Surgery on neuroendocrine tumours

Best Practice & Research Clinical Endocrinology & MetabolismVol. 21, No. 1, pp. 87–109, 2007

doi:10.1016/j.beem.2006.12.004available online at http://www.sciencedirect.com

6

Surgery on neuroendocrine tumours

Goran Akerstrom* 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 tophysicians in their recognition and treatment requirements, and surgical treatment of thesetumours has become increasingly important for symptom palliation and survival. For somecarcinoid tumours the extent of surgery may depend on tumour size. Midgut carcinoid is themost common cause of the carcinoid syndrome, requiring surgery for primary and mesenterictumours to minimize the risk for abdominal complications but also for removal of liver metas-tases to palliate hormonal symptoms. Among endocrine pancreatic tumours, insulinoma andgastrinoma often cause severe symptoms of hormone excess despite their inconspicuoussize, 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 hormonalsymptoms and have favourable survival.

Key words: neuroendocrine tumours; gastrointestinal; pancreatic; liver metastases; surgicaltreatment.

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 tohypergastrinaemia in <1% of patients with autoimmune chronic atrophic gastritis

* Corresponding author. Tel.: þ46 18 6114624; Fax: þ46 18 504414.

E-mail address: [email protected] (G. Akerstrom).

1521-690X/$ - see front matter ª 2007 Elsevier Ltd. All rights reserved.

mailto:[email protected]

http://www.sciencedirect.com

88 G. Akerstrom 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 commonvitamin B12 malabsorption and pernicious anaemia (in 50%). The patients are generallyasymptomatic, and the diagnosis is often revealed accidentally during gastroscopy.These carcinoids typically appear as multiple small gastric polyps together with entero-chromaffin-like (ECL) cell hyperplasia/dysplasia in atrophic mucosa of the gastric bodyand fundus. The number of polyps varies; some appear solitary and may be difficult todistinguish from adenopolyps, which are also common in CAG patients. Only fewlarger lesions are ulcerated or bleeding. Most are benign, without invasion beyondthe submucosa, and have a low proliferation index. The CAG-associated carcinoidshave a low incidence of regional lymph-node metastases (<5%) and exceptional distantmetastases (<2%), and disease-related deaths are rarely reported.

Gastric carcinoidfound at endoscopy

Histology of tumour biopsy and multiple biopsies from the gastric body mucosaDetermine serum gastrin

Presence of atrophic gastritis

yes no

Type 1 carcinoid Presence of MEN1 syndrome High s-gastrin No gastric acid

yes no

Type 2 carcinoid Type 3 carcinoid

High s-gastrinHigh gastric acid secretion

Gastric pH <2Increased gastric mucosal thickness

Tumour >1 cmDeep 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 gastri-

tis (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 invasionand can be removed by endoscopic mucosal resection.5 Local surgical excision is rec-ommended for rare larger or invasive tumours; exceptional cases with large multifocallesions may require gastric resection. Antrectomy may cause regression of ECL dyspla-sia and small carcinoids, but is not generally recommended since clinically significantlesions tend to remain unaffected.6 Follow-up with yearly endoscopic surveillanceand repeated gastroscopy with multiple gastric biopsies is needed, and treatmentwith somatostatin analogues may prevent recurrence.4

Type 2 gastric carcinoids associated with Zollinger–Ellison syndrome in multipleendocrine neoplasia type 1 patients

ECL cell hyperplasia occurs in 80% of multiple endocrine neoplasia type 1 (MEN1) pa-tients with the Zollinger–Ellison syndrome (ZES), and ultimately 15–30% of MEN1/ZESpatients develop carcinoids in the gastric body and fundus and occasionally in the an-trum.1–4,7 The mucosa thickness is increased, in contrast to a distinct atrophy of type 1lesions, and the patients have increased gastric acid secretion (Figure 1). Patients withsporadic ZES may often also have ECL cell hyperplasia, but rarely (<1%) gastriccarcinoids.

The type 2 gastric carcinoids account for w6% of gastric carcinoids. They areoften multiple and usually small (<1–2 cm), but generally larger than type 1 tu-mours, with occasional markedly larger tumours of up to 4–5 cm or more. Thehistological pattern generally is similar to type 1 lesions, but with absence of mu-cosal atrophy. The malignant potential is intermediate between CAG-associated andsporadic gastric carcinoids, with some tumours appearing rather as neuroendocrinecarcinoma with local invasion, angioinvasion and high proliferation rate. Lymph-nodemetastases occur in w30% of patients and liver metastases in 10–20%.4,8 The ag-gressive tumours with liver metastases have been more frequent with long-standingZES. Poorly differentiated gastric endocrine carcinomas have occasionally beenassociated with MEN1.

Surgical treatment. Surgery in type 2 gastric carcinoids is focused on removing thesource of hypergastrinaemia, generally by excision of typical duodenal gastrinomasof the MEN1 patients via duodenotomy, together with clearance of lymph-node me-tastases (see below).8–10 Treatment of the gastric carcinoids per se may be as fortype 1 lesions, with endoscopic mucosectomy for tumours <1 cm. Liberal surgicalexcision or gastric resection together with regional lymph gland clearance is donefor larger and multifocal tumours or those with deep wall invasion or angioinvasion.In cases with multiple tumours somatostatin analogue treatment may be used toreduce tumour growth, especially if hypergastrinaemia has not been reversed bysurgery.4

Type 3 sporadic gastric carcinoids

Type 3 sporadic gastric carcinoids account for w20% of gastric carcinoids and occur innon-atrophic gastric mucosa without endocrine cell proliferation in patients with nor-mal gastrin. They are most frequent in males, mean age w50 years.1–4 Determinationof 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 thirdsof the lesions have infiltrated the muscularis, and 50% have invaded all layers of the


gastric wall. Some tumours occur in the antral or prepyloric region, although most arelocated in the gastric body and fundus. Most tumours originate in ECL cells, but othercell types may be present and associated with a less favourable prognosis. Regionallymph-node metastases occur in 20–50%, also with small tumours, and liver metasta-ses eventually develop in two thirds of the patients.4,11 The sporadic carcinoids canhave atypical histology, with pleomorphism, high mitosis rate, and often higher Ki67index. 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 sporadicgastric carcinoids.1 The syndrome is due to release of histamine and is characterizedby a patchy ‘geographic’ flush, cutaneous oedema, bronchospasm, salivary gland swell-ing and lacrimation. Urinary estimates of the histamine metabolite methylimidazole-acetic acid (MelmAA) serves as tumour marker, and patients may have slightelevation of urinary 5-hydroxy-indoleacetic acid (5-HIAA) values.

