Type 1: gastric NETs associated with chronic atrophic gastritis

These tumours account for 70–80% of gastric NETs¹¹ (Table 6.3). They occur occasionally in young individuals, but most commonly in older patients, with a mean age around 65 years, and there is a 3:1 female to male predominance.¹⁵

These NETs develop in patients with autoimmune CAG type A,^13,16 where atrophy of the fundic mucosa is accompanied by pentagastrin-resistant achlorhydria and vitamin B₁₂ malabsorption. More than half of the patients also have pernicious anaemia (Table 6.3). Reduction of gastric acid and increase in pH stimulates gastrin secretion from gastrin (G) cells in the antrum, and the resulting hypergastrinaemia induces hyperplasia of the fundic ECL cells. Diffuse argyrophilic hyperplasia of the non-antral mucosa occurs in 65% of patients with CAG and micronodular/adenomatoid hyperplasia in 30%, whereas the precarcinoid and dysplastic, enlarged micronodules develop mainly in patients with gross NETs. The tumour development progresses from the specified stages of hyperplasia, through dysplastic stages, to neoplastic intramucosal or invasive NETs.¹⁴

It is important to emphasise that, although CAG is common in elderly individuals, only few affected patients (1%) ultimately develop gastric NETs. The tumours occur mainly in patients with a long duration of a markedly raised serum gastrin, who have more prevalent hyperplastic changes. The CAG-associated NETs contain predominantly ECL cells, intermingled with other specific or poorly defined endocrine cells.

The type 1 gastric NETs are predominantly located within the body or the fundus of the stomach or in the transitional zone to the antrum.^16,17 They are frequently multicentric, consisting of multiple, small gastric polyps and invariably associated with ECL cell hyperplasia and microscopic tumours. The number of gross lesions can, however, be limited and some tumours may thus appear as solitary. Individual tumours can present as broad-based, round polypoid lesions, reddish to yellowish, depending on the thickness of the covering mucosa. Some lesions can be flat and broad, or appear as discoloured spots or simply as slight mucosal protrusions. Only a few are ulcerated or bleeding. The number and size vary from innumerable pinpoint-sized tumours to a few or solitary prominent lesions ranging from a few millimetres up to 1–1.5 cm, and only occasionally larger tumours (> 2 cm). The polypoid NETs may be difficult to distinguish from hyperplastic polyps, which are also more frequent in patients with CAG.

Small type 1 gastric NETs are almost always benign with low risk of invasion beyond the submucosa. Larger lesions (> 1 cm) are also predominantly benign but may rarely have invasion of the muscularis propria (< 10%).¹⁵ CAG-associated NETs have a lower incidence of metastases and more favourable outcome than other types of gastric NETs. Metastases to regional lymph nodes occur in 5% and distant metastases in around 2%.^9,15,18 However, earlier reports with a greater proportion of large lesions described more frequent metastases.¹⁹ Disease-related deaths are exceptional.

Occasional CAG patients have harboured larger, considerably more invasive tumours, representing poorly differentiated neuroendocrine carcinomas or composite endocrine tumours/adenocarcinoma (see below). All these have an unfavourable prognosis.

Type 2: NETs associated with ZES in MEN1 patients

These gastric NETs constitute 6–8% of all gastric NETs,¹¹ and are thus much less common than those associated with atrophic gastritis (Table 6.3). They occur in patients with MEN1 and gastrin-producing tumours as a cause of ZES, with equal female:male distribution, at a mean age of 45–50 years.¹⁶

ECL cell hyperplasia is found in almost 80% of MEN1 patients with ZES, and fundic gastric NETs develop in up to 5–30% of these patients.^15,20 In addition to the hyperplasia and dysplasia of ECL cells in the fundic mucosa, the oxyntic mucosal thickness is invariably increased, in contrast to the atrophy of type 1 lesions. These NETs also develop in a hyperplasia–dysplasia–neoplasia sequence, but have mainly been associated with diffuse hyperplasia, and less evident micronodular changes. However, gastric NETs in sporadic ZES are rare, and virtually only ZES in association with MEN1 seems to promote growth of gastric NETs.²¹ The MEN1 syndrome is caused by an inherited mutation of the MEN1 tumour suppressor gene located on chromosome 11q13.²² As in other MEN1 lesions, the gastric NETs in MEN1 lose their single remaining functional copy of the MEN1 gene by chromosomal deletions.²³ In MEN1 patients without ZES, gastric NETs are extremely rare.²⁴ Thus, hypergastrinaemia seems to be required for development of gastric NETs from ECL cell hyperplasia. However, additional factors are obviously needed for tumour formation, since only 1% of patients with hypergastrinaemia due to atrophic gastritis and < 1% of patients with sporadic ZES develop gastric NETs.^20,24,25

The type 2 gastric NETs are located in the gastric body and fundus, and occasionally in the antrum, and are composed mainly of ECL cells with sparse other cell types. They are most often multiple and small (73% are smaller than 1.5 cm), although often larger than type 1 tumours, with a size varying from 0.5 to 2 cm. Occasionally, there are markedly larger tumours.¹³ The malignant potential is intermediate between that of CAG-associated gastric NETs and sporadic NETs, and 90% will not have infiltrated beyond the submucosa. However, lymph node metastases are present in up to 30% of the patients, and distant metastases, assumed to originate from gastric NETs, occur in 10–20%.¹⁵ MEN1 patients develop distant metastases from other MEN1-associated tumours as well, and the gastric NETs are not the most likely origin. The overall prognosis will depend more on the other MEN1 lesions, and the prognosis is usually rather favourable for the type 2 NETs.²¹ However, rare cases of highly malignant neuroendocrine gastric carcinomas with poor prognosis have also occurred in some MEN1/ZES patients.²⁴

Type 3: sporadic gastric NETs

Tumours with no association to hypergastrinaemia account for 15–20% of the gastric NETs and have features that markedly differ from type 1 and type 2 lesions (Table 6.3).¹⁶ They occur sporadically, are usually solitary, and grow much more aggressively. Many are already disseminated at diagnosis.¹⁶ These NETs have a male predominance, with a male:female ratio of 3:1; mean age of presentation is reportedly around 50 years. The sporadic gastric NETs occur in non-atrophic gastric mucosa, without endocrine cell proliferation. Determination of serum calcium and examination of the family history may help exclude the MEN1 syndrome, which should be suspected in all patients with foregut NETs unrelated to atrophic gastritis.

The sporadic tumours are often large; 70% are > 1 cm with a mean size of 3.2 cm (Fig. 6.1).^15,16 Two-thirds of the lesions will have infiltrated the muscularis propria and 50% invaded all layers of the gastric wall.¹⁵ Some tumours occur in the antral, prepyloric regions, although the majority are located in the body and fundus of the stomach. Most tumours originate in argyrophilic ECL cells, but a mixture of other cell types and EC cells may be present, and are associated with a less favourable prognosis. Regional lymph node metastases have been described in 71% of the patients, and liver metastases have ultimately developed in 69% of the patients. Half of patients are alive after follow-up of 5 years, but patients with distant metastases have a 10% 5-year survival.^1,15,26

The sporadic NETs are generally well differentiated, but often of grade 2 with Ki67 index > 2%. According to previous classification they may have typical or atypical histology, where atypical implies marked nuclear pleomorphism, increased number of mitoses, and areas of necrosis. The atypical tumours are larger, more frequently invasive and commonly associated with metastases at diagnosis.⁹ A series of sporadic gastric NETs with atypical morphology reported a mean size of 5 cm and unfavourable survival.²⁷

An atypical carcinoid syndrome has developed in 5–10% of the patients with sporadic gastric NETs and is associated with tumour release of histamine. The syndrome is characterised by bright red cutaneous flushing, often with a patchy ‘geographic’ distribution, cutaneous oedema, intense itching, bronchospasm, salivary gland swelling and lacrimation.^11,16 The atypical carcinoid syndrome is related to histamine secretion, and urinary estimates of the histamine metabolite methylmidazole-acetic acid (MelmAA) may serve as a tumour marker. Most gastric NETs are deficient in the enzyme L-amino acid decarboxylase, and only a few patients have elevated levels of serotonin. Urinary excretion of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) is therefore less appropriate as a tumour marker.¹⁷ However, the precursor 5-hydroxytryptophan (5-HTP) may be excreted and partly decarboxylated in the kidney, and patients with disseminated sporadic gastric NETs may exhibit some elevated urinary 5-HIAA values.

