NETs with somatostatin reactivity occur in the ampullary or periampullary region, almost exclusively in the ampulla of Vater, causing obstructive jaundice, pancreatitis or bleeding [22, 34, 35]. A clinical somatostatinoma syndrome is very rare. The tumours appear as 1–2 cm homogeneous ampulla nodules, which only occasionally are polypoid, larger or ulcerated. Regional lymph node or liver metastases are present in nearly 50 % of patients. Unlike conventional NETs, the tumours have a glandular growth pattern and may characteristically contain special laminated psammoma bodies. The lesions are often associated with von Recklinghausen’s neurofibromatosis (neurofibromatosis type 1, NF1) and occasionally with pheochromocytoma [22, 34, 35]. The ampullary somatostatin-rich NETs may be locally excised, together with clearance of regional lymph glands, but since there is no established correlation between tumour size and metastases, pancreaticoduodenectomy has been recommended in younger patients [32].

Gangliocytic paragangliomas are rare tumours, occurring almost exclusively in the second portion of the duodenum, and are sometimes associated with NF1 [33]. The tumours consist of a mixture of paraganglioma, ganglioneuroma and NET tissue, with reactivity for somatostatin and pancreatic polypeptide (PP). The tumours may be recognised incidentally or because of bleeding. They may be large but are generally benign and often have an excellent prognosis following surgical excision [33].

More unusual WDNETs have reactivity for other hormones, such as calcitonin, PP and serotonin [12, 22, 33, 36, 37]. Most of these tumours occur as small polyps (<2 cm) in the proximal duodenum. Multiple tumours should raise suspicion of an associated MEN 1 syndrome. The majority are low-grade malignant and often suitable for endoscopic mucosal resection or local surgical excision, only rare large tumours require pancreaticoduodenectomy [33, 36, 37].

A distinct group of duodenal NETs without release or staining for hormones is also recognised. These tumours have a somewhat different biology and have less often metastasised than the gastrinomas and somatostatinomas [22, 33, 36, 37]. Some are asymptomatic and incidentally found at endoscopy, others present with non-specific abdominal symptoms, gastrointestinal bleeding and sometimes vomiting or weight loss. Most tumours are located in the first portion of the duodenum, occasionally in the second part and rarely in the third portion (horizontal duodenum). The majority stains for CgA and some for synaptophysin and/or NSE [36, 37]. Up to one-third of the patients have had other primary malignancies as well, including adenocarcinomas of the gastrointestinal tract, prostate or other organs [36, 37]. More than half of the tumours are smaller than 2 cm and generally have a good prognosis after resection. Lesions smaller than 1 cm can be endoscopically excised, but re-examination with follow-up endoscopy is required to ensure complete removal. Size >2 cm, invasion beyond the submucosa and presence of mitotic figures are independent risk factors for metastases (grade 2 tumours). Tumours with these risk factors are likely to recur also after apparently curative surgery, even if no lymph node metastases have been detected, whereas lesions smaller than 2 cm rarely metastasise [36, 37]. Rare duodenal tumours may cause an ectopic Cushing’s syndrome due to ACTH secretion [33].

The treatment suggested for larger tumours is segmental duodenal resection or pancreaticoduodenectomy in order to decrease the risk of recurrence [36, 37]. Periampullary tumours behave in malignant fashion and need more radical surgery. Patients with metastasising duodenal NETs may survive for decades, substantiating that NETs are less aggressive than adenocarcinomas.

PDNECs (large or small cell) in the duodenum are exceptionally rare, occurring most often in the ampulla of Vater, and the patients present with obstructive jaundice and invariably with a rapidly fatal course [36, 37].

(For excellent review including endoscopic management of gastroduodenal NETs, see [22]).