Surgical treatment. Sporadic gastric carcinoids are treated with gastric resection com-bined with regional lymph-node clearance. Tumours >2 cm or those with atypical his-tology 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 isonly 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 gen-erally large, with a median size of w4–5 cm, often appearing ulcerating or fungat-ing. The prognosis is poor, with median survival of 8 months, but some individualsmay survive longer.4,13,14 The tumours are generally not available for surgery,though occasionally surgical debulking together with chemotherapy may be consid-ered in patients with mixtures of well-differentiated and poorly differentiatedtumours.

Figure 2. Sporadic, solitary gastric carcinoid with lymph-gland metastasis removed by gastric resection.

From Akerstrom et al (2006, Endocrine Surgery 3rd edition, Lennard TWJ (ed); Elsevier) with permission.


Midgut carcinoids

The midgut carcinoids are most common of carcinoids, accounting for w25% andoccurring at w65 years of age. They originate most frequently in the terminal ileumwith 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 smallertumours often appear in the nearby intestine. Mesenteric lymph-node metastases arecommon also with small tumours, and microscopic metastases are almost invariablypresent.15,16 These metastases will often grow conspicuously large and may be mistakento represent the primary tumour.1 Fibrosis induced around the metastases tends tocontract the mesentery and may kink and obstruct the intestine. The mesenterictumour is often attached by fibrosis to the serosa of the horizontal duodenum, whichmay become occluded with continued growth. The mesenteric vessels are oftenencased by the mesenteric tumour and fibrosis, ultimately resulting in venous stasisand incipient ischaemia in segments of the small intestine. Operation may worsen fibro-sis 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 anddiarrhoea for several years before diagnosis. Many patients get increased abdominalpain attacks with time, and approximately 40% are discovered at emergency surgeryfor intestinal obstruction. In other patients the diagnosis is settled after detection ofliver metastases, sometimes together with features of the carcinoid syndrome, whichinitially may be discrete with flush induced after intake of certain food or alcohol.Extra-abdominal metastases may occur in the skeleton, lungs, mediastinal and peripherallymph glands, ovaries, breast and skin. The carcinoid syndrome occurs in w20% ofpatients with liver metastases or extensive retroperitoneal lymphatic spread. Thesepatients suffer from flush, diarrhoea, right-sided heart valve fibrosis, and occasionallybronchial constriction. The heart disease may be diagnosed by echocardiography andmay require thoracic surgery with valve replacement before major abdominal surgery.

Practice points

� type 1 CAG-related gastric carcinoids <1 cm – endoscopic excision andsurveillance 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 andoptimal treatment of larger MEN1-associated carcinoids


Diagnosis

Raised levels of the serotonin metabolite 5-HIAA in 24-hour urine samples is specificfor carcinoids but present only in advanced cases, generally with liver metastases.Plasma chromogranin A measurement is less specific but can provide earlier diagnosisand is often preferred to monitor disease progress. Computed tomography (CT) withcontrast enhancement can efficiently demonstrate mesenteric metastases and retro-peritoneal tumour extension, reveal relation to the mesenteric artery and vein, andwill also visualize liver metastases (Figure 3). Octreoscan can determine spread tothe liver and to extra-abdominal sites. Needle biopsy of liver metastases with stainingfor chromogranin A and synaptophysin is used to diagnose carcinoids, and serotoninreactivity verifies a midgut origin.

Early surgical treatment

Midgut carcinoids can be recognized at laparotomy by typical features of a small ilealtumour and large mesenteric metastases surrounded by fibrosis.15–18 The primarytumour should be removed by wedge resection of the mesentery with dissection oflymph-node metastases around the mesenteric artery and vein aiming to preserveintestinal vascular supply and limit the intestinal resection (Figure 4). With grossly rad-ical tumour removal, patients may remain symptom-free for extended time periods;however, due to the tenacity of carcinoid tumours, they should undergo careful andlife-long surveillance, since eventual recurrence of liver metastases can be expectedin approximately 85% of midgut carcinoid patients.

Surgical treatment for advanced carcinoids

Treatment with long-acting somatostatin analogues and interferon-a can often provideefficient control of the carcinoid syndrome. During treatment the mesenteric tumourand 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.


obstruction and compromised intestinal circulation. Some patients develop abdominalpain, weight loss, diarrhoea, and even cachexia due to incipient ischaemia and malab-sorption.15–18 Prophylactic surgical removal of mesenteric metastases is recommendedat 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 themesenteric artery and vein, with preservation of the mesenteric circulation and onlya limited intestinal resection, avoiding the creation of a short bowel syndrome.

Repeated surgery may be needed if mesenteric metastases have been left or haveprogressed after primary surgery. These operations are difficult due to fibrosis be-tween regions of intestine, and mistakes may result in fistulation, intestinal devascula-rization, or creation of a short bowel.18

Prophylaxis against carcinoid crisis

Surgery in patients with the carcinoid syndrome may initiate a carcinoid crisis withhyperthermia, shock, arrhythmia, excessive flush or bronchial obstruction. This is

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 Akerstrom et al (2006, Endocrine Surgery 3rd edition, ed. Lennard TWJ; Elsevier) with permission.


prevented by routine preoperative administration of intravenous somatostatin ana-logue (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 forabdominal complications, palliate the carcinoid syndrome, and also appears to increasesurvival. Survival of patients with midgut carcinoids has improved with active and com-bined medical and surgical treatment, but depends on the extent of disease. Presenceof liver metastases and carcinoid heart disease have been the most significant adverseprognostic factors. Patients with inoperable liver metastases (see below) had a 5-yearsurvival of w50%, and survival was w40% with inoperable liver and mesentericmetastases.17,19

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 mostcommon 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 thosewith other carcinoids (mean age w40 years), with female predominance, and alsochildren may be affected. Patients with larger tumours and metastases have oftenbeen younger than those with clinically benign tumours.