Poorly differentiated gastric neuroendocrine carcinomas

The poorly differentiated neuroendocrine carcinomas (NECs) are highly malignant neoplasms, with generally extensive local invasion and metastases already at diagnosis. They are not associated with the carcinoid syndrome and occur at a mean age of 60–70 years, with male predominance.^15,28 Atrophic gastritis has been revealed in half of the patients, but is not believed to cause the tumour, since only a minority of patients have hypergastrinaemia.¹⁵ The majority of tumours are located in the gastric corpus or fundus, but 10–20% may occur in the antrum.^15,28 The tumours are generally large, with median size of around 4–5 cm,¹³ invariably deeply invading the gastric wall and associated with metastases. The majority of lesions appear as ulcerated tumours and a quarter are fungating.²⁸ They all tend to be of histological grade 3, and often have solid structures with necrosis, a high degree of atypia, frequent mitoses and high proliferation index in Ki67 staining (generally around 20–40%). Almost all tumours show vascular and perineural invasion. In contrast to the well-differentiated gastric NETs, the poorly differentiated NECs may have sparse immunoreactivity to chromogranin A, at least in the majority of tumour cells.⁹ Immunoreactivity to synaptophysin (and possibly NSE or PGP9.5) may verify the neuroendocrine differentiation and separate these tumours from exocrine carcinomas. The prognosis is poor with a median survival of 8 months, albeit some individuals are reported to be still alive after follow-up of 10–15 years.^9,15,28

The possibility of progression from well-differentiated gastric NETs, especially type 3 lesions, to NECs has been suggested by a few cases with coexisting well and poorly differentiated gastric NETs.^9,24

Aberration of the p53 tumour suppressor gene and chromosomal deletion of the long arm of chromosome 18 are common in poorly differentiated NECs, and occasionally found also in type 3 sporadic gastric NETs.⁹ These genetic defects occur in gastrointestinal exocrine carcinomas and may promote aggressive tumour growth. Genetic studies of rare mixed neuroendocrine/exocrine gastric carcinomas indicate that the endocrine tumour component may originate in adenocarcinoma cells.²⁹

Clinical evaluation

Treatment

Gastrinomas

Gastrin-cell (G-cell) tumours – gastrinomas – are the most prevalent and constitute 60% of the duodenal neuroendocrine tumours; 15–30% of G-cell tumours cause clinical ZES, the remainder are clinically silent.^17,47 Most gastrinomas are located in the first and second parts of the duodenum. They are frequently small (often around 0.5 cm or smaller), with early metastases to regional lymph nodes reported in 30–70% of patients.^15,48–51 The regional lymph node metastases may be considerably larger than the primary tumours, which sometimes may be difficult to detect even at operation. There is generally considerable delay before liver metastases develop, and this is claimed to provide a favourable interval for surgical treatment.⁵⁰ It has been recognised that 40–60% of gastrinomas responsible for ZES are located within the duodenal submucosa.^48,49 MEN1/ZES patients have, in nearly 90% of cases, multifocal duodenal gastrinomas.^48,49 The duodenal gastrinomas in ZES are slow-growing, indolent malignancies despite their tendency to spread with local lymph node metastases. Duodenal gastrinomas in ZES are rarely identified by endoscopy because of their small size, and they are also often difficult to visualise during surgery. Endoscopic transillumination has been advocated, but it is more efficient to perform a long duodenotomy, allowing discovery of gastrinomas after inversion and palpation of the duodenal mucosa.^48,52

Somatostatin-rich NETs

NETs with somatostatin reactivity comprise 15–20% of duodenal neuroendocrine tumours. These tumours are most often clinically hormonally non-functioning.^47,54,55 They occur almost exclusively in the ampulla of Vater, causing obstructive jaundice, pancreatitis or bleeding. The tumours appear as 1- to 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, these tumours have a glandular growth pattern and characteristically contain special laminated psammoma bodies. They can be identified with chromogranin stain. One-third of these lesions are associated with von Recklinghausen’s neurofibromatosis (neurofibromatosis type 1, NF1) and occasionally with phaeochromocytoma.⁵⁶ Depending on the size of the tumours and the age of the patient, the somatostatin-rich NETs may be locally excised or removed by pancreatico-duodenectomy.

Gangliocytic paragangliomas

Gangliocytic paragangliomas are rare tumours, occurring almost exclusively in the second portion of the duodenum, and are sometimes associated with neurofibromatosis (NF1).⁵⁷ The tumours consist of a mixture of paraganglioma, ganglioneuroma and NET tissue with reactivity for somatostatin and pancreatic polypeptide (PP). The tumours are generally benign, recognised only incidentally or because of bleeding, and have an excellent prognosis following surgical excision.

Other duodenal NETs

More unusual well-differentiated duodenal NETs may display reactivity for other hormones, such as calcitonin, PP and serotonin.⁵⁷ Most of these tumours are found in the proximal part of the duodenum as small polyps (< 2 cm). Multiple tumours should raise suspicion of an associated MEN1 syndrome. The majority of these tumours are low-grade malignant and often suitable for local surgical excision.⁵⁸ Only rarely do large tumours require pancreatico-duodenectomy.

A distinct group of duodenal NETs without release or staining for hormones is also recognised. These tumours have a somewhat different biology and metastasise less often than the gastrinomas and somatostatinomas.⁵⁷ Some of them are asymptomatic and are found incidentally on endoscopic examination. Others present with non-specific abdominal symptoms, gastrointestinal bleeding and sometimes with vomiting or weight loss.⁵⁷ 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 stain for chromogranin A, and some for synaptophysin and/or NSE.⁵⁷ Up to one-third of the patients have had other primary malignancies as well, including adenocarcinomas of the gastrointestinal tract, prostate or other organs.⁵⁹

More than half of the tumours are smaller than 2 cm and generally have a good prognosis after resection. Size > 2 cm, invasion beyond the submucosa or presence of mitotic figures are independent risk factors for metastases.⁴⁷ Tumours with these risk factors are also likely to recur after apparently curative surgery, even if no lymph node metastases have been detected, whereas lesions smaller than 2 cm rarely metastasise.⁵⁸

Lesions smaller than 1 cm can possibly be endoscopically excised, but re-examination with follow-up endoscopy is required to ensure complete removal.⁵⁸ Tumours smaller than 2 cm, without signs of invasion of the muscularis, can be treated by open local excision. The treatment suggested for larger tumours is segmental resection or pancreatico-duodenectomy in order to decrease the risk of recurrence.⁵⁸ Periampullary tumours behave in a malignant fashion and need more radical surgery. Patients with metastasising duodenal NETs may survive for decades, substantiating that these NETs are less aggressive than adenocarcinomas.