Many patients with Si-NETs have experienced long periods of unspecific episodic abdominal pain and diarrhoea, often misinterpreted as irritable bowel syndrome or food allergy before the disease has been clinically diagnosed [10, 43, 45, 55]. Others have had unrecognised features of the carcinoid syndrome with discrete flush misinterpreted as menopausal complaints or palpitations and intolerance for specific food or alcohol [10, 43, 45, 56]. Intestinal bleeding has generally been rare with Si-NETs due to the submucosal location of the primary tumour and has been more likely to occur with more rare, larger, polypoid, fungating primary tumours [43, 45]. Bleeding may also occur when mesenteric metastases have grown into the horizontal duodenum or in the presence of intestinal venous stasis and incipient ischaemia [12, 43, 45]. Intermittent pain attacks have been common and often increased in frequency until the patient has developed subacute or acute intestinal obstruction requiring surgery. In around 50 % of patients, the Si-NET diagnosis has become evident after needle biopsy of liver metastases [12, 43, 45].

The carcinoid syndrome, described in 1954 by Thorson, has been reported to occur in approximately 20 % of patients with jejunoileal NETs, though the frequency may be higher at referral centres [12, 40–43, 53]. The syndrome includes flushing, diarrhoea, right-sided heart valve disease and bronchoconstriction. Serotonin (5-hydroxytryptamine), derived from the amino acid tryptophan, has been identified as the major cause of the syndrome [10, 41, 45]. Serotonin is inactivated by monoamine oxidase in the liver and in the kidney converted to 5-HIAA, which is excreted in the urine. Presence of the carcinoid syndrome generally implies that the patient has liver metastases, with secretion directly into the systemic circulation [12, 41, 45]. Occasionally the syndrome may occur in patients with large retroperitoneal or ovarian lesions, where the secretion exceeds the capacity of the monoamine detoxification or can bypass the liver and drain directly into the systemic circulation [12, 41, 45]. The syndrome is related to release also of other vasoactive factors tachykinins (substance P, neuropeptide K), prostaglandins and occasionally norepinephrine [12, 45, 57].

Secretory diarrhoea is the most common feature of the syndrome (reported in around 70 %), but may initially be mild and unspecific. Diarrhoea tends to be most prevalent in the morning and is often meal related. The diarrhoea may have other causes in NET patients, especially when previously operated upon or having advanced disease [12, 40, 45]. The commonly performed distal small intestinal resection leads to reduced bile salt absorption; treatment with bile acid-binding agents (cholestyramine) may provide relief. Somatostatin analogues in high doses may cause malabsorption diarrhoea, with foamy, floating diarrhoea after meals, which can be treated with pancreatic enzymes (Creon). Patients with long-standing poorly controlled carcinoid syndrome may develop niacin deficiency and pellagra (a syndrome with diarrhoea, dementia and dermatitis), which can be prevented by niacin supplementation. Other causes are a short bowel after surgery and partial intestinal obstruction. In patients with the large mesenteric tumours, intestinal venous stasis or ischaemia may contribute significantly to stool frequency. Occlusion of main mesenteric vein branches may cause severe watery diarrhoea and malnutrition, due to severely oedematous, fluid-leaking intestinal segments [12, 41, 45, 51, 52].

Cutaneous flushing (reported in around 65 %) affects the face, neck and upper chest and is the most characteristic feature of the carcinoid syndrome [12, 41, 45, 56]. Flushing may nevertheless easily be overlooked, especially in females at menopause. The flush may be provoked by stress, alcohol, certain food, aged cheese or coffee. It is often of short duration, lasting for 1–5 min, but may occasionally be prolonged for hours or even days. Flushing may occasionally be severe and long-standing, and with chronic flush, the patients may develop telangiectasies and persistent blue-cyanotic discolouration of the skin on the nose and chins.

Heart valve fibrosis, with plaque-like fibrotic endocardial thickening, affects the tricuspid and pulmonary valves, as a late consequence of a severe and long-standing carcinoid syndrome and high serotonin levels [12, 41, 45, 58–60]. This will cause retraction and fixation of the heart valves and subsequently regurgitation and stenosis, leading to tricuspid regurgitation and pulmonary valve stenosis. Tricuspid valve abnormalities was in one series reported in 65 % of patients with the carcinoid syndrome, and 19 % had pulmonary valve stenosis [60]. In less than 10 % the fibrosis may involve also the left-sided heart valves, in case of a patent oval foramen or when the pulmonary monoamine oxidase activity is exceeded, and then possibly contribute to bronchoconstriction.