The majority (w90%) of appendiceal carcinoids measure <1 cm in diameter, arenot situated in the appendiceal base, and are invariably cured by appendectomy. Tu-mours >2 cm require hemicolectomy and ileocaecal lymph-node clearance. Thisshould be done also for all tumours in the appendix base, since they may originatein the colon and cause local recurrence. For tumours measuring 1–2 cm hemicolec-tomy is recommended if there is invasion in the mesoappendix or residual tumourin the resection margins, and in the presence of lymph-node metastases. For thesame-size lesions confined to the appendiceal wall, guidelines suggest appendectomyalone with low risk for metastases. However, hemicolectomy may be recommendedwhen operative specimens show high proliferative activity (high Ki67 index), highmitotic index, or signs of angioinvasion, but the evidence base is lacking.20,21 Follow-up may be considered in such patients, and raised serum chromogranin A may thensupport extended operation. Appendiceal carcinoids metastasize to regional lymphnodes more often than to the liver. In the presence of massive liver or retroperitonealmetastases the patients may occasionally appear with the carcinoid syndrome. Survival

Practice points

� mesenteric metastases of midgut carcinoids with surrounding fibrosis maycause intestinal obstruction and ischaemia� removal of primary and mesenteric carcinoid tumour may prevent or delay

abdominal complications


is excellent with only locoregional tumour, but with distant metastases 10-year sur-vival has been w30%.

A rare variant of appendiceal carcinoid, goblet-cell carcinoid or adenocarcinoid, havemixed endocrine and exocrine features. This carcinoid often presents with a diffuselyinflamed appendix, and occurs at a later age (w50 years).1,20,21 The tumours areaggressive, often with peritoneal and ovarian metastases, sometimes appearing asmucinous adenocarcinoma. They do not express somatostatin receptors, and cannotbe visualized by Octreoscan. The tumour entity should be treated with right-sidedhemicolectomy and lymph-node clearance in combination with chemotherapy. Fordisseminated tumours aggressive surgical reduction – including peritonectomy andoophorectomy – may be required, according to recent guidelines for colorectal carci-nomas. Goblet-cell carcinoids have a 10-year survival of w60%.20

Colon carcinoids

Colon carcinoids constitute w8% of carcinoids, and affect older persons (mean agew60 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 distalcolorectal tumours. Occasional right-sided, differentiated tumours may produceserotonin, and have raised urinary 5-HIAA values. Colon carcinoids are oftenexophytic and large (w5 cm) and cause general malignant symptoms (as colon ade-nocarcinoma), but rarely bleed. Only occasional right-sided lesions are positive onoctreoscan, many are aggressive, with a high proliferation rate, regional lymph-node metastases, or even more often liver metastases. Attempts should be madeto achieve radical resection by hemicolectomy or subtotal colectomy with lymph-node clearance, but often only debulking is possible. Overall 5-year survival hasbeen w40%, being slightly worse than for colon adenocarcinoma, and mainly relatedto tumour stage.

Poorly differentiated (small-cell) neuroendocrine carcinoma occurs in the rightcolon, frequently associated with an adjacent adenoma or adenocarcinoma.3 Thesetumours are generally metastasized at diagnosis and are mainly treated withchemotherapy; only occasional patients require palliative surgery, but have poorsurvival.

Practice points

� appendiceal carcinoids <1 cm are cured by appendectomy, tumours >2 cmrequire 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 carcinoidsmeasuring 1–2 cm


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 mostoften at w55 years of age. The tumours are most frequent on the anterior or lateralrectal 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 inasymptomatic patients. Tumours <1 cm have low incidence of nodal metastases(0–3%) and no distant spread; tumours measuring 1–2 cm have regional and distantmetastases in 7–34%, whereas tumours >2 cm (found in w15%) have local and distantmetastases in 67–100%. Presence of muscularis layer invasion is more common withlarger tumours and relates to spread with lymph-node and liver metastases. The largertumours may have mucosal scarring or ulceration with bleeding, and may haveadvanced local infiltration, and sometimes perirectal fixation like adenocarcinoma.The larger tumours may be associated with pain, change in bowel habits, constipationand weight loss. The carcinoid syndrome does not occur with rectal carcinoids.Octreoscan is rarely positive in rectal carcinoids due to lack of somatostatin recep-tors, 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 raisedin 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 muscularisinvasion.1,23–26 Tumours measuring 1–2 cm should be investigated by transanal endo-sonography or magnetic resonance imaging (MRI). Absence of muscularis invasion orregional metastases justifies local excision rather than rectal resection. Presence ofeither favours aggressive excision, generally by anterior rectal resection with totalmesorectal excision and regional lymph-node clearance. This is also recommendedin cases with tumours >2 cm without general dissemination. In patients with distantmetastases 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 lymph-node 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 rectalcarcinoids


ENDOCRINE PANCREATIC TUMOURS (EPTS)

Insulinomas

Insulinomas constitute w25% of EPTs and are the most common of functioning tu-mours, 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 multi-ple tumours.

Symptoms of insulinoma are often misinterpreted. Catecholamine response tohypoglycaemia causes sweating, weakness, anxiety, tachycardia and hunger. More char-acteristic symptoms are due to neuroglucopenia, with anxiety, behavioural change,epileptic seizures, confusion, coma, and sometimes focal symptoms, visual distur-bances (diplopia), speech difficulties and pareses. Patients tend to become obese sincethey learn to avoid hypoglycaemia by nightly meals.

Diagnosis

Diagnosis is made by a supervised fasting test showing hypoglycaemia (serum glucoseconcentrations <45 mg/dL, or <2.5 mM) and inappropriately high serum insulin. Thismeans detectable but not obligatory raised insulin levels, since w20% of patients havenormal insulin during fasting hypoglycaemia.28 A corresponding rise in C-peptide iscrucial to verify that insulin secretion is endogenous and to exclude factitia, i.e. self-administration of insulin or peroral antidiabetic medication, claimed to be more com-mon than insulinoma. Proinsulin levels in normal individuals are usually <20% of totalimmunoreactive insulin but tend to be higher in patients with insulinoma. Proinsulin/insulin ratio >50% may indicate malignant insulinoma, but occurs also with 25% of be-nign insulinomas. Oral sulphonylurea antidiabetics may cause hypoglycaemia with risein 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 prox-imity of the pancreas. Spiral CT with contrast enhancement, or occasionally MRI, areroutinely performed to rule out presence of liver metastases and to detect larger tu-mours that could indicate malignancy, but these techniques have low sensitivity forsmall insulinomas.

