Gastrointestinal neuroendocrine tumours
Introduction
In 1907 Oberndorfer first used the name carcinoid to describe rare ileal tumours with less malignant behaviour than common large bowel carcinomas. Subsequently it became a common name for tumours derived from a widely distributed neuroendocrine cell system, and the carcinoids were classified according to embryological origin into foregut carcinoids (lungs, thymus, stomach, duodenum, pancreas), midgut carcinoids (small bowel to proximal colon) and hindgut carcinoids (distal colon and rectum). The new WHO classification from 2010 introduced the term neuroendocrine tumours (NETs) instead of carcinoid. NETs of the gastrointestinal tract (GEP-NETs) are most common (∼ 60%), followed by NETs of the bronchopulmonary system, whereas other locations (ovaries, testes, hepatobiliary system, among others) have been less frequent (Table 6.1).1 GEP-NETs are relatively rare, but had increased in incidence to 6.2 per 100 000 in 2005.2 Since GEP-NETs are overall indolent, their prevalence is high, making them the second most common gastrointestinal (GI) cancer after colon cancer and more prevalent than pancreatic, gastric, oesophageal or hepatic cancer.3
Table 6.1
| Site | Occurrence (%) |
| Extragastrointestinal (lung, thymic, ovary, uterus) |
∼ 30 |
| Oesophagus | < 1 |
| Stomach | 4–8 |
| Duodenum/pancreas | < 2 |
| Small intestine | 25–30 |
| Appendix | 6 |
| Colon | 10 |
| Rectum | 15 |
Many small-intestinal NETs may be clinically silent and subclinical tumours have been detected at autopsy with an incidence of 8%.4 Appendiceal NETs have been commonly found in autopsy studies and previous clinical series, although recent reports indicate an increased proportion of small-intestinal, pulmonary, gastric and rectal NETs, mainly due to increased awareness and improved detection.1,2
The recent WHO classification divides NETs in stages according to proliferation rates determined by Ki67/Mib-1 antibody staining (against proliferation antigen) and mitotic index (number of mitoses per 2 mm2 or 10 high-power fields) (Box 6.1).5–9 Grade 1 tumours have a low rate of mitosis and low proliferation rate, Ki67 index ≤ 3%, Grade 2 tumours have Ki67 index 3–20% and Grade 3 tumours Ki67 index > 20%.5–9 The most poorly differentiated grade 3 tumours, neuroendocrine carcinoma (NEC), have increased rates of mitoses and higher proliferation index of ≥ 20–40%. The Ki67 proliferation index has become of increased importance in clinical planning. Extensive surgery is more likely to be beneficial for differentiated tumours with low proliferation, in contrast to chemotherapy, which generally has little effect in low proliferating, typicallly small-intestinal NETs.
Chromogranin A and synaptophysin immunostains, which identify proteins of neurosecretory granules, are commonly used to identify NETs. Antibodies against cytosolic markers – neuron-specific enolase (NSE) and PGP9.5 – have also been used for identification of certain tumours, but have generally not been as specific.10 For poorly differentiated lesions chromogranin staining may be variable and involve only subsets of cells. Synaptophysin reactivity alone, in the absence of chromogranin staining, may indicate an exocrine tumour with endocrine differentiation, or a so-called mixed exocrine–endocrine carcinoma. Dominant secretion (e.g. serotonin, histamine, gastrin, somatostatin) may also be detected in NETs, and occasionally ectopic hormone production is seen, such as adrenocorticotropic hormone (ACTH) and corticotropin-releasing factor (CRF). The latter two sometimes cause an ectopic Cushing’s syndrome in association with NETs (Table 6.2).10
Table 6.2
Classification of NETs, hormone production and syndromes7
*ACTH, adrenocorticotropic hormone; ADH, antidiuretic hormone (vasopressin); CRF, corticotropin-releasing factor; GRH, growth hormone; hCG, human choriogonadotropin (α/β subunits); NKA, neurokinin A; PP, pancreatic polypeptide; PYY, peptide YY.
Oesophageal NETs
Oesophageal NETs are exceedingly rare, and occur with male predominance at an age of around 60 years.11 Most tumours are found in the lower third of the oesophagus or in the gastro-oesophageal junction. Symptoms are non-specific and similar to adenocarcinoma or squamous cell carcinoma, and patients rarely exhibit a carcinoid syndrome. Lymph node metastases have been present at diagnosis in 50% of patients; survival correlates with stage of the disease and overall is poor.