Duodenal NECs

Poorly differentiated NECs in the duodenum are exceptionally rare. Most occur in the ampulla of Vater, and the patients present with obstructive jaundice and invariably with a rapidly fatal course.¹⁷

Morphological features

The primary small-intestinal NET is most commonly located in the terminal parts of the ileum, often appearing as a small, flat and fibrotic submucosal tumour, measuring around 1 cm or less (Fig. 6.2),^60,61 occasionally with some central navelling. Sometimes the tumour is so tiny that it is difficult to detect at surgery, appearing only as a limited area of fibrosis or circumscribed thickening of the intestinal wall. In up to one-third of patients, multiple smaller neuroendocrine polyps occur in the nearby intestine, most likely caused by lymphatic dissemination.⁶¹ In a few cases additional larger neuroendocrine polyps have been found in proximal parts of the intestine, and may appear to represent additional primary tumours. Among patients subjected to surgery, the incidence of mesenteric metastases has been as high as 70–90%, irrespective of tumour size. When growing close to the intestinal wall such metastases have sometimes been mistaken for primary tumours. In contrast to NETs located elsewhere in the gastrointestinal tract, microscopic or gross metastases have also occurred in association with the smallest primary tumours.⁶¹ Unusual large primary tumours sometimes extend directly into a conglomerate of mesenteric lymph gland metastases. The mesenteric metastases typically grow conspicuously larger than the primary tumour, and characteristically evoke a marked desmoplastic reaction with pronounced mesenteric fibrosis⁶¹ (Fig. 6.3). The fibrosis might result from local effects of serotonin, growth factors and other substances secreted from the neuroendocrine metastases.^60,62

With more extensive fibrosis the distal ileal mesentery often becomes contracted and tethers the mesenteric root to the retroperitoneum, with fibrous bands attaching to the serosa of the horizontal duodenum. Occasionally, fibrosis and tumour extend over parts of the transverse or the sigmoid colon.⁶¹

The mesenteric tumour and fibrosis can often cause partial or complete small-intestinal obstruction by kinking and fibrotic entrapment of the intestine, whereas the primary tumour is only occasionally large enough to obstruct the intestinal lumen.⁶¹ Obstruction of the duodenum tends to occur at advanced stages. The mesenteric vessels are often encased or occluded by the growing mesenteric tumour, with resulting local venous stasis and ischaemia in the small intestine, and occasionally frank impairment of the intestinal circulation. Variable segments of the small intestine thus appear dark blue to reddish due to incipient venous gangrene (Fig. 6.4), or occasionally pale and cyanotic due to deficient arterial circulation.^60,61 A specific angiopathy, called vascular elastosis, occurs with advanced small-intestinal NETs and causes marked thickening of mesenteric vessel walls due to elastic tissue proliferation in the adventitia; this contributes to the intestinal vascular impairment.⁶³ However, compression by tumour and fibrosis has in our experience been the obvious cause in patients where intestinal ischaemia was revealed at operation.^60,61

Fibrotic attachments between intestines invariably become more pronounced after surgery and frequently create a conglomerate of distal small-intestinal loops and caecum, which becomes fixed to the posterior and anterior abdominal wall.

Distant metastases from small-intestinal NETs occur most commonly in the liver and the patients then often present with variable features of the carcinoid syndrome. Liver metastases are often bilateral and diffusely spread; approximately 10% of patients have fewer or dominant lesions, sometimes with conspicuous growth of individual lesions. Around 10% of patients present with liver metastases, without mesenteric lesions. Spread to extra-abdominal sites can involve the skeleton (spine and orbital framing are predilection sites), the lungs, CNS, mediastinal and peripheral lymph nodes, ovaries, breast and the skin.⁶⁰ A neck lymph gland metastasis can sometimes be the primary clinical sign of a disseminated tumour.

Clinical symptoms

The small-intestinal NETs grow slowly and many patients have experienced long periods of prodromal symptoms before the disease has been clinically recognised.^60,61 Some patients have had symptoms of borborygmi or episodic abdominal pain, others have had unrecognised features of the carcinoid syndrome, with diarrhoea, discrete flush, palpitations or intolerance for specific food or alcohol. Intestinal bleeding is generally rare with small-intestinal NETs due to the moderate size and submucosal location of the primary tumour. Bleeding has been mainly encountered at later stages, with larger, ulcerating primary tumours, or if mesenteric metastases have grown in the intestinal wall.^61,62 Such metastases have a special tendency to grow into the horizontal duodenum and sometimes cause bleeding. In other cases bleeding has occurred as a result of intestinal venous stasis.

Intermittent attacks of abdominal pain may initially occur, and increase in frequency until the patient develops obvious subacute or acute intestinal obstruction requiring surgery. In 30–45% of patients the small-intestinal NETs are thus revealed at operation for intestinal obstruction, where the patients often have been submitted to surgery without awareness of the diagnosis.⁶² In another 50% of patients the diagnosis becomes evident after detection of liver metastases, and some of the patients initially appear with features of the carcinoid syndrome.

Diagnosis

Surgery

Many patients with small-intestinal NETs will be subjected to acute laparotomy due to intestinal obstruction without suspicion of the correct diagnosis. It is important to appreciate then that the NET is common among small-bowel neoplasms, and findings at laparotomy are often typical with a tiny ileal primary tumour, and conspicuously larger mesenteric metastases with marked mesenteric desmoplastic reaction.^{60,61,70–73} The primary tumour and mesenteric metastases should be removed by wedge resection of the mesentery and limited intestinal resection, and lymph node metastases should be cleared as far as possible by dissection around the mesenteric artery and vein and their branches.⁷¹ This procedure is generally indicated even in the presence of liver metastases. If the surgery has been inadequately performed, because the surgeon believed he or she was facing inoperable adenocarcinoma, this will result in the primary tumour and especially the bulk of mesenteric metastases not being removed. Re-operation is then strongly recommended to remove the remaining mesenteric tumour, which may otherwise cause future abdominal complications.^{60,61,70–73}

If grossly radical removal of the primary tumour and mesenteric metastases has been accomplished, small-intestinal NET patients may often remain symptom free for long periods. However, small-intestinal NETs are markedly tenacious and recurrence should be looked out for, as the majority of patients (> 80%) will ultimately develop liver metastases if follow-up is long enough (Fig. 6.5).^60,61,70,73 The small-intestinal NETs are unusually slow-growing tumours, and clinically overt recurrence occurs after a median of 10 years and up to 25 years.^60,73 Earlier diagnosis of such recurrence may be more sensitively based on serum chromogranin A estimates, rather than urinary 5-HIAA measurements.

Many patients with small-intestinal NETs lack acute abdominal symptoms, and instead present with liver metastases and sometimes also features of the carcinoid syndrome at the time of diagnosis. Only a few decades ago, life expectancy was poor in patients with liver metastases and carcinoid syndrome, with an expected median survival of around 2 years, and abdominal surgery was not often considered.¹⁰ Now, symptoms of the carcinoid syndrome may be efficiently controlled by medical treatment with somatostatin analogues and interferon, and these and other new treatment modalities have increased life expectancy and quality of life.^10,60,61,70

Abdominal complications have become of increased concern and have appeared as a principal cause of death in patients with small-intestinal NETs.^60,70 Such threatening complications have widened indications for abdominal surgery in patients undergoing medical treatment for the advanced NETs.

Due to continued growth and increased intestinal entrapment by mesenteric tumour or fibrosis, patients often experience abdominal pain and will require surgery for relief of partial or complete intestinal obstruction.^60,61,70,71 Since incipient intestinal ischaemia may cause similar symptoms of feeding-related crampy abdominal pain, laparotomy may be urgently needed to distinguish these causes. Liberal operative intervention is also indicated because incipient venous ischaemia may contribute adversely to the patient’s condition with diarrhoea and general malaise. Occasional patients present with severe abdominal pain, weight loss, and even malnutrition and cachexia due to the intestinal ischaemia (Fig. 6.6).^{60,61,70–73} Abdominal pain is unlikely to occur due to the carcinoid syndrome, and weight loss and malnutrition are rarely caused merely by a large tumour burden in small-intestinal NET patients. Complications of the mesenteric tumour are evident in a large proportion of patients with small-intestinal NETs subjected to laparotomy, and are important to recognise since these patients may benefit from considerable long-term palliation following surgery.^70–73

The natural course of mesenterico-intestinal disease with small-intestinal NETs can be variable, but surgery at an early stage is a distinct advantage, as it may provide an exceptional chance to remove the mesenteric tumour before more extensive involvement of major mesenteric vessels has occurred.^61,70–73 The authors thus advocate removal of the mesenterico-intestinal tumour as a prophylactic procedure even in asymptomatic patients considered for medical therapy.⁷³ During periods of medical treatment patients are likely to benefit markedly from close cooperation between internists and surgeons, with liberal surgical consultations when abdominal symptoms occur.

