Surgery on neuroendocrine tumours

Best Practice & Research Clinical Endocrinology & Metabolism Vol. 21, No. 1, pp. 87–109, 2007 doi:10.1016/j.beem.2006.12.004 available online at http://www.sciencedirect.com 6 Surgery on neuroendocrine tumours Göran Åkerström * MD Professor Per Hellman MD Associate Professor Department of Surgical Sciences, University Hospital, SE-751 85 Uppsala, Sweden Neuroendocrine tumours of the gastrointestinal tract and pancreas present a major challenge to physicians in their recognition and treatment requirements, and surgical treatment of these tumours has become increasingly important for symptom palliation and survival. For some carcinoid tumours the extent of surgery may depend on tumour size. Midgut carcinoid is the most common cause of the carcinoid syndrome, requiring surgery for primary and mesenteric tumours to minimize the risk for abdominal complications but also for removal of liver metastases to palliate hormonal symptoms. Among endocrine pancreatic tumours, insulinoma and gastrinoma often cause severe symptoms of hormone excess despite their inconspicuous size, but they can be successfully removed with improved pre- and intraoperative localization. Other tumours – glucagonoma, VIPoma, and non-functioning endocrine pancreatic tumours – are often large or metastasizing, but generally require surgical debulking to alleviate hormonal symptoms and have favourable survival. Key words: neuroendocrine tumours; gastrointestinal; pancreatic; liver metastases; surgical treatment. CARCINOIDS Gastric carcinoids Gastric carcinoids constitute w4% of all carcinoids and 1% of gastric neoplasms. Type 1 gastric carcinoids Type 1 carcinoids account for w70% of gastric carcinoids, and develop secondary to hypergastrinaemia in <1% of patients with autoimmune chronic atrophic gastritis * Corresponding author. Tel.: þ46 18 6114624; Fax: þ46 18 504414. E-mail address: goran.akerstrom@surgsci.uu.se (G. Åkerström). 1521-690X/$ - see front matter ª 2007 Elsevier Ltd. All rights reserved. 88 G. Åkerström and P. Hellman (CAG) (Figure 1).1–4 Absence of gastric acid secretion causes the hypergastrinaemia. The tumours are most frequent in female patients, w60 years of age, with common vitamin B12 malabsorption and pernicious anaemia (in 50%). The patients are generally asymptomatic, and the diagnosis is often revealed accidentally during gastroscopy. These carcinoids typically appear as multiple small gastric polyps together with enterochromaffin-like (ECL) cell hyperplasia/dysplasia in atrophic mucosa of the gastric body and fundus. The number of polyps varies; some appear solitary and may be difficult to distinguish from adenopolyps, which are also common in CAG patients. Only few larger lesions are ulcerated or bleeding. Most are benign, without invasion beyond the submucosa, and have a low proliferation index. The CAG-associated carcinoids have a low incidence of regional lymph-node metastases (<5%) and exceptional distant metastases (<2%), and disease-related deaths are rarely reported. Gastric carcinoid found at endoscopy Histology of tumour biopsy and multiple biopsies from the gastric body mucosa Determine serum gastrin Presence of atrophic gastritis yes no Type 1 carcinoid High s-gastrin No gastric acid Presence of MEN1 syndrome yes no Type 2 carcinoid Type 3 carcinoid High s-gastrin High gastric acid secretion Gastric pH <2 Increased gastric mucosal thickness Tumour >1 cm Deep wall/angio-invasion Endoscopic resection no yes surgery Endoscopic follow-up Somatostatin analogues Figure 1. Management of patients with gastric carcinoid found at endoscopy. Demonstration of atrophic gastritis in the gastric body mucosa is a key point, allowing classification as type 1 gastric carcinoid. If atrophic gastritis is not found, the patient should undergo screening for multiple endocrine neoplasia type 1 (MEN1) syndrome and Zollinger–Ellison syndrome (ZES) (type 2 gastric carcinoid). If neither chronic atrophic gastritis (CAG) nor MEN1 is diagnosed, the patient has the more aggressive type 3, sporadic gastric carcinoid. Redrawn from Delle Fave et al (2005, Best Practice and Research in Clinical Gastroenterology 19: 668) with permission. Surgery on neuroendocrine tumours 89 Surgical treatment. Type 1 carcinoids <1 cm are indolent with minimal risk for invasion and can be removed by endoscopic mucosal resection.5 Local surgical excision is recommended for rare larger or invasive tumours; exceptional cases with large multifocal lesions may require gastric resection. Antrectomy may cause regression of ECL dysplasia and small carcinoids, but is not generally recommended since clinically significant lesions tend to remain unaffected.6 Follow-up with yearly endoscopic surveillance and repeated gastroscopy with multiple gastric biopsies is needed, and treatment with somatostatin analogues may prevent recurrence.4 Type 2 gastric carcinoids associated with Zollinger–Ellison syndrome in multiple endocrine neoplasia type 1 patients ECL cell hyperplasia occurs in 80% of multiple endocrine neoplasia type 1 (MEN1) patients with the Zollinger–Ellison syndrome (ZES), and ultimately 15–30% of MEN1/ZES patients develop carcinoids in the gastric body and fundus and occasionally in the antrum.1–4,7 The mucosa thickness is increased, in contrast to a distinct atrophy of type 1 lesions, and the patients have increased gastric acid secretion (Figure 1). Patients with sporadic ZES may often also have ECL cell hyperplasia, but rarely (<1%) gastric carcinoids. The type 2 gastric carcinoids account for w6% of gastric carcinoids. They are often multiple and usually small (<1–2 cm), but generally larger than type 1 tumours, with occasional markedly larger tumours of up to 4–5 cm or more. The histological pattern generally is similar to type 1 lesions, but with absence of mucosal atrophy. The malignant potential is intermediate between CAG-associated and sporadic gastric carcinoids, with some tumours appearing rather as neuroendocrine carcinoma with local invasion, angioinvasion and high proliferation rate. Lymph-node metastases occur in w30% of patients and liver metastases in 10–20%.4,8 The aggressive tumours with liver metastases have been more frequent with long-standing ZES. Poorly differentiated gastric endocrine carcinomas have occasionally been associated with MEN1. Surgical treatment. Surgery in type 2 gastric carcinoids is focused on removing the source of hypergastrinaemia, generally by excision of typical duodenal gastrinomas of the MEN1 patients via duodenotomy, together with clearance of lymph-node