Endoscopic ultrasound (EUS) has been increasingly used, with nearly 90% sensitivityfor visualization of insulinomas. It has appeared as the most efficient method for pre-operative localization, although some isoechoic (6%) or pedunculated tumours may failto be visualized.29,30 EUS can reveal important relation to the pancreatic duct, and ifintroduced in the horizontal duodenum allows visualization also of the uncinate pro-cess; some of the equipment may be used for tumour biopsy.

The selective arterial stimulation (SAS) test utilizes injection of calcium into majorarteries supplying the pancreas and concomitant hepatic vein sampling for insulin, andcan regionalize an insulinoma to the head, body or tail of the pancreas.31 The SAS testis essential in reoperative cases, but may also be used before primary operation whenother localization studies are negative. An SAS test demonstrating insulin secretionfrom multiple areas of the pancreas supports a diagnosis of multiple insulinoma(MEN1 patients) or nesidioblastosis.32


Intraoperative ultrasound (IOUS) is now considered a necessary prerequisite forinsulinoma operation together with complete pancreatic exploration and palpationat 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 atumour and facilitate dissection from the pancreatic duct, and also reveal tumourbilobation that has to be appreciated at enucleation.

Surgical treatment

Most insulinomas are intraoperatively palpable as a firmer nodule with sensitivity ofw90%. Tumours deep within the pancreatic head and in the uncinate process are dif-ficult to palpate, and any lesion is difficult to detect in patients with previous pancre-atitis. Combination of IOUS and palpation increases the sensitivity of insulinomadetection to nearly 100%, but requires complete surgical exploration. The head ofthe pancreas is delivered by the Kocher manoeuvre, with the uncinate process care-fully dissected towards the porto-mesenteric vein (Figure 5). The pancreatic tail is mo-bilized to the mesenteric vein, allowing bidigital palpation and IOUS investigation fromboth dorsal and ventral surfaces.

Most insulinomas, especially in the head of the pancreas, may be safely enucleatedwith cautious ligation of ductal structures. Occasional pancreatic head tumours adja-cent to the pancreatic duct may be more safely enucleated towards a catheter intro-duced by ERCP or duodenotomy. Pancreatico-duodenectomy is only rarely requiredwith large tumours and a suspicion of malignancy. Also pancreatic tail tumours maybe enucleated, but tail resection is chosen for distal tumours close to the duct to min-imize the risk of pancreatic effusion. Distal pancreatic resection is often made spleen-preserving with benign tumours, but this is avoided with large or suspected malignantEPTs, since the splenic hilum is often a first site of metastases.

Laparoscopic removal of insulinoma with enucleation or tail resection has beenapplied in many centres, and can be associated with markedly reduced hospital stayand increased patient comfort. The operation is facilitated by laparoscopic ultrasonog-raphy, 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.


higher risk of pancreatic effusion (20–40%). This operation can be chosen for carefullyselected lesions and should be performed by expert laparoscopists.32

Blind pancreatic resection should not be undertaken if no insulinoma is found, butin such cases the abdomen should be closed and the patient subjected to furtherinvestigation to verify the biochemical diagnosis and exclude factitious insulin adminis-tration. More extensive localization procedures are applied before reoperation, oftenincluding the SAS intra-arterial calcium injection test.27

Adult nesidioblastosis

Although this represents a controversial issue, adult nesidioblastosis with diffuse b-cellproliferation may cause symptomatic hypoglycaemia.32,33 These patients typically havepostprandial rather than fasting-provoked hyperinsulinaemic hypoglycaemia, and diag-nosis is confirmed by a meal test causing hypoglycaemia and inappropriate insulin andC-peptide levels. The diagnosis is supported if the SAS test shows insulin secretionfrom multiple areas of the pancreas, which may lead to gradient-guided subtotalpancreatic resection.

Nesidioblastosis has been more common in patients previously subjected to bari-atric surgery. The hypoglycaemia may be reversed by 60–90% distal pancreatic resec-tion, but cure has not been universal; it is apparently sometimes less efficient infemales, and some patients have been palliated by medical treatment with calciumblockers. A suggested preoperative treatment period with diazoxide may help deter-mine 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 andcannot 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 malignantinsulinoma, and even palliative debulking may yield survival benefit. However, mostmalignant insulinomas have disseminated metastases in the liver, lungs and lymph nodes,and are scarcely available for tumour reduction, with survival strongly dependent onresponse to chemotherapy. Some patients have larger, apparently dedifferentiatedmalignant 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-yearsurvival of 29% has been reported in patients with metastasizing malignant insulinoma.

Practice points

� most insulinomas (90%) are benign small tumours and can be efficiently treatedby 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


Gastrinoma: Zollinger–Ellison syndrome (ZES)

Gastrinomas comprise w20% of functioning EPTs. The majority are sporadic, but asmany as 30% occur as a part of the MEN1 syndrome.27 Gastrinomas and ZES areuncommon causes of peptic ulcer disease, with recurrent, atypical, multiple and com-plicated ulcers, sometimes concomitant diarrhoea, and/or oesophagitis, and in 20%only diarrhoea. Gastrin levels are often markedly increased, together with raised basalacid output with low gastric pH. Serum gastrin >1000 pg/mL and gastric pH <2 isdiagnostic of ZES. In other patients a secretin test may be required, and is diagnosticwith paradoxal rise in gastrin, 200 pg/mL over baseline, but 15% of ZES patients havenegative test. The important differential diagnosis is atrophic gastritis, where patientshave 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 duodenalgastrinomas have been recognized as the most common gastrinomas, causing60% of sporadic ZES and 90% of MEN1-associated ZES, where multiple tumoursare common (Figure 6). The duodenal gastrinomas are typically tiny submucosaltumours, often �0.5 cm, most frequent in the first and second portion of duode-num. They have great tendency to set lymph-node metastases (w45%), but livermetastases occur late and in a minority of patients (w10%), allowing for thepossibility of successful surgical removal. This tumour entity may represent theprimary tumour in patients with ‘primary lymph-node gastrinoma’, diagnosed inup to 10% of patients with ZES, where the primary tumour may be remarkablyslow-growing and may remain undetected.