Gastric NETs
Gastric NETs are rare tumours, constituting less than 1% of gastric neoplasms and approximately 8% of all GEP-NETs (Table 6.1).1,11 Most of these tumours are derived from enterochromaffin-like (ECL) cells of the gastric fundus and corpus. The tumours are immunoreactive to chromogranin A, synaptophysin and histamine, and can be identified with the specific marker vesicular monoamine transporter isoform 2 (VMAT2).12 The majority of gastric NETs occur secondary to hypergastrinaemia in patients with chronic atrophic gastritis (CAG) (type 1 gastric NETs). These NETs are typically multicentric and develop concomitant with ECL cell hyperplasia in the fundus and corpus, or occasionally in the transitional zone to the antrum.13 Similar non-antral and multicentric NETs and ECL cell hyperplasia have less frequently been diagnosed in patients with hypergastrinaemia and multiple endocrine neoplasia type 1 (MEN1)-related Zollinger–Ellison syndrome (ZES) (type 2 gastric NETs). Both type 1 and 2 gastric NETs develop from ECL cell hyperplasia in a stepwise progression through dysplasia to formation of carcinoid NETs.13–15
The incidence of gastric NETs has increased, due to more frequent gastroscopic examinations, such as during population screening for gastric cancer, or when screening studies have been performed in patients with atrophic gastritis or pernicious anaemia.13
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
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.
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.
Gastrinoma
Tumours with sparse staining for gastrin may occur in association with chronic atrophic gastritis. Tumours with intense positive staining for gastrin are rare in the stomach, and are more commonly located in the prepyloric mucosa close to the duodenum. Few gastric NETs cause hypergastrinaemia and peptic ulcer disease, but they still represent an exceptional but possible origin of gastrin excess and ZES.17 Rare tumours may present with ectopic Cushing’s syndrome due to ACTH secretion.
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
Diagnosis
Diagnosis of CAG type 1 NETs is based on demonstration of high levels of serum gastrin, lack of gastric acid secretion and demonstration of atrophy of the oxyntic mucosa, with concomitant ECL cell hyperplasia in mucosal biopsies from the fundus (Table 6.3). The serum levels of gastrin are also high in patients with MEN1 gastrinomas, although these patients have contrasting high gastric acidity.
Thorough gastroscopic examination should be performed to evaluate multiplicity and size of the gastric NETs. Tumour biopsies should be stained with specific endocrine tumour markers and proliferation markers (chromogranin A, Ki67 staining), and should carefully investigate infiltrative depth and possible vascular invasion. In addition, biopsy samples should be taken from antrum (two biopsies) and fundus (four biopsies) to reveal concomitant ECL cell hyperplasia or dysplasia, the presence of atrophic gastritis, or the contrasting increased oxyntic mucosa thickness of rare MEN1/ZES (Table 6.3).30,31 Multiple NET polyps in the gastric fundus in an elderly individual are most likely to represent CAG-associated NETs, since MEN1-associated NETs are rare. A larger, solitary tumour is more likely to be sporadic (Fig. 6.1), and the largest ulcerating and most prominent lesions may be poorly differentiated. Endoscopic ultrasound (EUS) should be added to the gastroscopic examination in type 1 and 2 lesions of size > 1 cm and all type 3 lesions to give information about infiltrative depth.30,32 EUS may also reveal associated lesions in the pancreas or duodenum in MEN1 patients, and possibly also show metastases to regional lymph nodes or the liver.32
Biochemical screening for other MEN1 endocrinopathies should include analysis of serum calcium and parathyroid hormone, pituitary-related hormones such as growth hormone, prolactin and insulin-like growth factor 1 (IGF-1), and pancreatic hormones (Box 6.2). For cases with the atypical carcinoid syndrome, screening should include urinary analysis of the histamine metabolite MelmAA.13 Serum values of chromogranin A are generally raised in patients with CAG and ECL cell hyperplasia. These values are also the most important tumour markers, and since they tend to reflect the tumour load, they are often used to monitor patients undergoing treatment for advanced gastric NETs.33
Computed tomography (CT) with contrast enhancement is routinely performed for tumour delineation and to detect regional lymph node or liver metastases. Scintigraphy using [111In]octreotide scintigraphy (OctreoScan) can often efficiently reveal metastatic spread from differentiated NETs.30,31,34
Treatment
CAG-associated type 1 gastric NETs
These may disappear spontaneously, and few show more marked progression. Small, multicentric lesions may be followed with annual repeated endoscopy.17,25,30,31,35,36