Liver metastases

The treatment of liver metastases can use many modalities: medical treatment, surgery, radiofrequency (RF) ablation, liver embolisation, transplantation, radiolabelled octreotide therapy and [¹³¹I]meta- iodobenzylguanidine (¹³¹I-MIBG) therapy.^{10,46,60,61,70–74} An initial period of medical treatment with somatostatin analogues and interferon can help alleviate symptoms and slow disease progression. It also allows some time for observation and makes surgery or ablation of liver disease safer. Liver surgery is more likely to be beneficial in patients with classical small-intestinal NETs of low grade (high differentiation and low proliferation rate demonstrated by Ki67 staining).¹⁰

Prophylaxis against carcinoid crisis

Operation and embolisation in patients with the carcinoid syndrome always entail the risk of inducing a carcinoid crisis, with hyperthermia, shock, arrhythmia, excessive flush or bronchial obstruction.

As prophylaxis to prevent crisis during surgery or intervention, patients with small-intestinal NETs should preferably be pretreated with octreotide (patient’s regular dose or daily 100 μg × 3, s.c.). Adrenergic drugs should generally be avoided if hypotension should occur during surgery.^11,60,96 Patients with foregut NETs and atypical carcinoid syndrome are treated with octreotide, histamine blockade and cortisone, and avoidance of histamine-releasing agents (morphine and tubocurarine). In patients with carcinoid flush syndrome we routinely provide i.v. octreotide (500 μg in 500 mL saline, 50 μg/h) during surgery or embolisation procedures, and the same treatment or increased dose (100 μg/h) is given if carcinoid crisis should occur.^60,96

Medical treatment

Somatostatin analogues (octreotide, lanreotide) have been a breakthrough in the treatment of NETs.^10,11,46 By binding to specific somatostatin receptors (types 2 and 5) the analogues reduce the release of bioactive peptides from tumour cells and may also block peripheral responses of target cells. They may also inhibit tumour growth, induce apoptosis, counteract angiogenesis and have, in randomised evaluation, recently been demonstrated to reduce tumour growth in metastatic small-intestinal NETs.¹⁰⁰

The analogues are usually given in daily doses of 50–150 μg × 3 s.c. Higher doses (> 3000 μg/day) have resulted in slightly greater tumour reduction but otherwise no greater response rate. Tachyphylaxis often occurs after 9–12 months of treatment and may often indicate a requirement for increased dosage. Long-acting formulations (octreotide-LAR, lanreotide-PR, Somatuline Autogel) offering the possibility of easier use by monthly administration have become routine. Side-effects of all analogues include gallstone formation, pancreatic enzyme deficiency and symptoms relating to biliary colic, sometimes necessitating cholecystectomy.

Interferon-α (IFN-α) reduces hormone secretion and stimulates natural killer cells with effects on cell growth in tumours with slow progression.^{10,46,97–99} Clinically, IFN-α administration induces biochemical and subjective responses in about 50% of the patients, with antitumour effects in around 10% and stabilisation of the disease in 35%.^98,99 Recently, a pegylated form has become available (PegIntron®) for subcutaneous administration once a week, and with possible improved tolerance. Combinations of somatostatin analogue and interferon therapy may increase response rate. Interferon is associated with more adverse effects than somatostatin analogues, mainly flu-like symptoms initially, and later on chronic fatigue and sometimes depression. Autoimmune phenomena may be induced, causing thyroid dysfunction by antithyroid antibodies and occasionally other complications. Neutralising interferon antibodies may develop and interfere with the effects.⁴⁶ Some patients have to discontinue treatment, and the rather high risk of side-effects has limited the use of interferon.

Radiotherapy

External radiotherapy is generally not efficient in treating NETs but it can be used for long-term palliation of brain metastases, and especially for alleviation of pain due to bone metastases.¹⁰

Internal or tumour-targeted radiation has been developed during recent years, using ¹³¹I-MIBG and radioactive somatostatin analogues.^101,102 Effects of ¹³¹I-MIBG therapy have been limited, with subjective responses in 30–40% of patients and biochemical responses in less than 10%.¹⁰¹ Predosing with non-labelled MIBG has resulted in prolonged biochemical and clinical responses.

NETs usually express somatostatin receptor subtypes 2 and 5, which become internalised in tumour cells after binding of radiolabelled octreotide.^46,102 New compounds with beta- and gamma-emitting isotopes linked to somatostatin analogues have been developed ([⁹⁰Y-DOTA]octreotide and [¹⁷⁷Lu-DOTA, Tyr³]octreotate), with affinity for different somatostatin receptors and better tumour penetration.^102,103 Some of these compounds have shown promising responses and moderate side-effects.^46,102,103

Survival

Age-adjusted overall 5-year survival for all small-intestinal NETs in Sweden between 1960 and 2000 was 67%, which was similar to the series from the SEER Program of the National Cancer Institute (NCI), 1973–1999.^1,104

Patients with inoperable liver metastases in the Uppsala series had 50% 5-year survival and survival was 42% with inoperable liver and mesenteric lymph node metastases.⁷² Survival was better for younger age groups (< 50 years), and worse for patients with para-aortal lymph node spread and peritoneal carcinomatosis.^72,74 Other negative factors for survival (except for liver metastases and heart disease) have been high 5-HIAA values, old age (> 75 years), tumour discovered during emergency surgery, significant weight loss and presence of extra-abdominal metastases.^{70,72,74,104–106}

Atypical goblet-cell NETs

Adenocarcinoid or goblet-cell NET represents a more malignant variant, with elements of NETs and mucinous adenocarcinomas, the most common origin being in the appendix.107–110 This type has also been named ‘atypical’ or ‘intermediate’ carcinoid. The tumour is more malignant than the classical NET, and resembles classical adenocarcinoma with respect to prognosis and survival. The tumours do not express somatostatin receptors and cannot be visualised by OctreoScan®. Special histological markers may be used to identify the lesions. Although many goblet-cell NETs may be localised, some have aggressive spread in the mesoappendix and intraperitoneally. Treatment for this tumour has mainly included extended ileocolic and mesenteric resection, often performed as re-operation, and additionally chemotherapy.^107–110 The goblet-cell NETs have had unpredictable and generally less favourable survival, with a 60% 10-year survival rate.^107–110 Recently a more aggressive therapy has been proposed, adding cytoreductive surgery and intraperitoneal heated chemotherapy.¹¹¹ The cytoreductive therapy has included omentectomy, splenectomy and peritonectomy.

Presentation

The development of the tumour usually occurs in the sixth decade, about 10 years earlier than non-NET rectal tumours. The majority – up to about 60% – are small, less than 1.0 cm in greatest dimension (Fig. 6.11),^112,113 and may be discovered after presenting symptoms such as perianal pain, pruritus ani or haematochezia leading to endoscopic procedures. However, most patients are asymptomatic and the tumours are found incidentally, which is prognostically beneficial compared with symptomatic presentation. The smaller tumours usually present as submucosal yellowish nodules, and up to 75% may be within reach of digital examination at 8 cm from the anal verge. The findings at digital palpation can be variable and described as firm, smooth or rubbery in consistency. Diagnosis is made after histopathological evaluation of biopsies or after removal of the whole nodule. Patients with tumours < 1 cm exhibit a low risk for metastases (< 2%).^112–115

Patients with larger tumours generally have more symptoms, and those with metastatic disease may present with generalised symptoms such as weight loss and even cachexia. The carcinoid syndrome is extremely rare among these patients and only exceptionally present in cases with liver metastases. Occasional large tumours can be fixed to perirectal tissues and may initially be difficult to distinguish from rectal adenocarcinoma. Previous reports have proposed an increased incidence of concurrent colonic adenocarcinoma.