Research agenda

� clarify clinical criteria for diagnosis and treatment of adult nesidioblastosis� evaluate surgery for malignant insulinoma

Figure 6. Multiple duodenal gastrinoma in a multiple endocrine neoplasia type 1 (MEN1) patient.


Preoperative localization

CT or MRI is routinely performed in patients with ZES to visualize lymph-node andliver metastases prior to surgery.27 Octreoscan can often (in w90% of cases) revealgastrinoma lymph-node and liver metastases and occasional larger primary tumours.However, small duodenal tumours are not detectable, and instead larger lymph-node metastases around the pancreatic head are easily mistaken for the primarytumour. EUS can detect pancreatic and a few larger duodenal gastrinomas, and oftenlymph-gland metastases, but rarely the smallest duodenal tumours. The selective arte-rial stimulation test (the SAS, Imamura test) was originally developed with injection ofpentagastrin for visualization of gastrinoma, and may provide tumour regionalizationand demonstrate liver metastases.34 Even in the absence of positive localization diag-nosis, the patients with ZES should be liberally submitted to surgery, since thesepatients especially are likely to have resectable duodenal gastrinomas.

Surgical treatment

The surgical cure rate in ZES patients increased markedly when it became appreciatedthat most gastrinomas occurs in the duodenum.35 The duodenal gastrinomas may bevisualized by longitudinal duodenotomy at surgery with inversion of the lumen forcareful palpation of the entire duodenum (Figure 6). The smallest duodenal submuco-sal tumours can be removed by mucosal dissection, larger tumours (>5 mm) requirefull-thickness duodenal wall excision. Pancreatico-duodenectomy may be required forgastrinomas in the pancreatic head and occasional larger or multiple duodenaltumours. Surgery in patients with gastrinoma should include clearance of lymph-node metastases around the pancreas and duodenum, and should aim to removealso resectable liver metastases (see below).35,36

Gastrinomas should be considered potentially malignant. Survival is favourable inpatients with duodenal gastrinomas with lymph-node metastases, removal of whichpossibly limits further spread, and few (w10%) of these patients develop liver me-tastases.35,36 Adverse prognostic factors are large primary pancreatic tumours, pres-ence of liver or bone metastases, and very high serum gastrin. The small duodenalgastrinomas 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.

Glucagonomas

Glucagonomas are uncommon, representing w10% of functioning EPTs, most fre-quent at ages of w50 years.27,37 The patients have a characteristic pruritic skinrash, migrating necrolytic erythema starting in the groin and ingues and migrating

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


to extremities, they also have deep vein thrombosis and thrombophlebitis, and at theadvanced stage sometimes severe cachexia. Diagnosis is settled by demonstration ofraised plasma glucagon and is often delayed, even in the presence of typical skin le-sions. 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 thehigh risk for thrombosis and pulmonary embolism. The glucagonomas are generallydistally located in the pancreas and are often large (4–15 cm) (Figure 7). The tu-mours are malignant in w80% and often have regional lymph-gland metastases,sometimes mistaken to represent the primary tumour. Treatment is distal subtotalpancreatic resection and clearance of regional lymph-gland metastases. Disease pro-gression may be slow despite metastases, and the patients will often during an ex-tended disease course be subjected to sequential excision of lymph nodes or livermetastases with 5 years or more between recurrent lesions. A 10-year survival ofw50% has been reported.

VIPomas

Tumours secreting vasoactive intestinal peptide (VIP) cause the WDHA (watery diar-rhoea, hypokalaemia, achlorhydria) syndrome, with severe secretory diarrhoea, acido-sis and dehydration.37 Flush may occur due to the vasodilatory effect of VIP, and somepatients have hypercalcaemia. The diagnosis is made by demonstration of raised VIPvalues. Because of the risk for severe dehydration, the patients need intensive treat-ment with somatostatin analogue and intravenous fluid and electrolyte resuscitation.The tumours are generally large and located within the pancreatic tail; 50% have me-tastases at diagnosis. Treatment is surgical excision, and debulking surgery should beconsidered in patients with metastases, consisting of pancreatectomy and resectionor ablation of liver metastases and even resection of lung metastases if present. Rou-tine cholecystectomy may facilitate somatostatin analogue treatment. A 10-year sur-vival 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).


Non-functioning endocrine pancreatic tumours

The non-functioning EPTs are not related to any clinical syndrome of hormoneexcess.27,38–41 They may have no hormone secretion, due to absence of secretorygranulae, or may release amounts too low to cause clinical symptoms. Most have in-creased serum values of chromogranin A; also common are raised values of pancreaticpolypeptide (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 in-creased 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 bettersurvival prospects than patients with adenocarcinoma. The non-functioning EPTs aremost often diagnosed at the age of w50–60 years, but also occur in younger individ-uals where they may be discovered as unusually large tumours without the typical ma-lignant cachexia of pancreatic carcinoma.27,38,39

Diagnosis of the non-functioning tumours can be made by demonstrating hypervas-cularization on contrast-enhanced CT and positive octreoscan, raised serum levels ofchromogranin A or serum PP, or by ultrasound-guided fine or semi-fine needle biopsystained with chromogranin A or synaptophysin.

The non-functioning EPTs most commonly occupy the pancreatic head (60%) butmay occur in the entire pancreas. They may cause jaundice or discomfort due to localextension or pain due to pancreatitis, though jaundice is often absent, also with largepancreatic head tumours. Although growth is typically slow compared to that of ade-nocarcinomas, the progress is variable; some are indolent, with growth only of theprimary lesion, whereas others progress rapidly with lymph-node and liver metastases.High Ki67 proliferation index (>5%) and high frequency of chromosomal rearrange-ments have been associated with more rapid progression.40 Generally extra-abdominalspread from EPTs occurs late.

Even when survival is extended, the pancreatic tumours per se may be the causeof morbidity. The tumours tend to grow into surrounding structures, the ventricle,the duodenum, or the transverse colon, and may then be associated with obstruc-tion or bleeding.38,39 With continuous growth in the pancreatic head and body themesenteric vein is often invaded and occluded, causing portal hypertension andincreased tendency to gastrointestinal bleeding and eventually mesenteric thrombosisand intestinal ischaemia. Also the coeliac, hepatic, and mesenteric arteries may beinvolved.