metastases (see below).8–10 Treatment of the gastric carcinoids per se may be as for type 1 lesions, with endoscopic mucosectomy for tumours <1 cm. Liberal surgical excision or gastric resection together with regional lymph gland clearance is done for larger and multifocal tumours or those with deep wall invasion or angioinvasion. In cases with multiple tumours somatostatin analogue treatment may be used to reduce tumour growth, especially if hypergastrinaemia has not been reversed by surgery.4 Type 3 sporadic gastric carcinoids Type 3 sporadic gastric carcinoids account for w20% of gastric carcinoids and occur in non-atrophic gastric mucosa without endocrine cell proliferation in patients with normal gastrin. They are most frequent in males, mean age w50 years.1–4 Determination of serum calcium and the family history helps to exclude MEN1 (Figure 1). The sporadic tumours are single, often large, usually >2 cm (Figure 2). Two thirds of the lesions have infiltrated the muscularis, and 50% have invaded all layers of the 90 G. Åkerström and P. Hellman Figure 2. Sporadic, solitary gastric carcinoid with lymph-gland metastasis removed by gastric resection. From Åkerström et al (2006, Endocrine Surgery 3rd edition, Lennard TWJ (ed); Elsevier) with permission. gastric wall. Some tumours occur in the antral or prepyloric region, although most are located in the gastric body and fundus. Most tumours originate in ECL cells, but other cell types may be present and associated with a less favourable prognosis. Regional lymph-node metastases occur in 20–50%, also with small tumours, and liver metastases eventually develop in two thirds of the patients.4,11 The sporadic carcinoids can have atypical histology, with pleomorphism, high mitosis rate, and often higher Ki67 index. The atypical tumours are larger (mean w5 cm), are more frequently invasive, and have unfavourable survival.1,12 An ‘atypical carcinoid syndrome’ may develop in 5–10% of patients with sporadic gastric carcinoids.1 The syndrome is due to release of histamine and is characterized by a patchy ‘geographic’ flush, cutaneous oedema, bronchospasm, salivary gland swelling and lacrimation. Urinary estimates of the histamine metabolite methylimidazoleacetic acid (MelmAA) serves as tumour marker, and patients may have slight elevation of urinary 5-hydroxy-indoleacetic acid (5-HIAA) values. Surgical treatment. Sporadic gastric carcinoids are treated with gastric resection combined with regional lymph-node clearance. Tumours >2 cm or those with atypical histology or gastric wall invasion are most appropriately dealt with by gastrectomy.13,14 The 5-year survival has been w50%, but in patients with distant metastases it is only 10%.1,3 Type 4 poorly differentiated gastric neuroendocrine tumours Poorly differentiated (small-cell) neuroendocrine carcinomas are highly malignant, with generally extensive local invasion and disseminated metastases at diagnosis.1 Atrophic gastritis has been revealed in half of the patients. The tumours are generally large, with a median size of w4–5 cm, often appearing ulcerating or fungating. The prognosis is poor, with median survival of 8 months, but some individuals may survive longer.4,13,14 The tumours are generally not available for surgery, though occasionally surgical debulking together with chemotherapy may be considered in patients with mixtures of well-differentiated and poorly differentiated tumours. Surgery on neuroendocrine tumours 91 Practice points  type 1 CAG-related gastric carcinoids <1 cm – endoscopic excision and surveillance is generally adequate, with minimal risk for metastases  type 2 MEN1 ZES-associated gastric carcinoids – endoscopic excision is done for smaller tumours (<1 cm), larger and invasive lesions require resection  type 3 sporadic gastric carcinoids – require aggressive surgical resection with lymph-node clearance Research agenda  evaluate criteria for safe endoscopic excision of CAG-related carcinoids and optimal treatment of larger MEN1-associated carcinoids Midgut carcinoids The midgut carcinoids are most common of carcinoids, accounting for w25% and occurring at w65 years of age. They originate most frequently in the terminal ileum with a submucosal and often small primary tumour that is seldom the cause of obstruction, and rarely bleeds.1,3,5–8 Due to spread within submucosal lymphatics, multiple smaller tumours often appear in the nearby intestine. Mesenteric lymph-node metastases are common also with small tumours, and microscopic metastases are almost invariably present.15,16 These metastases will often grow conspicuously large and may be mistaken to represent the primary tumour.1 Fibrosis induced around the metastases tends to contract the mesentery and may kink and obstruct the intestine. The mesenteric tumour is often attached by fibrosis to the serosa of the horizontal duodenum, which may become occluded with continued growth. The mesenteric vessels are often encased by the mesenteric tumour and fibrosis, ultimately resulting in venous stasis and incipient ischaemia in segments of the small intestine. Operation may worsen fibrosis and leave a conglomerate of distal intestinal loops fixed to the abdominal wall. Symptoms Due to slow progress, carcinoid patients may have non-specific abdominal pain and diarrhoea for several years before diagnosis. Many patients get increased abdominal pain attacks with time, and approximately 40% are discovered at emergency surgery for intestinal obstruction. In other patients the diagnosis is settled after detection of liver metastases, sometimes together with features of the carcinoid syndrome, which initially may be discrete with flush induced after intake of certain food or alcohol. Extra-abdominal metastases may occur in the skeleton, lungs, mediastinal and peripheral lymph glands, ovaries, breast and skin. The carcinoid syndrome occurs in w20% of patients with liver metastases or extensive retroperitoneal lymphatic spread. These patients suffer from flush, diarrhoea, right-sided heart valve fibrosis, and occasionally bronchial constriction. The heart disease may be diagnosed by echocardiography and may require thoracic surgery with valve replacement before major abdominal surgery. 