Tumours exceeding 1.0 cm in greatest dimension are much more prone to dissemination. Thus, patients with tumours between 1.0 and 1.9 cm have an intermediate incidence of metastatic spread (10–15%), while patients with larger tumours (> 2 cm) exhibit a 60–80% incidence of distant metastases. The main sites for tumour spread are regional lymph nodes and the liver, and less commonly lung and bone.¹¹³

Rectal NETs may prognostically and in terms of management be divided according to their size. Patients with tumours < 1 cm seldom demonstrate symptoms, have a favourable outcome, are generally cured by local excision and almost never have metastases. Patients with tumours > 2 cm usually present with symptoms and the majority have metastases to regional lymph nodes, lung or liver. Thus, the smaller (< 1 cm) and the larger (> 2 cm) tumours have a predictable outcome, whereas tumours measuring 1.0–1.9 cm in diameter are unpredictable.^112,113 Although patients with smaller tumours generally may be considered as cured after tumour excision, patients with tumours measuring 1.0–1.9 cm need to be thoroughly examined for the presence of local infiltration and metastatic disease, and should also be closely surveyed. Transrectal endosonography should be used for more precise assessment of tumour extension, possible infiltration in the muscularis propria, and to reveal regional lymph node metastases. CT or MRT can clarify local tumour growth in the pelvis, and also the presence of lymph node and liver metastases. Octreotide scintigraphy (OctreoScan®) is often negative in patients with rectal NETs due to lack of or few somatostatin receptors, but should nevertheless be used since some tumours express these receptors and this may provide effective treatment options.

Diagnosis and immunohistochemistry

The diagnosis is usually made after histopathological examination. Rectal NETs are derived from neuroendocrine enterochromaffin cells surrounded by a dense fibrous stroma.112–115 The most sensitive histological tumour markers are neuron-specific enolase (NSE), being positive in 87%, and prostate-specific acid phosphatase (in 80–100%), which makes differentiation from prostatic carcinoma difficult.¹¹⁶ A limited fraction of cells generally are positive for chromogranin A and may also stain for serotonin. Several studies have concluded that there is a correlation between Ki67 expression, tumour size and risk of metastases, although the Ki67 expression generally was low.¹¹⁷ Classical tumour markers like CA19-9, CA50 and α-fetoprotein are poorly expressed or absent, while carcinoembryonic antigen (CEA) has been demonstated in up to 25% of cells. The CEA expression is possibly related to the occasional rectal NET that exhibits histopathological signs of both adenocarcinoma and NET, referred to as adenocarcinoids. Rectal NETs generally show multihormonal expression, in which glucagon, somatostatin, pancreatic polypeptide, substance P and β-endorphins may be detected. The immunoreactivity for the different markers is generally unevenly distributed in groups of cells exhibiting focal and patchy distribution. This may indicate development of multiclonal lesions, where additional genetic derangements are prone to occur, causing more aggressive disease in fractions of tumour cells as well as in individual patients.

The tumours measuring < 1 cm in diameter are only occasionally locally infiltrative, whereas tumours > 2 cm almost invariably show signs of atypical histopathology, including infiltration of muscularis propria, invasion of lymphovascular and perineural structures, and a high number of mitotic figures. These tumours are frequently associated with distant metastases, local invasion and reduced survival.

It is rare that release of measurable peptides occurs in the circulation, implying that s-chromogranin A or urinary 5-HIAA are less useful diagnostic or surveillance tools for rectal NETs.

Treatment

Our experience of individual patients with large tumours and distant metastases supports this view. Thus, we suggest surgery in these patients, often in combination with preoperative downstaging by chemotherapy, or, in cases with expression of somatostatin receptors documented by OctreoScan®, treatment with ¹⁷⁷Lu-labelled somatostatin analogues, which can be highly effective in some patients.¹¹⁹ However, patients with atypical histopathological features are less likely to benefit from the aggressive surgical treatment.

IFN-α and paclitaxel have, in some patients, resulted in reduced disease progression and also regression of metastases. Occasional patients with liver metastases may benefit from hepatic artery chemoembolisation. In carefully selected cases liver resection may be indicated, with the understanding, however, that these patients generally have a poor outcome and short survival.

Outcome

Prediction of outcome in rectal NETs should rely on several factors such as tumour size, histology (typical or atypical features), microinvasiveness as well as presence of symptoms at presentation, but no study has yet evaluated all of these factors systematically. Nevertheless, tumour size and microinvasiveness have generally been accepted as the clinically most important factors.¹¹⁹ Overall 5-year survival for patients with rectal NETs is about 88%, ranging from 20–30% for patients with distant metastases to 91% for patients with localised disease.^1,113 Patients with deeply invasive tumours had a median survival of 6–7 months in one study. Patients with an NET confined to the submucosa and smaller than 1 cm will rarely die from the disease.^112–115 Mean survival after discovery of recurrence of rectal NETs has been reported as 4–5 months.

Recommendations

Patients with rectal NETs measuring 1.0–1.9 cm and those > 2 cm should be thoroughly investigated (MRT, CT, transrectal endosonography) for evidence of spread of disease, e.g. local or distant metastases. These patients should generally undergo surgery with the aim of achieving total tumour clearance, and the specimens should be thoroughly investigated for signs of atypical histopathology. The larger the tumour, the higher the risk of metastatic disease. There are no studies demonstrating benefit of preoperative medical or irradiation treatment. Patients with rectal NET > 1 cm, including those with infiltrative or disseminated disease, need follow-up, and if not removed may require palliation against pelvic pain. Selected individuals may be offered more aggressive medical (and surgical) treatment for distant metastases.

1. Modlin, I.M., Lye, K.D., Kidd, M., A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003; 97:934–959. 12569593 Excellent and valuable presentation of epidemiology and natural history in a comprehensive series of all types of carcinoid tumours.

2. Lawrence, B., Gustafsson, B.I., Kidd, M., et al, The epidemiology of gastroenteropancreatic neuroendocrine tumours. Endocrinol Metab Clin North Am 2011; 40:1–18 vii. 21349409 Presents recent epidemiology data.

3. Schimmack, S., Svedja, B., Lawrence, B., et al, The diversity and commonalities of gastroenteropancreatic neuroendocrine tumours. Langenbecks Arch Surg 2011; 396:273–398. 21274559

4. Berge, T., Linell, F., Carcinoid tumours. Frequency in a defined population during a 12-year period. Acta Pathol Microbiol Scand [A] 1976; 84:322–330. 961424

5. Rindi, G., Klöppel, G., Ahlman, H., et al, TNM staging of foregut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2006; 449:395–401. 1940781

6. Rindi, G., Klöppel, G., Couvelard, A., et al, TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2007; 451:757–762. 17674042

7. Bosman F., Carneiro F., Hruban R., et al, eds. WHO classification of tumours of the digestive system. Lyon, France: IARC Press, 2010. Updated WHO classification.

8. Klimstra, D.S., Modlin, I.R., Coppola, D., et al, The pathologic classification of neuroendocrine tumors. A review of nomenclature, grading and staging systems. Pancreas 2010; 39:707–712. 20664470

9. 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. 10029611

10. Öberg, K., Carcinoid tumors: current concepts in diagnosis and treatment. Oncologist 1998; 3:339–345. 10388123

11. Modlin, I.M., Kidd, M., Latich, I., et al, Current status of gastrointestinal carcinoids. Gastroenterology 2005; 128:1717–1751. 15887161

12. Rindi, G., Paolotti, D., Fiocca, R., et al, Vesicular monoamine transporter 2 as a marker of gastric enterochromaffin-like cell tumors. Virchows Arch 2000; 436:217–223. 10782879

13. Solcia, E., Fiocca, R., Villani, L., et al, Morphology and pathogenesis of endocrine hyperplasias, precarcinoid lesions, and carcinoids arising in chronic atrophic gastritis. Scand J Gastroenterol. 1991;180(Suppl.):146–159. 2042031

14. Solcia, E., Fiocca, R., Villani, L., et al, Hyperplastic, dysplastic, and neoplastic enterochromaffin-like-cell proliferations of the gastric mucosa. Classification and histogenesis. Am J Surg Pathol. 1995;19(Suppl. 1):S1–S7. 7762735

15. Rindi, G., Bordi, C., Rappel, S., et al, Gastric carcinoids and neuroendocrine carcinomas: pathogenesis, pathology, and behavior. World J Surg 1996; 20:168–172. 8661813 Important article with valuable information on epidemiology and prognosis for gastric neuroendocrine tumours.

