoneal attachments allows removal of the organ.

When the spleen is enlarged or adherent to surrounding organs or the diaphragm, preliminary mobilization may not be possible and the vascular pedicle is dissected first. Alternatively, the splenic artery may first be ligated in continuity so that the spleen shrinks in size, allowing it to be mobilized and the vessels to be ligated close to the splenic hilum. Drains are not routinely used (as they may actually increase the incidence of subphrenic sepsis), unless there is a possibility that the tail of the pancreas has been injured or there is persistent oozing due to a coagulation defect.

Traumatic splenectomy

In the majority of situations which require an emergency splenectomy for trauma (Table 15.5), the potential for injury is relatively obvious through a history of blunt or penetrating trauma. Delayed presentation, an unusual mechanism (e.g. post-colonoscopy) or the absence of a history through intoxication make a high index of suspicion essential. In addition, in patients with splenic enlargement, the mechanism may be relatively trivial. The cardinal features are those of significant blood loss, and local signs of peritoneal irritation (peritonitis or left shoulder tip pain).

Table 15.5 The American Association for the Surgery of Trauma classification of splenic trauma.

Patients that do not respond to initial resuscitation require an emergency laparotomy and usually a splenectomy along with a careful exploratory laparotomy to exclude injury to other structures. In the responding patient, cross-sectional imaging is advised.

Approximately 80% of splenic injuries may be managed conservatively, and of these the requirement for intervention is apparent within 72 hours in 95%. In the unstable patient, control of haemorrhage and restoration of circulating volume are paramount and consideration regarding organ preservation is of secondary importance. Unlike an elective splenectomy a midline laparotomy is usually performed with packing of the left upper quadrant which will normally control the splenic haemorrhage to allow the remainder of the abdomen to be examined. Having excluded other sources of haemorrhage, if examination of the spleen reveals bleeding from the splenic hilum, preservation is not appropriate and a splenectomy should be performed.

The purpuras

Haemolytic anaemias

Hypersplenism

This syndrome consists of splenomegaly and pancytopenia in the presence of an apparently normal bone marrow and the absence of an autoimmune disorder. There is sequestration and destruction of blood cells in the spleen, affecting predominantly white cells and platelets. Hypersplenism may complicate a number of inflammatory conditions (e.g. rheumatoid arthritis), infections (e.g. malaria), and myeloproliferative and lymphoproliferative disorders. In portal hypertension, splenic congestion frequently leads to splenomegaly and hypersplenism.

The enlarged spleen results in an expansion of the total blood volume to fill the increased vascular spaces of the enlarged spleen with pooling of cells and increased destruction within the sinusioids. This results in anaemia, leucopenia and thrombocytopenia, with reticulocytosis and leucoerythroblastosis in the marrow. Increased haemoglobin turnover results in increased amounts of urobilinogen in the urine. Splenectomy may be appropriate but the potential morbidity, the risks of late septic complications and the prognosis of the underlying cause of the hypersplenism require to be balanced with the potential alleviation of the pancytopenia.

Proliferative disorders

Miscellaneous conditions

Post-splenectomy immunization

Loss of lymphoid tissue reduces immune activity and impairs the response to bacteraemia. The risk of overwhelming post-splenectomy sepsis is greatest when splenectomy is performed in childhood.

The British Committee for Standards in Haematology recommends that all splenectomized patients and those with functional hyposplenism should receive pneumococcal immunization and patients not previously immunized should receive haemophilus influenza type b vaccine. Patients not previously immunized should receive meningococcal group C conjugate vaccine. Influenza immunization should be given. Life long prophylactic antibiotics are still recommended (oral phenoxymethylpenicillin or erythromycin). Elective splenectomy should be preceded by the administration of vaccines 2–3weeks prior to surgery, but are still effective if given postoperatively.