92 G. Åkerström and P. Hellman Diagnosis Raised levels of the serotonin metabolite 5-HIAA in 24-hour urine samples is specific for carcinoids but present only in advanced cases, generally with liver metastases. Plasma chromogranin A measurement is less specific but can provide earlier diagnosis and is often preferred to monitor disease progress. Computed tomography (CT) with contrast enhancement can efficiently demonstrate mesenteric metastases and retroperitoneal tumour extension, reveal relation to the mesenteric artery and vein, and will also visualize liver metastases (Figure 3). Octreoscan can determine spread to the liver and to extra-abdominal sites. Needle biopsy of liver metastases with staining for chromogranin A and synaptophysin is used to diagnose carcinoids, and serotonin reactivity verifies a midgut origin. Early surgical treatment Midgut carcinoids can be recognized at laparotomy by typical features of a small ileal tumour and large mesenteric metastases surrounded by fibrosis.15–18 The primary tumour should be removed by wedge resection of the mesentery with dissection of lymph-node metastases around the mesenteric artery and vein aiming to preserve intestinal vascular supply and limit the intestinal resection (Figure 4). With grossly radical tumour removal, patients may remain symptom-free for extended time periods; however, due to the tenacity of carcinoid tumours, they should undergo careful and life-long surveillance, since eventual recurrence of liver metastases can be expected in approximately 85% of midgut carcinoid patients. Surgical treatment for advanced carcinoids Treatment with long-acting somatostatin analogues and interferon-a can often provide efficient control of the carcinoid syndrome. During treatment the mesenteric tumour and fibrosis will often progress and increase vascular and intestinal entrapment, causing Figure 3. Computed tomography (CT) image of mesenteric metastasis from midgut carcinoid growing along the mesenteric vessels. Surgery on neuroendocrine tumours 93 Figure 4. Resection of midgut carcinoid primary tumour and mesenteric metastasis. (a) Mesenteric tumour may extensively involve the mesenteric root. (b) Mobilization of caecum, terminal ileum, and mesenteric root allows the tumour to be lifted, approached also from posterior angle, and separated from duodenum, pancreas and main mesenteric vessels with preservation of intestinal vascular supply and intestinal length. From Åkerström et al (2006, Endocrine Surgery 3rd edition, ed. Lennard TWJ; Elsevier) with permission. obstruction and compromised intestinal circulation. Some patients develop abdominal pain, weight loss, diarrhoea, and even cachexia due to incipient ischaemia and malabsorption.15–18 Prophylactic surgical removal of mesenteric metastases is recommended at an early stage, since later the disease may become impossible to manage surgically.18 With a special technique (Figure 4) the mesenteric metastases can be dissected from the mesenteric artery and vein, with preservation of the mesenteric circulation and only a limited intestinal resection, avoiding the creation of a short bowel syndrome. Repeated surgery may be needed if mesenteric metastases have been left or have progressed after primary surgery. These operations are difficult due to fibrosis between regions of intestine, and mistakes may result in fistulation, intestinal devascularization, or creation of a short bowel.18 Prophylaxis against carcinoid crisis Surgery in patients with the carcinoid syndrome may initiate a carcinoid crisis with hyperthermia, shock, arrhythmia, excessive flush or bronchial obstruction. This is 94 G. Åkerström and P. Hellman prevented by routine preoperative administration of intravenous somatostatin analogue (octreotide, 500 mg in 500 mL saline, 50 mg/h). Results of surgery and prognosis Removal of mesenteric metastases can relieve abdominal symptoms, reduce risk for abdominal complications, palliate the carcinoid syndrome, and also appears to increase survival. Survival of patients with midgut carcinoids has improved with active and combined medical and surgical treatment, but depends on the extent of disease. Presence of liver metastases and carcinoid heart disease have been the most significant adverse prognostic factors. Patients with inoperable liver metastases (see below) had a 5-year survival of w50%, and survival was w40% with inoperable liver and mesenteric metastases.17,19 Practice points  mesenteric metastases of midgut carcinoids with surrounding fibrosis may cause intestinal obstruction and ischaemia  removal of primary and mesenteric carcinoid tumour may prevent or delay abdominal complications Appendiceal carcinoids Appendiceal carcinoids have decreased in incidence to comprise w8% of carcinoids1–3,20,21, but they are still the most prevalent tumours of the appendix. The tumour is most common in the tip of the appendix, and rarely causes appendicitis; less than 10% are located in the appendix base. The overall rate of metastases has been w4%, with distant metastases in 0.7%. Patients have generally been younger than those with other carcinoids (mean age w40 years), with female predominance, and also children may be affected. Patients with larger tumours and metastases have often been younger than those with clinically benign tumours. The majority (w90%) of appendiceal carcinoids measure <1 cm in diameter, are not situated in the appendiceal base, and are invariably cured by appendectomy. Tumours >2 cm require hemicolectomy and ileocaecal lymph-node clearance. This should be done also for all tumours in the appendix base, since they may originate in the colon and cause local recurrence. For tumours measuring 1–2 cm hemicolectomy is recommended if there is invasion in the mesoappendix or residual tumour in the resection margins, and in the presence of lymph-node metastases. For the same-size lesions confined to the appendiceal wall, guidelines suggest appendectomy alone with low risk for metastases. However, hemicolectomy may be recommended when operative specimens show high proliferative activity (high Ki67 index), high mitotic index, or signs of angioinvasion, but the evidence base is lacking.20,21 Followup may be considered in such patients, and raised serum chromogranin A may then support extended operation. Appendiceal carcinoids metastasize to regional lymph nodes more often than to the liver. In the presence of massive liver or retroperitoneal metastases the patients may occasionally appear with the carcinoid syndrome. Survival Surgery on neuroendocrine tumours 95 is excellent with only locoregional tumour, but with distant metastases 10-year survival has been w30%. A rare variant of appendiceal carcinoid, goblet-cell carcinoid or adenocarcinoid, have mixed endocrine and exocrine features. This carcinoid often presents with a diffusely inflamed appendix, and occurs at a later age (w50 years).1,20,21 The tumours are