The carcinoid heart disease may lead to progressive right-sided heart failure and severe lethargy and used to be the cause of death in 50 % of patients with the carcinoid syndrome [12, 40, 48, 58–60]. Nowadays, after introduction of somatostatin analogues, patients more often die from progressive tumour disease. Affected patients may require heart surgery and prostheses replacement of fibrotic heart valves [59, 60]. The operation may lead to substantial improvement, but can especially in older persons be associated with complications [60]. The heart disease is efficiently diagnosed by echocardiography, which should invariably be performed prior to major abdominal surgery.

The primary Si- NETs generally escape detection by conventional bowel contrast studies because of limited size [10, 12, 21, 61]. Typical arcading of entrapped intestines, with segments of partial obstruction, may be revealed with advanced disease and occasionally the signs of chronic obstruction, with dilatation, and oedematous thickened bowel wall. In the presence of large bowel symptoms, entrapment of the sigmoid or transverse colon may be important to identify prior to surgery. Concomitant colorectal adenocarcinoma has been reported, and it may be necessary to exclude coexisting recto-sigmoidal adenocarcinoma by endoscopy, prior to surgery or during follow-up of Si-NETs.

CT can rarely visualise a primary Si-NET, but will often reveal mesenteric lymph node metastases, retroperitoneal extension of such masses and liver metastases. The presence of a circumscribed mesenteric mass with radiating densities is highly suspicious for an Si-NET mesenteric metastasis. Dynamic CT with contrast enhancement is important prior to operation, by possibility to reveal relation between the mesenteric metastases and the main mesenteric vessels [12, 45]. In cases with intestinal ischaemia, CT may show a characteristic image of dilated peripheral veins (Fig. 25.6) and oedematous loops of intestine. CT with contrast enhancement is often the primary method for visualisation of liver metastases, but fails to identify the smallest lesions. MRI can sometimes be more efficient than CT for demonstration of liver metastases. Percutaneous US with power Doppler enhancement, and use of US contrast, may increase sensitivity for the detection of liver metastases and is mainly used to visualise liver metastases and to guide fine or semi-fine-needle biopsy of the liver or mesenteric metastases for histological diagnosis and grading.

Needle biopsy specimens from metastases are often used for diagnosis. The NET cells stain immunocytochemically with neuroendocrine tumour markers, mainly CgA and synaptophysin, and reactivity with serotonin-specific antisera implies that a primary tumour should be searched for in the midgut [12, 21, 45]. Most jejunoileal NETs show a mixed insular and glandular growth pattern; occasional tumours have a pure insular and trabecular pattern and have been reported to have slightly less favourable prognosis [12, 21]. Proliferation rate determined with the Ki-67/MIB antibody has often been very low <2 % in classical Si-NETs. Occasional tumours have higher proliferation rate (grade 2) or may change to higher grade during the disease course [12, 21]. Very rare lesions present as PDNEC with poorly differentiated pattern and high proliferation rate with poor prognosis and sparse effects of surgery.

Since Si-NETs patients may be subjected to acute laparotomy due to abdominal pain or intestinal obstruction with unknown diagnosis, it is important that surgeons in general learn that the Si-NETs are common small bowel neoplasms and also come to recognise the typical features of a small ileal tumour and conspicuously larger mesenteric metastases with surrounding fibrosis [12, 43, 45, 48, 49, 63, 64]. Since an intestinal bypass may complicate more radical surgery, the locoregional tumour should if possible be removed by mesenteric wedge resection and intestinal resection, with clearance of lymph node metastases around the mesenteric artery and vein branches [12, 49]. The procedure is generally justified also in patients with moderately spread liver metastases. If the surgery has been inadequately performed, reoperation for removal of a remaining mesenteric tumour may be considered, as the patient may otherwise risk future abdominal complications [12, 43, 45, 48, 49, 63]. If grossly radical locoregional tumour removal has been accomplished, the Si-NETs patients often remain symptom-free for long periods from treatment with somatostatin analogues and interferon (IFN-α). However, the Si-NETs are markedly tenacious and recurrence with liver metastases should be expected in the vast majority of patients (60–80 %) if follow-up is long enough [43, 45, 48, 49, 63]. Since the Si-NETs are slow-growing tumours, clinically overt recurrence may occur after long duration of up to 10–25 years [45, 49, 63]. Earlier recurrence may be diagnosed by serum CgA estimates, rather than the urinary 5-HIAA measurements.