16. Modlin, I.M., Kidd, M., Lye, K.D., Biology and management of gastric carcinoid tumours: a review. Eur J Surg 2002; 168:669–683. 15362575 Excellent review article about gastric carcinoids, in which the authors describe cellular background and important clinical features of the different gastric carcinoids.

17. Åkerström, G., Management of carcinoid tumors of the stomach, duodenum, and pancreas. World J Surg 1996; 20:173–182. 8661814

18. Borch, K., Ahren, B., Ahlman, H., et al, Gastric carcinoids: biologic behavior and prognosis after differentiated treatment in relation to type. Ann Surg 2005; 242:64–73. 15973103

19. Borch, K., Atrophic gastritis and gastric carcinoid tumours. Ann Med 1989; 21:291–297. 2789800

20. Lehy, T., Roucayrol, A.M., Mignon, M., Histomorphological characteristics of gastric mucosa in patients with Zollinger–Ellison syndrome or autoimmune gastric atrophy: role of gastrin and atrophying gastritis. Microsc Res Tech 2000; 48:327–338. 10738314

21. Jensen, R.T., Management of the Zollinger–Ellison syndrome in patients with multiple endocrine neoplasia type 1. J Intern Med 1998; 243:477–488. 9681846

22. Chandrasekharappa, S.C., Guru, S.C., Manickam, P., et al, Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 1997; 276:404–407. 9103196

23. Debelenko, L.V., Emmert-Buck, M.R., Zhuang, Z., et al, The multiple endocrine neoplasia type I gene locus is involved in the pathogenesis of type II gastric carcinoids. Gastroenterology 1997; 113:773–781. 9287968

24. Bordi, C., Falchetti, A., Azzoni, C., et al, Aggressive forms of gastric neuroendocrine tumors in multiple endocrine neoplasia type I. Am J Surg Pathol 1997; 21:1075–1082. 9298884

25. Sjöblom, S.M., Sipponen, P., Järvinen, H., Gastroscopic follow up of pernicious anaemia patients. Gut 1993; 34:28–32. 8432447

26. Gough, D.B., Thompson, G.B., Crotty, T.B., et al, Diverse clinical and pathologic features of gastric carcinoid and the relevance of hypergastrinemia. World J Surg 1994; 18:473–479. 7725731

27. Wilander, E., El-Salhy, M., Pitkänen, P., Histopathology of gastric carcinoids: a survey of 42 cases. Histopathology 1984; 8:183–193. 6724533

28. Matsui, K., Jin, X.M., Kitagawa, M., et al, Clinicopathologic features of neuroendocrine carcinomas of the stomach: appraisal of small cell and large cell variants. Arch Pathol Lab Med 1998; 122:1010–1017. 9822131

29. Kim, K.M., Kim, M.J., Cho, B.K., et al, Genetic evidence for the multi-step progression of mixed glandular–neuroendocrine gastric carcinomas. Virchows Arch 2002; 440:85–93. 11942581

30. Ruszniewski, P., Delle, Fave G., et al, Well-differentiated gastric tumors/carcinomas. Neuroendocrinology. 2006;84(3):158–164. 17312375 Recent ENET guidelines on gastric NETs.

31. Kulke, M.H., Anthony, L.B., Bushnell, D.L., et al, NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas. Pancreas. 2010;39(6):735–752. 20664472

32. Yoshikane, H., Tsukamoto, Y., Niwa, Y., et al, Carcinoid tumors of the gastrointestinal tract: evaluation with endoscopic ultrasonography. Gastrointest Endosc 1993; 39:375–383. 8514069

33. Granberg, D., Wilander, E., Stridsberg, M., et al, Clinical symptoms, hormone profiles, treatment, and prognosis in patients with gastric carcinoids. Gut 1998; 43:223–228. 10189848

34. Krenning, E.P., Kooij, P.P., Pauwels, S., et al, Somatostatin receptor: scintigraphy and radionuclide therapy. Digestion. 1996;57(Suppl. 1):57–61. 8813472

35. Borch, K., Renvall, H., Kullman, E., et al, Gastric carcinoid associated with the syndrome of hyper-gastrinemic atrophic gastritis. A prospective analysis of 11 cases. Am J Surg Pathol 1987; 11:435–444. 3592060

36. Papa, A., Cammarota, G., Tursi, A., et al, Histologic types and surveillance of gastric polyps: a seven year clinico-pathological study. Hepatogastroenterology 1998; 45:579–582. 9638455

37. Hopper, A.D., Bourke, M.J., Hougan, L.F., et al, En-bloc resection of multiple type 1 gastric carcinoids by endoscopic multi-band mucosectomy. J Gastroenterol Hepatol 2009; 24:1516–1521. 19743997

38. Ichikawa, J., Tanabe, S., Koizumi, W., et al, Endoscopic mucosal resection in the management of gastric carcinoid tumors. Endoscopy 2003; 35:203–206. 12584637

39. Delle Fave, G., Capurso, G., Milione, M., et al, Endocrine tumours of the stomach. Best Pract Res Clin Gastroenterol 2005; 19:659–673. 16253892

40. Eckhauser, F.E., Llooyd, R.V., Thompson, N.W., et al, Antrectomy for multicentric, argyrophil gastric carcinoids: a preliminary report. Surgery 1988; 104:1046–1053. 3194832

41. Hirschowitz, B.I., Griffith, J., Pellegrin, D., et al, Rapid regression of enterochromaffinlike cell gastric carcinoids in pernicious anemia after antrectomy. Gastroenterology 1992; 102:1409–1418. 1551550

42. Ahlman, H., Kölby, L., Lundell, L., et al, Clinical management of gastric carcinoid tumors. Digestion. 1994;55(Suppl. 3):77–85. 7698542

43. Åkerström, G., Hessman, O., Skogseid, B., Timing and extent of surgery in symptomatic and asymptomatic neuroendocrine tumors of the pancreas in MEN 1. Langenbecks Arch Surg 2002; 386:558–569. 11914931

44. Richards, M.L., Gauger, P., Thompson, N.W., et al, Regression of type II gastric carcinoid in multiple endocrine neoplasia type 1 patients with Zollinger–Ellison syndrome after surgical excision of all gastrinomas. World J Surg 2004; 28:652–658. 15383867

45. Shinohara, T., Ohyama, S., Nagano, H., et al, Minute gastric carcinoid tumor with regional lymph node metastasis. Gastric Cancer 2003; 6:262–266. 14716522

46. Öberg, K., Ahlman, H. Medical management of neuroendocrine gastrointestinal tumors. In: Schartz A.E., Persemlidis D., Gagner M., eds. Endocrine surgery. New York: Marcel Dekker; 2004:685–696.