aggressive, often with peritoneal and ovarian metastases, sometimes appearing as mucinous adenocarcinoma. They do not express somatostatin receptors, and cannot be visualized by Octreoscan. The tumour entity should be treated with right-sided hemicolectomy and lymph-node clearance in combination with chemotherapy. For disseminated tumours aggressive surgical reduction – including peritonectomy and oophorectomy – may be required, according to recent guidelines for colorectal carcinomas. Goblet-cell carcinoids have a 10-year survival of w60%.20 Practice points  appendiceal carcinoids <1 cm are cured by appendectomy, tumours >2 cm require right-sided hemicolectomy  appendectomy alone is generally sufficient for tumours measuring 1–2 cm, but hemicolectomy may occasionally be considered Research agenda  define histological parameters for risk evaluation in appendiceal carcinoids measuring 1–2 cm Colon carcinoids Colon carcinoids constitute w8% of carcinoids, and affect older persons (mean age w60 years).1,3,22,23 Most tumours (50%) occur in the caecum and are occasionally (<5%) associated with the carcinoid syndrome, which is not encountered with distal colorectal tumours. Occasional right-sided, differentiated tumours may produce serotonin, and have raised urinary 5-HIAA values. Colon carcinoids are often exophytic and large (w5 cm) and cause general malignant symptoms (as colon adenocarcinoma), but rarely bleed. Only occasional right-sided lesions are positive on octreoscan, many are aggressive, with a high proliferation rate, regional lymphnode metastases, or even more often liver metastases. Attempts should be made to achieve radical resection by hemicolectomy or subtotal colectomy with lymphnode clearance, but often only debulking is possible. Overall 5-year survival has been w40%, being slightly worse than for colon adenocarcinoma, and mainly related to tumour stage. Poorly differentiated (small-cell) neuroendocrine carcinoma occurs in the right colon, frequently associated with an adjacent adenoma or adenocarcinoma.3 These tumours are generally metastasized at diagnosis and are mainly treated with chemotherapy; only occasional patients require palliative surgery, but have poor survival. 96 G. Åkerström and P. Hellman Rectal carcinoids Rectal carcinoids have a rising incidence, comprising w11% of all carcinoids and 1.5% of rectal tumours.1–3,22,23 They are more common in Afro-Americans and occur most often at w55 years of age. The tumours are most frequent on the anterior or lateral rectal walls 4–13 cm above the dentate line. The majority (w60%) are small, solitary, yellowish submucosal polyps <1 cm in diameter, incidentally detected by endoscopy in asymptomatic patients. Tumours <1 cm have low incidence of nodal metastases (0–3%) and no distant spread; tumours measuring 1–2 cm have regional and distant metastases in 7–34%, whereas tumours >2 cm (found in w15%) have local and distant metastases in 67–100%. Presence of muscularis layer invasion is more common with larger tumours and relates to spread with lymph-node and liver metastases. The larger tumours may have mucosal scarring or ulceration with bleeding, and may have advanced local infiltration, and sometimes perirectal fixation like adenocarcinoma. The larger tumours may be associated with pain, change in bowel habits, constipation and weight loss. The carcinoid syndrome does not occur with rectal carcinoids. Octreoscan is rarely positive in rectal carcinoids due to lack of somatostatin receptors, and chromogranin A is often not secreted and is not valuable as a tumour marker. Carcinoembryonic antigen (CEA) and prostate-specific antigen (PSA) levels are raised in 25% and 80%, respectively. Surgical treatment Rectal carcinoids <1 cm can generally be safely removed by endoscopic excision. Excised specimens should be histologically examined to exclude muscularis invasion.1,23–26 Tumours measuring 1–2 cm should be investigated by transanal endosonography or magnetic resonance imaging (MRI). Absence of muscularis invasion or regional metastases justifies local excision rather than rectal resection. Presence of either favours aggressive excision, generally by anterior rectal resection with total mesorectal excision and regional lymph-node clearance. This is also recommended in cases with tumours >2 cm without general dissemination. In patients with distant metastases prognosis is generally poor, with overall 5-year survival of w30%. Practice points  rectal carcinoids <1 cm can be removed by endoscopic excision  large rectal carcinoids (1–2 cm) without infiltration or regional metastases can be locally excised; presence of either favours anterior resection and lymphnode clearance  tumours >2 cm are treated by anterior resection with mesorectal excision and lymph-node clearance Research agenda  evaluate transanal endoscopic ultrasound for locoregional staging of rectal carcinoids Surgery on neuroendocrine tumours 97 ENDOCRINE PANCREATIC TUMOURS (EPTS) Insulinomas Insulinomas constitute w25% of EPTs and are the most common of functioning tumours, often occurring at an age of w40–60 years.27 Most are sporadic, but 5–10% are associated with the hereditary MEN1 syndrome, which typically may cause multiple tumours. Symptoms of insulinoma are often misinterpreted. Catecholamine response to hypoglycaemia causes sweating, weakness, anxiety, tachycardia and hunger. More characteristic symptoms are due to neuroglucopenia, with anxiety, behavioural change, epileptic seizures, confusion, coma, and sometimes focal symptoms, visual disturbances (diplopia), speech difficulties and pareses. Patients tend to become obese since they learn to avoid hypoglycaemia by nightly meals. Diagnosis Diagnosis is made by a supervised fasting test showing hypoglycaemia (serum glucose concentrations <45 mg/dL, or <2.5 mM) and inappropriately high serum insulin. This means detectable but not obligatory raised insulin levels, since w20% of patients have normal insulin during fasting hypoglycaemia.28 A corresponding rise in C-peptide is crucial to verify that insulin secretion is endogenous and to exclude factitia, i.e. selfadministration of insulin or peroral antidiabetic medication, claimed to be more common than insulinoma. Proinsulin levels in normal individuals are usually <20% of total immunoreactive insulin but tend to be higher in patients with insulinoma. Proinsulin/ insulin ratio >50% may indicate malignant insulinoma, but occurs also with 25% of benign insulinomas. Oral sulphonylurea antidiabetics may cause hypoglycaemia with rise in insulin, C-peptide and