Many Si-NETs patients present with liver metastases and sometimes also features of the carcinoid syndrome. Life expectancy used to be poor in patients with liver metastases and the carcinoid syndrome; now symptoms may be efficiently controlled with somatostatin analogues and IFN-α, which together with other new treatment modalities have markedly increased life expectancy and life quality [21, 45, 49, 63]. The carcinoid heart disease used to be a principal death cause in Si-NETs patients, together with abdominal complications, which played a significant role in 40 % of patients [12, 63]. Possibly due to treatment with efficient biotherapy, the heart disease has become less common, and a majority of patients now die with spread malignancy or liver failure after an extended disease course [41, 61, 63]. Improved survival by somatostatin analogue treatment documented by the PROMID study has widened indications for locoregional tumour removal in patients with advanced Si-NETs [41, 63–65]. Because partial intestinal obstruction or incipient intestinal ischemia may cause similar symptoms of feeding-related abdominal pain, laparotomy can be needed to distinguish these causes.

Abdominal pain is unlikely to be caused merely by the carcinoid syndrome, and complications of the mesenteric tumour are important to recognise since considerable long-term palliation may be achieved by appropriate surgery [63, 64]. Not all mesenteric metastases will cause extensive fibrosis, and the course of the mesenterico-intestinal disease can be variable, but elective surgery at an early stage may allow removal of the mesenteric tumours with more limited intestinal resection before involvement of major mesenteric vessels becomes too extensive [12, 63, 64]. The authors advocate removal of the mesenterico-intestinal tumour also in asymptomatic patients and suggest liberal surgical consultations when abdominal symptoms occur during periods of medical treatment [63]. Too late surgical consultation may allow the disease to be increasingly difficult or impossible to manage surgically.

The extension below or above the horizontal duodenum (as can be depicted with coronal CT) is crucial for preoperative evaluation, as this can determine if metastases are regional or located high in the mesenteric root (Fig. 25.7). At operation the advanced Si-NETs may appear inoperable, if high mesenteric metastases with surrounding fibrosis appear to encase the mesenteric root and the major intestinal vascular supply [12, 43, 45, 49, 63]. Incautious wedge resection in the fibrotic and contracted mesentery may risk to seriously compromise the intestinal circulation. It is recommended to begin the operation with palpation of the small bowel from the Treitz ligament to the caecum, to identify the primary tumour, exclude the presence of multiple intestinal tumours and allow judgement of the length of the small intestine that needs to be removed. Ischaemic changes and venous stasis can be found to comprise limited intestinal segments, and the locoregional tumour can then be safely removed by a distal intestinal resection. This is preferably combined with caecal resection or right hemicolectomy, with proximal vascular ligature, and extended wedge resection for improved clearance of regional metastases [49]. For tumours originating in the proximal intestine, segmental small intestinal resection is performed.

With advanced growth of bulky mesenteric tumours with higher location in the mesenteric root, above the horizontal duodenum, the management can be more complex (Fig. 25.8) [12, 45, 49]. The majority of these metastases originate from distal intestinal tumours and tend to be deposited onto the right side of the main mesenteric vessels. A method has been proposed (Fig. 25.9), where the right colon and the mesenteric root are mobilised from adhesions to the retroperitoneum to the level of the horizontal duodenum and the pancreas [12, 45, 49]. Staple transection of the right colon then allows visualisation of the mesenteric artery and vein from the right side and possibility for vascular control above the mesenteric tumour during excision. With posterior view in the lifted mesenteric root, fibrotic bands can be transected and the tumour dissected from the serosa of the horizontal duodenum, occasionally, with duodenal wall excision or short duodenal resection in case of tumour invasion. It may then be possible to free-dissect the mesenteric tumour from the major vessels and carefully preserve the arcades of collateral circulation along the intestine and limit the required intestinal resection [12, 45, 49] (Fig. 25.10).