Surgical treatment

Surgery is indicated for removal of the primary tumour to reduce the risk of mesen-teric vein involvement or gastric outlet obstruction, and to facilitate efficient chemo-therapy; it may be undertaken also in the presence of low-volume liver metastases.Also the largest EPTs can often be removed by extended pancreatico-duodenectomyor subtotal pancreatectomy, even in the presence of portal hypertension, sometimeswith the use of vein graft (from internal jugular, saphenous, or splenic vein) to restorepatency of the mesenteric vein (Figure 8).38,39,41 Involvement of the mesenterico-coeliac arterial axis has been claimed to contraindicate surgery, but in our experiencethe central axis arteries may often be dissected free (Figure 8), or they may be graft-substituted. Extensive dissection around the mesenteric artery may cause severe diar-rhoea due to denervation of intestinal plexa, and may significantly impair the patient’sgeneral condition.


The rate of metastases varies from 62 to 92%. Results of surgery for large non-functioning tumours have reported 5-year survival of 65% and 10-year survival of49%.38–41 Survival advantage has been evident in the absence of liver metastases,orif such metastases have been resected. Merely palliative surgery with remainingtumour has resulted in poor survival. The operative mortality of aggressive surgeryhas varied from 0 to 15%; the risks have been associated mainly with complicationsdue to mesenteric vein or artery occlusion.41 Peroperative morbidity has variedbetween 6 and 39%; pancreatic effusion and abscess formation have been problematicin many series, but generally resolve with efficient drainage.

Endocrine pancreatic tumours associated with MEN1

Pancreatic involvement occurs clinically in 30–75% of patients with MEN1.27,40,42 ZEShas been the most common EPT syndrome in MEN1, encountered in 20–60% ofpatients, insulinoma is found in w30%, VIPomas in w5%, and symptomatic glucagono-mas are exceptional. Non-functioning EPTs occur in w50% of MEN1 patients. TheMEN1 syndrome can be revealed in w30% of ZES patients and in 5–10% ofinsulinomas.

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.

Practice points

� non-functioning EPTs are generally hypervascular tumours with positiveoctreoscan and raised serum levels of chromogranin A or PP� surgical removal should be attempted also for the larger non-functioning EPTs


Tumour disease accounts for w50% of deaths in MEN1, and pancreatic malignancyhas been the cause of death in a majority.42–44 The MEN1 pancreas contains numerousmicroadenomas, only a few of which will grow into clinical tumours.45 In the absenceof distant metastases, surgery is advocated for MEN1 insulinomas and rare VIPomas orglucagonomas42,45, but has been controversial with MEN1 ZES because long-term cureis rarely achieved. However, in follow-up studies, ZES is a late feature with metastasesalready in 30–50% of patients, and we propose surgery also for ZES patients for pre-vention of malignancy and to facilitate medical treatment.46 Non-functioning EPTs canoften be diagnosed earlier by biochemical markers (pancreatic hormones, especiallyPP, and chromogranin A), and we suggest that MEN1 patients should be subjectedto pancreatic exploration even in the absence of hormone excess syndrome whenthese markers are unequivocally raised and EUS indicates the presence of tu-mours.42,45–48

Surgical treatment

MEN1 patients are most often subjected to distal subtotal 80–85% pancreatectomycombined with enucleation of tumours in the pancreatic head (Figure 9).42,45,46,49 Con-comitant duodonotomy is done in patients with raised gastrin or ZES to identify andremove duodenal gastrinomas (Figure 9). This active strategy appears to decrease thenumber of patients with metastases or deaths due to pancreatic tumours, but random-ized evaluation is lacking.46 Pancreatico-duodenectomy is occasionally required inMEN1 patients with large tumours of any entity in the pancreatic head or duodenum,and has been proposed for efficient eradication of MEN1 ZES. However, pancreatico-duodenectomy is not routinely proposed for MEN1 ZES patients since this implies dif-ficulties in treating recurrent tumours. Moreover, after pancreatico-duodenectomy,liver metastases cannot be treated with embolization because of risk for ascendinginfection 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.


Reoperation, with enucleation or resection of new tumours, may be required inMEN1 patients and has in our experience been efficient and uneventful. Total pancre-atectomy may theoretically be needed for large malignant tumours, but has only occa-sionally been performed in our MEN1 patients.

LIVER SURGERY

Liver metastases

Liver metastases in patients with carcinoids or EPT should be evaluated for surgicalresection or local ablation with the aim of reducing the tumour burden and alleviatinga hormonal syndrome.19,50–55 Most patients have multiple bilaterally spread livermetastases, and altogether only w5–10% have apparently solitary or dominant metas-tases available for surgery. Hepatic lobectomy or segmental resections are used liber-ally for removal of solitary or larger metastases, often combined with wedge resectionor enucleation of additional smaller lesions. Two-stage liver resection combined withportal embolization for triggering liver regeneration may reduce the risk for liverinsufficiency.

Other options include radiofrequency ablation (RFA), embolization, and treatmentwith lutetium-labelled somatostatin analogues.27,40,53 RFA can be done at open surgeryin conjunction with the intestinal operation or as a percutaneous ultrasound-guidedprocedure, and has widened indications for surgery of bilateral liver tumours. Onlya limited number of metastases (w5–10) can be treated with combinations of surgeryand RFA. RFA has a complication rate of w5%, and in particular central bile ducts maybe damaged by RFA close to the hepatic hilum.53 Sustained symptom palliation andreduction of tumour markers can be achieved after removal of large, dominant livermetastases if w90% of the tumour volume can be excised.19,50–55 Smaller metastasesremaining after liver surgery may resolve after chemotherapy.