proinsulin, and should be excluded by plasma measurement. Preoperative localization Most insulinomas are small and benign, with size >6 mm to commonly around 1 cm; 90% are <2 cm. Exceptionally rare ectopic tumours (<1%) have occurred in the proximity of the pancreas. Spiral CT with contrast enhancement, or occasionally MRI, are routinely performed to rule out presence of liver metastases and to detect larger tumours that could indicate malignancy, but these techniques have low sensitivity for small insulinomas. Endoscopic ultrasound (EUS) has been increasingly used, with nearly 90% sensitivity for visualization of insulinomas. It has appeared as the most efficient method for preoperative localization, although some isoechoic (6%) or pedunculated tumours may fail to be visualized.29,30 EUS can reveal important relation to the pancreatic duct, and if introduced in the horizontal duodenum allows visualization also of the uncinate process; some of the equipment may be used for tumour biopsy. The selective arterial stimulation (SAS) test utilizes injection of calcium into major arteries supplying the pancreas and concomitant hepatic vein sampling for insulin, and can regionalize an insulinoma to the head, body or tail of the pancreas.31 The SAS test is essential in reoperative cases, but may also be used before primary operation when other localization studies are negative. An SAS test demonstrating insulin secretion from multiple areas of the pancreas supports a diagnosis of multiple insulinoma (MEN1 patients) or nesidioblastosis.32 98 G. Åkerström and P. Hellman Intraoperative ultrasound (IOUS) is now considered a necessary prerequisite for insulinoma operation together with complete pancreatic exploration and palpation at surgery (Figure 5).27,32 The IOUS should be done by an experienced investigator, and can identify tumours larger than 2–3 mm. It can guide the safest approach to a tumour and facilitate dissection from the pancreatic duct, and also reveal tumour bilobation that has to be appreciated at enucleation. Surgical treatment Most insulinomas are intraoperatively palpable as a firmer nodule with sensitivity of w90%. Tumours deep within the pancreatic head and in the uncinate process are difficult to palpate, and any lesion is difficult to detect in patients with previous pancreatitis. Combination of IOUS and palpation increases the sensitivity of insulinoma detection to nearly 100%, but requires complete surgical exploration. The head of the pancreas is delivered by the Kocher manoeuvre, with the uncinate process carefully dissected towards the porto-mesenteric vein (Figure 5). The pancreatic tail is mobilized to the mesenteric vein, allowing bidigital palpation and IOUS investigation from both dorsal and ventral surfaces. Most insulinomas, especially in the head of the pancreas, may be safely enucleated with cautious ligation of ductal structures. Occasional pancreatic head tumours adjacent to the pancreatic duct may be more safely enucleated towards a catheter introduced by ERCP or duodenotomy. Pancreatico-duodenectomy is only rarely required with large tumours and a suspicion of malignancy. Also pancreatic tail tumours may be enucleated, but tail resection is chosen for distal tumours close to the duct to minimize the risk of pancreatic effusion. Distal pancreatic resection is often made spleenpreserving with benign tumours, but this is avoided with large or suspected malignant EPTs, since the splenic hilum is often a first site of metastases. Laparoscopic removal of insulinoma with enucleation or tail resection has been applied in many centres, and can be associated with markedly reduced hospital stay and increased patient comfort. The operation is facilitated by laparoscopic ultrasonography, but may be complicated – especially in the case of pancreatic head tumours – by Figure 5. (a) Pancreatic head insulinoma which is possible to enucleate after release of attachments to mesenteric vein and with pancreatic duct proven by intraoperative ultrasound (IOUS) to be at some distance. (b) IOUS revealing typical hypoechogenic image of insulinoma. Surgery on neuroendocrine tumours 99 higher risk of pancreatic effusion (20–40%). This operation can be chosen for carefully selected lesions and should be performed by expert laparoscopists.32 Blind pancreatic resection should not be undertaken if no insulinoma is found, but in such cases the abdomen should be closed and the patient subjected to further investigation to verify the biochemical diagnosis and exclude factitious insulin administration. More extensive localization procedures are applied before reoperation, often including the SAS intra-arterial calcium injection test.27 Adult nesidioblastosis Although this represents a controversial issue, adult nesidioblastosis with diffuse b-cell proliferation may cause symptomatic hypoglycaemia.32,33 These patients typically have postprandial rather than fasting-provoked hyperinsulinaemic hypoglycaemia, and diagnosis is confirmed by a meal test causing hypoglycaemia and inappropriate insulin and C-peptide levels. The diagnosis is supported if the SAS test shows insulin secretion from multiple areas of the pancreas, which may lead to gradient-guided subtotal pancreatic resection. Nesidioblastosis has been more common in patients previously subjected to bariatric surgery. The hypoglycaemia may be reversed by 60–90% distal pancreatic resection, but cure has not been universal; it is apparently sometimes less efficient in females, and some patients have been palliated by medical treatment with calcium blockers. A suggested preoperative treatment period with diazoxide may help determine the extent of the required pancreatic resection. Malignant insulinomas Malignant insulinomas occur in 5–10% of patients with endogenous hypoglycaemia.27,32 Some patients have severe hypoglycaemia requiring continuous glucose infusion and cannot undergo a fasting test. The primary pancreatic tumour is often large (>4 cm). Diagnosis is based on demonstration of local invasion, lymph-node or liver metastases. Aggressive attempts to resection should be considered in patients with malignant insulinoma, and even palliative debulking may yield survival benefit. However, most malignant insulinomas have disseminated metastases in the liver, lungs and lymph nodes, and are scarcely available for tumour reduction, with survival strongly dependent on response to chemotherapy. Some patients have larger, apparently dedifferentiated malignant insulinoma, with slight insulin hypersecretion and less severe hypoglycaemia. These patients