47. Burke, A.P., Sobin, L.H., Federspiel, B.H., et al, Carcinoid tumors of the duodenum. A clinicopathologic study of 99 cases. Arch Pathol Lab Med 1990; 114:700–704. 1694655

48. Thompson, N.W., Vinik, A.I., Eckhauser, F.E., Microgastrinomas of the duodenum: a cause of failed operations for the Zollinger–Ellison syndrome. Ann Surg 1989; 209:396–404. 2930285

49. Pipeleers-Marichal, M., Somers, G., Willems, G., et al, Gastrinomas in the duodenums of patients with multiple endocrine neoplasia type 1 and the Zollinger–Ellison syndrome. N Engl J Med 1990; 322:723–727. 1968616

50. Modlin, I.M., Lawton, G.P., Duodenal gastrinoma: the solution to the pancreatic paradox. J Clin Gastroenterol 1994; 19:184–188. 7806825

51. Cisco, R.M., Norton, J.A., Surgery for gastrinoma. Adv Surg 2007; 41:165–176. 17972563

52. Thompson, N.W., Bondeson, A.G., Bondeson, L., et al, The surgical management of gastrinoma in MEN I syndrome patients. Surgery 1989; 106:1081–1085. 2573955

53. Pipeleers-Marichal, M., Donow, C., Heitz, P.U., et al, Pathologic aspects of gastrinomas in patients with Zollinger–Ellison syndrome with and without multiple endocrine neoplasia type 1. World J Surg 1993; 17:481–488. 8103250 Important article emphasing high incidence of tiny duodenal gastrinomas as a cause of sporadic and MEN1-related Zollinger–Ellison syndrome.

54. Wheeler, M.H., Curley, I.R., Williams, E.D., The association of neurofibromatosis, pheochromocytoma, and somatostatin-rich duodenal carcinoid tumor. Surgery 1986; 100:1163–1169. 2878497

55. Ricci, J.L., Carcinoid of the ampulla of Vater: local resection or pancreaticoduodenectomy. Cancer 1993; 71:686–690. 8094317

56. Kheir, S.M., Helpern, N.B., Paraganglioma of the duodenum in association with congenital neurofibromatosis: possible relationship. Cancer 1984; 53:2491–2496. 6201261

57. Burke, A.P., Federspiel, B.H., Sobin, L.H., et al, Carcinoids of the duodenum: a histologic and immunohistochemical study of 65 tumors. Am J Surg Pathol 1989; 13:828–837. 2476943

58. Zyromski, N.J., Kendrick, M.L., Nagomey, D.M., et al, Duodenal carcinoid tumors: how aggressive should we be? J Gastrointest Surg 2001; 5:588–593. 12086896

59. Wilson, R.W., Gal, A.A., Cohen, C., et al, Serotonin immunoreactivity in pancreatic endocrine neoplasms (carcinoid tumors). Mod Pathol 1991; 4:727–732. 1788265

60. Åkerström, G., Hellman, P., Öhrvall, U. Midgut and hindgut carcinoid tumors. In: Doherty G.M., Skogseid B., eds. Surgical endocrinology. Philadelphia: Lippincott Williams & Wilkins; 2001:447–459.

61. Makridis, C., Öberg, K., Juhlin, C., et al, Surgical treatment of midgut carcinoid tumors. World J Surg 1990; 14:377–385. 2368441

62. Funa, K., Papanicolaou, V., Juhlin, C., et al, Expression of platelet-derived growth factor β-receptors on stromal tissue cells in human carcinoid tumors. Cancer Res 1990; 50:748–753. 2153446

63. Eckhauser, F.E., Argenta, L.C., Strodel, W.E., et al, Mesenteric angiopathy, intestinal gangrene and midgut carcinoids. Surgery 1981; 90:720–728. 7281010

64. Matuchansky, C., Launay, J.M., Serotonin, catecholamines, and spontaneous midgut carcinoid flush: plasma studies from flushing and nonflushing sites. Gastroenterology 1995; 108:743–751. 7533112

65. Knowlessar, O.D., Law, D.H., Sleisinger, M.H., Malabsorption syndrome associated with metastatic carcinoid tumor. Am J Med 1959; 27:673–677. 14411502

66. Westberg, G., Wängberg, B., Ahlman, H., et al, Prediction of prognosis by echocardiography in patients with midgut carcinoid syndrome. Br J Surg 2001; 88:865–872. 11412260

67. Lundin, L., Hansson, H.E., Landelius, J., et al, Surgical treatment of carcinoid heart disease. J Thorac Cardiovasc Surg 1990; 100:552–561. 2145480

68. Örlefors, H., Sundin, A., Ahlström, H., et al, Positron emission tomography with 5-hydroxytryptophan in neuroendocrine tumors. J Clin Oncol 1998; 16:2534–2541. 9667275

69. Frilling, A., Sotiropoulos, G.C., Radtke, A., et al, The impact of ⁶⁸Ga-DOTATOC positron emission tomography/computed tomography on the multimodal management of patients with neuroendocrine tumors. Ann Surg 2010; 252:850–856. 21037441

70. 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. 9426422 Survival and quality-of-life analyses in patients with advanced midgut carcinoids.

71. Öhrvall, U., Eriksson, B., Juhlin, C., et al, Method of dissection of mesenteric metastases in mid-gut carcinoid tumors. World J Surg 2000; 24:1402–1408. 11038214 Emphasises the importance of surgery for removal of mesenteric tumours in patients with midgut carcinoids. Describes technical aspects of a surgical procedure with low rate of complications.

72. Hellman, P., Lundström, T., Öhrvall, U., et al, Effect of surgery on the outcome of midgut carcinoid disease with lymph node and liver metastases. World J Surg 2002; 26:991–997. 12016480 Demonstrates clear effect and benefit of surgery of primary tumour as well as carcinoid metastases.

73. Makridis, C., Rastad, J., Öberg, K., et al, Progression of metastases and symptom improvement from laparotomy in midgut carcinoid tumors. World J Surg 1996; 20:900–907. 8678969

74. Norlén, O., Stålberg, P., Öberg, K., et al, Long-term results of surgery for small intestinal neuroendocrine tumors at a tertiary referral centre. World J Surg. 2012;36(6):1419–1431. 21984144 Reports large series of surgically treated small-intestinal NETs at referral centre.

75. McEntee, G.P., Nagorney, D.M., Kvols, C.K., et al, Cytoreductive hepatic surgery for neuroendocrine tumors. Surgery 1990; 108:1091–1096. 1701060

76. Wängberg, B., Westberg, G., Tylén, U., et al, Survival of patients with disseminated midgut carcinoid tumors after aggressive tumor reduction. World J Surg 1996; 20:892–899. 8678968 Provides survival data substantiating the importance of surgical resection of liver metastases in patients with midgut carcinoids.

77. Norton, J.A., Warren, R.S., Kelly, M.G., et al, Aggressive surgery for metastatic liver neuroendocrine tumors. Surgery 2003; 134:1057–1065. 14668741

78. Touzios, J.G., Kiely, J.M., Pitt, S.C., et al, Neuroendocrine hepatic metastases. Does aggressive management improve survival? Ann Surg 2005; 241:776–785. 15849513

79. Que, F.G., Sarmiento, J.M., Nagorney, D.M., Hepatic surgery for metastatic gastrointestinal endocrine tumors. Adv Exp Med Biol 2006; 574:43–56. 16836240

80. Steinmuller, T., Kianmanesh, R., Falconi, M., et al, Consensus guidelines for the management of patients with liver metastases from digestive (neuro) endocrine tumors: foregut, midgut, hindgut, and unknown primary. Neuroendocrinology 2008; 87:47–62. 18097131

81. Siperstein, A.E., Rogers, S.J., Hansen, P.D., et al, Laparoscopic thermal ablation of hepatic neuroendocrine tumor metastases. Surgery 1997; 122:1147–1155. 9426432

82. Hellman, P., Ladjevardi, S., Skogseid, B., et al, Radiofrequency tissue ablation using cooled tip for liver metastases of endocrine tumors. World J Surg 2002; 26:1052–1056. 12016482 Demonstrates results of RF for treatment of NET liver metastases.