Practice points

� surgery is indicated for removal of MEN1-related insulinoma and rare VIPomaor 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

Practice point

� alleviation of hormonal symptoms and improved survival can be achieved byresection of dominant liver metastases in patients with carcinoids and EPT


SUMMARY

Most carcinoid tumours are well-differentiated and slow-growing, and should be sur-gically excised when possible. Occasional tumour entities have low differentiation andhigh proliferation rates, and respond better to chemotherapy. Multiple gastric carci-noids occur most often as a result of gastrin excess in patients with CAG. These car-cinoids are generally benign and can generally be safely removed and controlled byendoscopy. A minority are associated with MEN1 ZES. In contrast, sporadic, solitarygastric carcinoids without association to CAG or MEN1 are highly malignant and in-variably require more extensive surgery. For midgut carcinoids surgical treatmentshould include efforts to remove mesenteric metastases that may cause severelong-term abdominal complications with intestinal obstruction and ischaemia. Small,non-invasive rectal carcinoids can be removed by endoscopy, whereas larger lesionsare often highly malignant and need extensive resection and often chemotherapy inaddition. With increased efficiency of pre- and interoperative localization, insulinomasand duodenal gastrinomas can be identified and safely removed, whereas pancreaticgastrinoma, glucagonoma, VIPoma, and non-functioning EPTs are often large and re-quire surgical debulking to reduce risks of local overgrowth and to palliate hormoneexcess. Attempts should also be made to surgically remove or ablate liver metastases,since this may markedly palliate hormonal symptoms and often improves survival. Thechallenge is to improve surgical technique in order to undertake operation with min-imal morbidity and mortality. Proliferation and genetic markers can help select patientsfor surgery and avoid poorly differentiated neuroendocrine carcinoma (with high Ki67proliferation index) which may be more efficiently managed with chemotherapy.

REFERENCES

1. Akerstrom G, Hellman P & Hessman O. Gastrointestinal carcinoids. In Lennard TWJ (ed). Endocrine

Surgery. Elsevier, 2006, pp. 163–198.

2. Modlin IM, Lye KD & Kidd M. A 5-decade analysis of 13,715 carcinoid tumours. Cancer 2003; 97:

934–959.

3. Modlin IM, Kidd M, Latich I et al. Current status of gastrointestinal carcinoids. Gastroenterology 2005;

128: 1717–1751.

*4. Delle Fave G, Capurso G, Milione M & Panzuto F. Endocrine tumours of the stomach. Best Practice &

Research. Clinical Gastroenterology 2005; 19: 659–673.

5. Ichikawa J, Tanabe S, Koizumi W et al. Endoscopic mucosal resection in the management of gastric

carcinoid tumors. Endoscopy 2003; 35: 203–206.

6. Ahlman H, Kolby L, Lundell L et al. Clinical management of gastric carcinoid tumors. Digestion 1994;

55(supplement 3): 77–85.

7. Bordi C, Corleto VD, Azzoni C et al. The antral mucosa as a new site for endocrine tumors in multiple

endocrine neoplasia type 1 and Zollinger–Ellison syndromes. The Journal of Clinical Endocrinology and

Metabolism 2001; 86: 2236–2242.

Research agenda

� investigate benefit of surgical resection and RF ablation for treatment of mul-tiple and recurrent liver metastases


8. Bordi C, Falchetti A, Azzoni C et al. Aggressive forms of gastric neuroendocrine tumors in multiple

endocrine neoplasia type I. The American Journal of Surgical Pathology 1997; 21: 1075–1082.

9. Richards ML, Gauger P, Thompson NW & Giordano TJ. Regression of type II gastric carcinoid in

multiple endocrine neoplasia type 1 patients with Zollinger–Ellison syndrome after surgical excision

of all gastrinomas. World Journal of Surgery 2004; 28: 652–658.

10. Norton JA, Melcher ML, Gibril F & Jensen RT. Gastric carcinoids tumors in multiple endocrine

neoplasia-1 patients with Zollinger–Ellison syndrome can be symptomatic, demonstrate aggressive

growth, and require surgical treatment. Surgery 2004; 136: 1267–1274.

11. Shinohara T, Ohyama S, Nagano H et al. Minute gastric carcinoid tumor with regional lymph node

metastasis. Gastric Cancer 2003; 6: 262–266.

12. Wilander E, El-Salhy M & Pitkanen P. Histopathology of gastric carcinoids: a survey of 42 cases. Histo-

pathology 1984; 8: 183–193.

13. Rindi G, Bordi C, Rappel S et al. Gastric carcinoids and neuroendocrine carcinomas: pathogenesis,

pathology and behavior. World Journal of Surgery 1996; 20: 168–172.

14. Rindi G, Azzoni C, La Rosa S et al. ECL cell tumor and poorly differentiated endocrine carcinoma of the

stomach: prognostic evaluation by pathological analysis. Gastroenterology 1999; 116: 532–542.

15. Ohrvall U, Eriksson B, Juhlin C et al. Method of dissection of mesenteric metastases in mid-gut

carcinoid tumors. World Journal of Surgery 2000; 24: 1402–1408.

16. Makridis C, Oberg K, Juhlin C et al. Surgical treatment of mid-gut carcinoids tumors. World Journal of

Surgery 1990; 14: 377–385.

*17. Makridis C, Ekbom A, Bring J et al. Survival and daily physical activity in patients treated for advanced

midgut carcinoid tumors. Surgery 1997; 122: 1075–1082.

18. Makridis C, Rastad J, Oberg K & Akerstrom G. Progression of metastases and symptom improvement

from laparotomy in midgut carcinoid tumors. World Journal of Surgery 1996; 20: 900–907.

*19. Hellman P, Lundstrom T, Ohrvall U et al. Effect of surgery on the outcome of midgut carcinoids disease

with lymph node and liver metastases. World Journal of Surgery 2002; 26: 991–997.

*20. Goede AC, Caplin ME & Winslet MC. Carcinoid tumor of the appendix. The British Journal of Surgery

2003; 90: 1317–1322.

21. Stinner B & Rothmund M. Neuroendocrine tumours (carcinoids) of the appendix. Best Practice &

Research. Clinical Gastroenterology 2005; 19: 729–738.

22. Ballantyne GH, Savoca PE, Flannery JT et al. Incidence and mortality of carcinoids of the colon. Data

from the Connecticut Tumor Registry. Cancer 1992; 69: 2400–2405.

23. Vogelsang H & Siewert JR. Endocrine tumours of the hindgut. Best Practice & Research. Clinical Gastro-

enterology 2005; 19: 739–752.

24. Koura AN, Giacco GG, Curley SA et al. Carcinoid tumors of the rectum: effect of size, histopathology

and surgical treatment on metastasis free survival. Cancer 1997; 79: 1294–1298.

25. Suzuki H & Ikeda K. Endoscopic mucosal resection and full thickness resection with complete defect

closure for early gastrointestinal malignancies. Endoscopy 2001; 33: 437–439.