especially are helped by surgical removal of the large pancreatic tumour, and in the absence of metastases can experience long-term survival or cure. Ten-year survival of 29% has been reported in patients with metastasizing malignant insulinoma. Practice points  most insulinomas (90%) are benign small tumours and can be efficiently treated by enucleation or distal pancreatic resection (possibly spleen-preserving)  insulinomas may be localized by endoscopic and intraoperative ultrasound  SAS intra-arterial stimulation test can localize insulinoma prior to reoperation  malignant insulinoma is suspected with tumour size >4 cm 100 G. Åkerström and P. Hellman Research agenda  clarify clinical criteria for diagnosis and treatment of adult nesidioblastosis  evaluate surgery for malignant insulinoma Gastrinoma: Zollinger–Ellison syndrome (ZES) Gastrinomas comprise w20% of functioning EPTs. The majority are sporadic, but as many as 30% occur as a part of the MEN1 syndrome.27 Gastrinomas and ZES are uncommon causes of peptic ulcer disease, with recurrent, atypical, multiple and complicated ulcers, sometimes concomitant diarrhoea, and/or oesophagitis, and in 20% only diarrhoea. Gastrin levels are often markedly increased, together with raised basal acid output with low gastric pH. Serum gastrin >1000 pg/mL and gastric pH <2 is diagnostic of ZES. In other patients a secretin test may be required, and is diagnostic with paradoxal rise in gastrin, 200 pg/mL over baseline, but 15% of ZES patients have negative test. The important differential diagnosis is atrophic gastritis, where patients have high gastrin without gastric acid (with high gastric pH, pH >3 excludes ZES). Previously most gastrinomas were large, malignant EPTs with early lymph-node (w45%) or liver (w60%) metastases and rapid progression. Since 1989 duodenal gastrinomas have been recognized as the most common gastrinomas, causing 60% of sporadic ZES and 90% of MEN1-associated ZES, where multiple tumours are common (Figure 6). The duodenal gastrinomas are typically tiny submucosal tumours, often 0.5 cm, most frequent in the first and second portion of duodenum. They have great tendency to set lymph-node metastases (w45%), but liver metastases occur late and in a minority of patients (w10%), allowing for the possibility of successful surgical removal. This tumour entity may represent the primary tumour in patients with ‘primary lymph-node gastrinoma’, diagnosed in up to 10% of patients with ZES, where the primary tumour may be remarkably slow-growing and may remain undetected. Figure 6. Multiple duodenal gastrinoma in a multiple endocrine neoplasia type 1 (MEN1) patient. Surgery on neuroendocrine tumours 101 Preoperative localization CT or MRI is routinely performed in patients with ZES to visualize lymph-node and liver metastases prior to surgery.27 Octreoscan can often (in w90% of cases) reveal gastrinoma lymph-node and liver metastases and occasional larger primary tumours. However, small duodenal tumours are not detectable, and instead larger lymphnode metastases around the pancreatic head are easily mistaken for the primary tumour. EUS can detect pancreatic and a few larger duodenal gastrinomas, and often lymph-gland metastases, but rarely the smallest duodenal tumours. The selective arterial stimulation test (the SAS, Imamura test) was originally developed with injection of pentagastrin for visualization of gastrinoma, and may provide tumour regionalization and demonstrate liver metastases.34 Even in the absence of positive localization diagnosis, the patients with ZES should be liberally submitted to surgery, since these patients especially are likely to have resectable duodenal gastrinomas. Surgical treatment The surgical cure rate in ZES patients increased markedly when it became appreciated that most gastrinomas occurs in the duodenum.35 The duodenal gastrinomas may be visualized by longitudinal duodenotomy at surgery with inversion of the lumen for careful palpation of the entire duodenum (Figure 6). The smallest duodenal submucosal tumours can be removed by mucosal dissection, larger tumours (>5 mm) require full-thickness duodenal wall excision. Pancreatico-duodenectomy may be required for gastrinomas in the pancreatic head and occasional larger or multiple duodenal tumours. Surgery in patients with gastrinoma should include clearance of lymphnode metastases around the pancreas and duodenum, and should aim to remove also resectable liver metastases (see below).35,36 Gastrinomas should be considered potentially malignant. Survival is favourable in patients with duodenal gastrinomas with lymph-node metastases, removal of which possibly limits further spread, and few (w10%) of these patients develop liver metastases.35,36 Adverse prognostic factors are large primary pancreatic tumours, presence of liver or bone metastases, and very high serum gastrin. The small duodenal gastrinomas have markedly slow progression with a 10-year survival of w90%, whereas pancreatic gastrinomas have more rapid progression with only a 60% 10-year survival. Practice points  duodenal gastrinomas are the most common cause of ZES, accounting for 60% of gastrinoma in sporadic ZES and 90% of gastrinoma in MEN1-related ZES  duodenal gastrinomas are most efficiently detected by duodenotomy Glucagonomas Glucagonomas are uncommon, representing w10% of functioning EPTs, most frequent at ages of w50 years.27,37 The patients have a characteristic pruritic skin rash, migrating necrolytic erythema starting in the groin and ingues and migrating 102 G. Åkerström and P. Hellman to extremities, they also have deep vein thrombosis and thrombophlebitis, and at the advanced stage sometimes severe cachexia. Diagnosis is settled by demonstration of raised plasma glucagon and is often delayed, even in the presence of typical skin lesions. The patients often experience marked palliation by nutritional supplement, which tends to heal the skin lesions, and by treatment with somatostatin analogue. They require antithrombotic medication, especially during surgery, because of the high risk for thrombosis and pulmonary embolism. The glucagonomas are generally distally located in the pancreas and are often large (4–15 cm) (Figure 7). The tumours are malignant in w80% and often have regional lymph-gland metastases, sometimes mistaken to represent the primary tumour. Treatment is distal subtotal pancreatic resection and clearance of regional lymph-gland metastases. Disease progression may be slow despite metastases, and the patients will often during an extended disease course be