83. Mazzaglia, P.J., Berber, E., Milas, M., et al, Laparoscopic radiofrequency ablation of neuroendocrine liver metastases: a 10-year experience evaluating predictors of survival. Surgery 2007; 142:10–19. 17629995

84. Eriksson, J., Stålberg, P., Eriksson, B., et al, Surgery and radiofrequency ablation for treatment of liver metastases from midgut and foregut carcinoids and endocrine pancreatic tumors. World J Surg 2008; 32:930–938. 18324347

85. Schell, S., Ramsay Camp, E., Caridi, J.G., et al, Hepatic artery embolization for control of symptoms, octreotide requirements, and tumor progression in metastatic carcinoid tumors. J Gastrointest Surg 2002; 6:664–670. 12399054

86. Strosberg, R.J., Choi, J., Cantor, A.B., et al, Selective hepatic artery embolization for treatment of patients with metastatic carcinoid and pancreatic endocrine tumors. Cancer Control 2006; 13:72–78. 16508629

87. Bloomston, M., Al-Saif, O., Klemanski, D., et al, Hepatic artery chemoembolization in 122 patients with metastatic carcinoid tumor: lessons learned. J Gastrointest Surg 2007; 11:264–271. 17458596

88. Granberg, D., Eriksson, L.G., Welin, S., et al, Liver embolization with trisacryl gelatin microspheres (embolosphere) in patients with neuroendocrine tumors. Acta Radiol 2007; 48:180–185. 17354139

89. Lewis, M.A., Hubbard, J., Multimodal liver-directed management of neuroendocrine hepatic metastases. Review article. Int J Hepatol Volume 2011; article ID 452343. Epub ahead of print. 22121491

90. Lehnert, T., Liver transplantation for metastatic neuroendocrine carcinoma: an analysis of 103 patients. Transplantation 1998; 66:1307–1312. 9846513

91. Le Treut, Y.P., Delpero, J.R., Dousset, B., et al, Results of liver transplantation in the treatment of metastatic neuroendocrine tumors. A 31-case French multicentric report. Ann Surg 1997; 225:355–364. 9114793

92. Pascher, A., Klupp, J., Neuhaus, P., Transplantation in the management of metastatic endocrine tumors. Best Pract Res Clin Gastroenterol 2005; 19:637–648. 16183532

93. van Vilsteren, F.G., Baskin-Bey, E.S., Nagorney, D.M., et al, Liver transplantation for gastroenteropancreatic neuroendocrine cancers: defining selection criteria to improve survival. Liver Transpl 2006; 12:448–456. 16498656

94. Olausson, M., Friman, S., Herlenius, G., et al, Orthotopic liver or multivisceral transplantation as treatment of metastatic neuroendocrine tumors. Liver Transpl 2007; 13:327–333. 17318853

95. Rosenau, J., Bahr, M.J., von Wasielewski, R., et al, Ki67, E-cadherin, and p53 as prognostic indicators of long-term outcome after liver transplantation for metastatic neuroendocrine tumors. Transplantation 2002; 73:386–394. 11884935

96. Åkerström, G., Falconi, M., Kianmanesh, R., et al, ENETS Consensus guidelines for the standards of care in neuroendocrine tumors: pre- and perioperative therapy in patients with neuroendocrine tumors. Neuroendocrinology 2009; 90:203–208. 19713712

97. Öberg, K., Funa, K., Alm, G., Effects of leukocyte interferon on clinical symptoms and hormone levels in patients with mid-gut carcinoid tumors and carcinoid syndrome. N Engl J Med 1983; 309:129–133. 6191217

98. Öberg, K., Eriksson, B., Janson, E.T., The clinical use of interferons in the management of neuroendocrine gastroenteropancreatic tumors. Ann N Y Acad Sci 1994; 733:471–478. 7978897

99. Öberg, K., Carcinoid tumors: molecular genetics, tumor biology, and update of diagnosis and treatment. Curr Opin Oncol 2002; 14:38–45. 11790979

100. Rinke, A., Muller, H.H., Schade-Brittinger, C., et al, Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotideLAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID study group. J Clin Oncol 2009; 27:4656–4663. 19704057

101. Taal, B.G., Zuetenhorst, H., Valdes Olmos, R.A., et al, [¹³¹I]MIBG radionuclide therapy in carcinoid syndrome. Eur J Surg Oncol 2002; 28:243. 11944956

102. Forrer, F., Valkema, R., Kvekkebom, D.J., et al, Peptide receptor radionuclide therapy. Best Pract Res Clin Endocrinol Metab 2007; 21:111–129. 17382268

103. Kvekkeboom, D.J., Kam, B.L., van Essen, M., et al, Treatment with the radiolabeled somatostatin analog [¹⁷⁷Lu-DOTA 0, Tyr 3]octreotate: toxicity, efficacy, and survival. J Clin Oncol 2008; 26:2124–2130. 18445841

104. Zar, N., Garmo, H., Holmberg, L., et al, Long-term survival in small intestinal carcinoid. World J Surg 2004; 28:1163–1168. 15490058

105. de Vries, H., Verschueren, R.C., Willemse, P.H., et al, Diagnostic, surgical and medical aspects of the midgut carcinoids. Cancer Treat Rev 2002; 28:11–25. 12027412

106. Musunuru, S., Chen, H., Rajpal, S., et al, Metastatic neuroendocrine hepatic tumors: resection improves survival. Arch Surg 2006; 141:1000–1004. 17043278

107. Goede, A.C., Caplin, M.E., Winslet, M.C., Carcinoid tumour of the appendix. Br J Surg 2003; 90:1317–1322. 14598408 Succinct and comprehensive review on appendiceal carcinoids.

108. Plöckinger, U., Couvelard, A., Falconi, M., et al, Consensus guidelines for the management of patients with digestive neuroendocrine tumours: well-differentiated tumour/carcinoma of the appendix and goblet cell carcinoma. Neuroendocrinology 2008; 87:20–30. 17934252

109. Donnel, M.E., Carson, J., Garstin, W.I.H., Surgical treatment of malignant carcinoids of the appendix. Int J Clin Pract 2007; 61:431–437. 16911574

110. Bucher, P., Gervaz, P., Ris, F., et al, Surgical treatment of appendiceal adenocarcinoid (goblet cell carcinoid). World J Surg 2005; 29:1436–1439. 16136284

111. Sugarbaker, P.H., Peritonectomy procedures. Surg Oncol Clin N Am 2003; 12:703–727. 14567026

112. Ramage, J.K., Goretzki, P.E., Manfredi, R., et al, Consensus guidelines for the management of patients with digestive neuroendocrine tumours: well-differentiated colon and rectum tumour/ carcinoma. Neuroendocrinology 2008; 87:31–39. 18097130 ENETS guidelines for management of colorectal NETs.

113. Vogelsang, H., Siewert, J.R., Endocrine tumours of the hindgut. Best Pract Res Clin Gastroenterol. 2005;19(5):739–751. 16253898

114. Kang, H., O’Connell, J.B., Leonard, M.J., et al, Rare tumors of the colon and rectum: a national review. Int J Colorectal Dis 2007; 22:183–189. 16845516

115. Naunheim, K.S., Zeitels, J., Kaplan, L.E., et al, Rectal carcinoid tumors – treatment and prognosis. Surgery 1983; 94:670–676. 6623366

116. Kimura, N., Sasano, N., Prostate-specific acid phosphatase in carcinoid tumors. Virchows Arch 1986; 410:247–251. 3026083

117. Hotta, K., Shimoda, T., Nakanishi, Y., et al, Usefulness of Ki-67 for predicting the metastastic potential of rectal carcinoids. Pathol Int 2006; 56:591–596. 16984615

118. Maeda, K., Maruta, M., Utsumi, T., et al, Minimally invasive surgery for carcinoid tumors in the rectum. Biomed Pharmacother. 2002;56(Suppl. 1):222s–2226. 12487287

119. Hillman, N., Herranz, L., Alvarez, C., et al, Efficacy of octreotide in the regression of a metastatic carcinoid tumour despite negative imaging with In-111-pentetreotide (Octreoscan). Exp Clin Endocrinol Diabetes 1998; 106:226–230. 9710364