26. Nakagoe T, Ishikawa H, Sawai T et al. Gasless video endoscopic transanal excision of rectal tumors

incompletely removed by colonoscopic snare polypectomy. Journal of Laparoendoscopic & Advanced Sur-

gical Techniques. Part A 2003; 13: 99–103.

27. Akerstrom G, Hellman P, Hessman O & Osmak L. Surgical treatment of endocrine pancreatic tumours.

Neuroendocrinology 2004; 80(supplement 1): 62–66.

28. Scarlett JA, Mako ME, Rubenstein AH et al. Factitious hypoglycemia: diagnosis by measurement of

serum C-peptide immunoreactivity and insulin-binding antibodies. The New England Journal of Medicine

1977; 297: 1029–1032.

29. Thompson NW, Dzako PF, Fritts LL et al. Role of endoscopic ultrasonography in the localization of

insulinomas and gastrinomas. Surgery 1994; 116: 1131–1138.

*30. Anderson MA, Carpenter S, Thompson NW et al. Endoscopic ultrasound is highly accurate and directs

management in patients with neuroendocrine tumors of the pancreas. The American Journal of Gastroen-

terology 2000; 95: 2271–2277.

31. Doppman JL, Chang R, Fraker DL et al. Localization of insulinomas to regions of the pancreas by intra-

arterial stimulation with calcium. Annals of Internal Medicine 1995; 123: 269.

32. Grant CS. Insulinoma. Best Practice & Research Clinical Gastroenterology 2005; 19: 783–798.


33. Service GJ, Thompson GB, Service FJ et al. Hyperinsulinemic hypoglycemia with nesidioblastosis after

gastric-bypass surgery. The New England Journal of Medicine 2005; 353: 249–254.

*34. Imamura M & Takahashi K. Use of selective arterial secretin injection test to guide surgery in patients

with Zollinger–Ellison syndrome. World Journal of Surgery 1993; 17: 433–438.

35. Norton JA, Fraker DL & Alexander HR. Surgery to cure the Zollinger–Ellison syndrome. The New

England Journal of Medicine 1999; 341: 635–644.

36. Yu F, Venzon DJ, Serrano J et al. Prospective study of the clinical course, prognostic factors, causes of

death, and survival in patients with long-standing Zollinger–Ellison Syndrome. Journal of Clinical Oncology

1999; 17: 615–630.

37. Doherty GM. Rare endocrine tumours of the GI tract. Best Practice & Research. Clinical Gastroenterology

2005; 19: 807–818.

38. Hellman P, Andersson M, Rastad J et al. Surgical strategy for large or malignant endocrine pancreatic

tumours. World Journal of Surgery 2000; 24: 1353–1360.

*39. Kouvaraki MA, Solorzano CC, Shapiro SE et al. Surgical treatment of non-functioning pancreatic islet

cell tumors. Journal of Surgical Oncology 2005; 89: 170–185.

40. Oberg K & Eriksson B. Endocrine tumours of the pancreas. Best Practice & Research. Clinical Gastroen-

terology 2005; 19: 753–782.

41. Bartsch DK, Schilling T, Ramaswamy A et al. Management of nonfunctioning isle cell carcinomas. World

Journal of Surgery 2000; 24: 1418–1424.

42. Akerstrom G, Hessman O, Hellman P & Skogseid B. Pancreatic tumours as part of the MEN-1

syndrome. Best Practice & Research. Clinical Gastroenterology 2005; 19: 819–830.

43. Dean PG, van Heerden JA, Farley DR et al. Are patients with multiple endocrine neoplasia type 1 prone

to premature death? World Journal of Surgery 2000; 1: 1437–1441.

44. Doherty GM, Olson JA, Frisella MM et al. Lethality of multiple endocrine neoplasia type 1. World Journal

of Surgery 1998; 22: 581–587.

*45. Akerstrom G, Hessman O & Skogseid B. Timing and extent of surgery in symptomatic and asymptom-

atic neuroendocrine tumours of the pancreas in MEN 1. Langenbeck’s Archives of Surgery 2002; 386:

558–569.

46. Skogseid B, Rastad J & Akerstrom G. Pancreatic endocrine tumors in multiple endocrine neooplasia

type 1. In Doherty G & Skogseid B (eds). Surgical Endocrinology. Philadelphia, Lippincott: Williams &

Wilkins, 2001, pp. 511–525.

47. Gauger PG, Scheiman JM, Wamsteker E-M et al. Role of endoscopic ultrasound in screening and treat-

ment of pancreatic endocrine tumours in asymptomatic patients with multiple endocrine neoplasia type

1. The British Journal of Surgery 2003; 90: 748–754.

48. Hellman P, Hennings J, Akerstrom G & Skogseid B. Endoscopic ultrasonography for evaluation of

pancreatic tumours in multiple endocrine neoplasia type 1. The British Journal of Surgery 2005; 92:

1508–1512.

49. Doherty GM. Multiple endocrine neoplasia type 1: duodenopancreatic tumors. Surgical Oncology 2003;

12: 135–143.

50. McEntee GP, Nagorney DM, Kvols CK et al. Cytoreductive hepatic surgery for neuroendocrine tumors.

Surgery 1990; 108: 1091–1096.

51. Wangberg B, Westberg G, Tylen U et al. Survival of patients with disseminated midgut carcinoid tumors

after aggressive tumor reduction. World Journal of Surgery 1996; 20: 892–899.

52. Nave H, Mossinger E, Feist H et al. Surgery as primary treatment in patients with liver metastases from

carcinoid tumors: a retrospective, unicentric study over 13 years. Surgery 2001; 129: 170–175.

*53. Hellman P, Ladjevardi S, Skogseid B et al. Radiofrequency tissue ablation using cooled tip for liver

metastases of endocrine tumors. World Journal of Surgery 2002; 26: 1052–1056.

54. Elias D, Lasser P, Ducreux M et al. Liver resection (and associated extrahepatic resections) for meta-

static well-diferentiated endocrine tumors: a 15-year single center prospective study. Surgery 2003;

133: 375–382.

*55. Norton JA, Warren RS, Kelly MF et al. Aggressive surgery for metastatic liver neuroendocrine tumors.

Surgery 2003; 134: 1057–1065.

Surgery on neuroendocrine tumours

Documents