subjected to sequential excision of lymph nodes or liver metastases with 5 years or more between recurrent lesions. A 10-year survival of w50% has been reported. VIPomas Tumours secreting vasoactive intestinal peptide (VIP) cause the WDHA (watery diarrhoea, hypokalaemia, achlorhydria) syndrome, with severe secretory diarrhoea, acidosis and dehydration.37 Flush may occur due to the vasodilatory effect of VIP, and some patients have hypercalcaemia. The diagnosis is made by demonstration of raised VIP values. Because of the risk for severe dehydration, the patients need intensive treatment with somatostatin analogue and intravenous fluid and electrolyte resuscitation. The tumours are generally large and located within the pancreatic tail; 50% have metastases at diagnosis. Treatment is surgical excision, and debulking surgery should be considered in patients with metastases, consisting of pancreatectomy and resection or ablation of liver metastases and even resection of lung metastases if present. Routine cholecystectomy may facilitate somatostatin analogue treatment. A 10-year survival of w40% is reported. Figure 7. Computed tomography (CT) image showing glucagonoma in the pancreatic tail surrounded by lymph-gland metastases in the splenic hilum (easily misinterpreted to represent the primary tumour). Surgery on neuroendocrine tumours 103 Non-functioning endocrine pancreatic tumours The non-functioning EPTs are not related to any clinical syndrome of hormone excess.27,38–41 They may have no hormone secretion, due to absence of secretory granulae, or may release amounts too low to cause clinical symptoms. Most have increased serum values of chromogranin A; also common are raised values of pancreatic polypeptide (PP) revealed in 50–70%, and fewer have low values of insulin/proinsulin, glucagon or calcitonin without symptoms.27,40 The non-functioning tumours have increased in frequency and now constitute 30–50% of EPTs. They account for 3–5% of pancreatic tumours, but are important to recognize because of markedly better survival prospects than patients with adenocarcinoma. The non-functioning EPTs are most often diagnosed at the age of w50–60 years, but also occur in younger individuals where they may be discovered as unusually large tumours without the typical malignant cachexia of pancreatic carcinoma.27,38,39 Diagnosis of the non-functioning tumours can be made by demonstrating hypervascularization on contrast-enhanced CT and positive octreoscan, raised serum levels of chromogranin A or serum PP, or by ultrasound-guided fine or semi-fine needle biopsy stained with chromogranin A or synaptophysin. The non-functioning EPTs most commonly occupy the pancreatic head (60%) but may occur in the entire pancreas. They may cause jaundice or discomfort due to local extension or pain due to pancreatitis, though jaundice is often absent, also with large pancreatic head tumours. Although growth is typically slow compared to that of adenocarcinomas, the progress is variable; some are indolent, with growth only of the primary lesion, whereas others progress rapidly with lymph-node and liver metastases. High Ki67 proliferation index (>5%) and high frequency of chromosomal rearrangements have been associated with more rapid progression.40 Generally extra-abdominal spread from EPTs occurs late. Even when survival is extended, the pancreatic tumours per se may be the cause of morbidity. The tumours tend to grow into surrounding structures, the ventricle, the duodenum, or the transverse colon, and may then be associated with obstruction or bleeding.38,39 With continuous growth in the pancreatic head and body the mesenteric vein is often invaded and occluded, causing portal hypertension and increased tendency to gastrointestinal bleeding and eventually mesenteric thrombosis and intestinal ischaemia. Also the coeliac, hepatic, and mesenteric arteries may be involved. Surgical treatment Surgery is indicated for removal of the primary tumour to reduce the risk of mesenteric vein involvement or gastric outlet obstruction, and to facilitate efficient chemotherapy; it may be undertaken also in the presence of low-volume liver metastases. Also the largest EPTs can often be removed by extended pancreatico-duodenectomy or subtotal pancreatectomy, even in the presence of portal hypertension, sometimes with the use of vein graft (from internal jugular, saphenous, or splenic vein) to restore patency of the mesenteric vein (Figure 8).38,39,41 Involvement of the mesentericocoeliac arterial axis has been claimed to contraindicate surgery, but in our experience the central axis arteries may often be dissected free (Figure 8), or they may be graftsubstituted. Extensive dissection around the mesenteric artery may cause severe diarrhoea due to denervation of intestinal plexa, and may significantly impair the patient’s general condition. 104 G. Åkerström and P. Hellman Figure 8. (a) Non-functioning tumour of the pancreatic body and tail with growth in the porto-mesenteric vein. (b) Drawing of the surgical procedure; the coeliac hepatic artery could be dissected from inclusion in the tumour capsule, a patch graft from the splenic vein being used to restore flow in the porto-mesenteric vein. The rate of metastases varies from 62 to 92%. Results of surgery for large nonfunctioning tumours have reported 5-year survival of 65% and 10-year survival of 49%.38–41 Survival advantage has been evident in the absence of liver metastases,or if such metastases have been resected. Merely palliative surgery with remaining tumour has resulted in poor survival. The operative mortality of aggressive surgery has varied from 0 to 15%; the risks have been associated mainly with complications due to mesenteric vein or artery occlusion.41 Peroperative morbidity has varied between 6 and 39%; pancreatic effusion and abscess formation have been problematic in many series, but generally resolve with efficient drainage. Practice points  non-functioning EPTs are generally hypervascular tumours with positive octreoscan and raised serum levels of chromogranin A or PP  surgical removal should be attempted also for the larger non-functioning EPTs Endocrine pancreatic tumours associated with MEN1 Pancreatic involvement occurs clinically in 30–75% of patients with MEN1.27,40,42 ZES has been the most common EPT syndrome in MEN1, encountered in 20–60% of patients, insulinoma is found in w30%, VIPomas in w5%, and symptomatic glucagonomas are exceptional. Non-functioning EPTs occur in w50% of MEN1 patients. The MEN1 syndrome can be revealed in w30% of ZES patients and in 5–10% of insulinomas. Surgery on neuroendocrine tumours 105 Tumour disease accounts for w50% of deaths in MEN1, and pancreatic malignancy has been the cause of death in a majority.42–44 The MEN1 pancreas contains numerous microadenomas, only a few of which will grow into clinical tumours.45 In the absence of distant metastases, surgery is advocated for MEN1 insulinomas and rare VIPomas or glucagonomas42,45, but has been controversial with MEN1 ZES because long-term cure is rarely achieved. However, in follow-up studies, ZES is a late feature with metastases already in 30–50% of patients, and we propose surgery also for ZES patients for prevention of malignancy and to facilitate medical treatment.46 Non-functioning EPTs can often be diagnosed earlier by biochemical markers (pancreatic hormones, especially PP, and chromogranin A), and we suggest that MEN1 patients should be subjected to pancreatic exploration even in the absence of hormone excess syndrome when these markers are unequivocally raised and EUS indicates the presence of tumours.42,45–48 Surgical treatment MEN1 patients are most often subjected to distal subtotal 80–85% pancreatectomy combined with enucleation of tumours in the pancreatic head (Figure 9).42,45,46,49 Concomitant duodonotomy is done in patients with raised gastrin or ZES to identify and remove duodenal gastrinomas (Figure 9). This active strategy appears to decrease the number of patients with metastases or deaths due to pancreatic tumours, but randomized evaluation is lacking.46 Pancreatico-duodenectomy is occasionally required in MEN1 patients with large tumours of any entity in the pancreatic head or duodenum, and has been proposed for efficient eradication of MEN1 ZES. However, pancreaticoduodenectomy is not routinely proposed for MEN1 ZES patients since this implies difficulties in treating recurrent tumours. Moreover, after pancreatico-duodenectomy, liver metastases cannot be treated with embolization because of risk for ascending infection via the hepatico-jejunostomy. Figure 9. The subtotal distal pancreatectomy commonly (80%) applied in multiple endocrine neoplasia type 1 (MEN1) patients (N Thompson procedure), combined with enucleation of tumours in the pancreatic head. Duodenotomy is undertaken in patients with raised serum gastrin. From Skogseid B et al. (2001, Surgical Endocrinology. Doherty GM, Skogseid B (eds), Philadelphia: Lippincott Williams & Wilkins, pp. 511–525) with permission. 106 G. Åkerström and P. Hellman Reoperation, with enucleation or resection of new tumours, may be required in MEN1 patients and has in our experience been efficient and uneventful. Total pancreatectomy may theoretically be needed for large malignant tumours, but has only occasionally been performed in our MEN1 patients. Practice points  surgery is indicated for removal of MEN1-related insulinoma and rare VIPoma or glucagonoma  surgery is also indicated for malignancy prevention in MEN1 ZES patients Research agenda  evaluate role of surgery for gastrinoma and non-functioning tumours in MEN1 LIVER SURGERY Liver metastases Liver metastases in patients with carcinoids or EPT should be evaluated for surgical resection or local ablation with the aim of reducing the tumour burden and alleviating a hormonal syndrome.19,50–55 Most patients have multiple bilaterally spread liver metastases, and altogether only w5–10% have apparently solitary or dominant metastases available for surgery. Hepatic lobectomy or segmental resections are used liberally for removal of solitary or larger metastases, often combined with wedge resection or enucleation of additional smaller lesions. Two-stage liver resection combined with portal embolization for triggering liver regeneration may reduce the risk for liver insufficiency. Other options include radiofrequency ablation (RFA), embolization, and treatment with lutetium-labelled somatostatin analogues.27,40,53 RFA can be done at open surgery in conjunction with the intestinal operation or as a percutaneous ultrasound-guided procedure, and has widened indications for surgery of bilateral liver tumours. Only a limited number of metastases (w5–10) can be treated with combinations of surgery and RFA. RFA has a complication rate of w5%, and in particular central bile ducts may be damaged by RFA close to the hepatic hilum.53 Sustained symptom palliation and reduction of tumour markers can be achieved after removal of large, dominant liver metastases if w90% of the tumour volume can be excised.19,50–55 Smaller metastases remaining after liver surgery may resolve after chemotherapy. Practice point  alleviation of hormonal symptoms and improved survival can be achieved by resection of dominant liver metastases in patients with carcinoids and EPT Surgery on neuroendocrine tumours 107 Research agenda  investigate benefit of surgical resection and RF ablation for treatment of multiple and recurrent liver metastases SUMMARY Most carcinoid tumours are well-differentiated and slow-growing, and should be surgically excised when possible. Occasional tumour entities have low differentiation and high proliferation rates, and respond better to chemotherapy. Multiple gastric carcinoids occur most often as a result of gastrin excess in patients with CAG. These carcinoids are generally benign and can generally be safely removed and controlled by endoscopy. A minority are associated with MEN1 ZES. In contrast, sporadic, solitary gastric carcinoids without association to CAG or MEN1 are highly malignant and invariably require more extensive surgery. For midgut carcinoids surgical treatment should include efforts to remove mesenteric metastases that may cause severe long-term abdominal complications with intestinal obstruction and ischaemia. Small, non-invasive rectal carcinoids can be removed by endoscopy, whereas larger lesions are often highly malignant and need extensive resection and often chemotherapy in addition. With increased efficiency of pre- and interoperative localization, insulinomas and duodenal gastrinomas can be identified and safely removed, whereas pancreatic gastrinoma, glucagonoma, VIPoma, and non-functioning EPTs are often large and require surgical debulking to reduce risks of local overgrowth and to palliate hormone excess. Attempts should also be made to surgically remove or ablate liver metastases, since this may markedly palliate hormonal symptoms and often improves survival. The challenge is to improve surgical technique in order to undertake operation with minimal morbidity and mortality. 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