Polyps < 1 cm are generally indolent and can be followed by yearly endoscopic surveillance. Tumours > 1 cm without invasion can be treated with endoscopic mucosal resection or multiple band mucosectomy.37 Few larger invasive tumours require local surgical excision and only rare larger, multifocal lesions need gastric resection.18,30,31,35,37–39 EUS is recommended for evaluation of invasiveness. In cases of malignant development or recurrence despite local surgical resection, partial or total gastrectomy with lymph node dissection is recommended.30
Antrectomy has been recommended for treatment of CAG-associated gastric NETs, with the aim of inhibiting antral overproduction of gastrin.40,41 The antrectomy is claimed to cause regression of ECL cell dysplasia and small NETs; however, large, invasive or metastatic lesions may remain unaffected.40–42 Resection of the antrum may therefore be considered for multicentric or recurrent tumour, and is often combined with surgical excision of larger type 1 NETs, but results and morbidity of this versus repeated endoscopic excision remain unclear.26,30,42
MEN1-related type 2 gastric NETs
These are more malignant than CAG-associated NETs. Surgical treatment should focus both on removal of the source of hypergastrinaemia and on excision of the gastric NETs. Concomitant exposure of both pancreas and duodenum, via duodenotomy, is done to locate both gastrinomas and possible MEN1 pancreatic lesions, and 80% distal pancreatic resection is most often performed.24,43,44 In type 2 ECLomas > 1 cm local excision is recommended, though endoscopic mucosal resection may be considered if EUS excludes muscularis layer invasion.30,32 Gastric resection with regional lymph node clearance is advocated for larger tumours.16,30
Sporadic type 3 gastric NETs
These are clearly malignant, with a risk of metastases even for the rare small tumours.45 Most tumours are large and require operative excision, often performed as gastric resection, combined with regional lymph node clearance. Tumours > 2 cm or those with atypical histology or gastric wall invasion or local metastases are most appropriately dealt with by gastrectomy.17,26
In cases with metastases, tumour debulking of lymph gland and liver metastases may alleviate symptoms of an associated carcinoid syndrome and apparently improve survival.16 Hepatic metastases may be treated with liver resection, hepatic artery embolisation or chemoembolisation, and radiofrequency (RF) ablation (see below).31 The somatostatin analogue octreotide may palliate symptoms in patients with the carcinoid syndrome. Chemotherapy is likely to be valuable when the proliferation index exceeds 5% and has response rates of 20–40%. Chemotherapy can be combined with other treatment modalities.31,46
Poorly differentiated NECs
These generally have a dismal prognosis, with a median survival of only 8 months.9,15,30,39 The tumours are rarely suitable for radical surgery and recurrence should be checked for after gastric resection. However, aggressive surgery together with chemotherapy may be an option to consider, especially in patients with mixtures of well and poorly differentiated tumours.9
Duodenal NETs
NETs of the duodenum are rare, and comprise less than 2% of all gastrointestinal neuroendocrine tumours.17,47 Duodenal adenomas or adenocarcinomas are much more frequent. However, the endocrine tumours are important to recognise because of a possible association with hormonal or hereditary syndromes and the consequential requirements of treatment. Duodenal NETs are so rare that it is difficult to identify prognostic factors and decide optimal treatment on an evidence base.
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
Duodenal tumours smaller than 5 mm can be enucleated with the overlying mucosa; larger tumours are excised with full thickness of the duodenal wall. Careful exploration is undertaken for the removal of lymph gland metastases around the pancreatic head. The duodenal gastrinoma is considered as a potentially curable entity of ZES, especially for non-MEN1/ZES.48,52 The prognosis is favourable after resection of duodenal gastrinomas in both sporadic and MEN1/ZES patients, with survival reaching 60–85% after 10 years.51–53
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.
Pancreatic NETs
Pancreatic islet cell tumours are generally classified according to their dominant hormone secretion, or depicted as clinically non-functioning if not associated with any clinical syndrome of hormone excess. Exceptionally, endocrine tumours of the pancreas stain intensely for serotonin (and may also contain other biogenic amines).17,59 They appear histologically as classical GEP-NETs, but few have been associated with the carcinoid syndrome. The tumours are managed surgically according to guidelines similar to those for other malignant endocrine pancreatic tumours. Hepatic metastases and a carcinoid syndrome may be treated with somatostatin analogues and interferon, or chemotherapy in the presence of a higher proliferation rate.
Jejuno-ileal (small-intestinal) NETs (midgut carcinoids)
The jejuno-ileal NETs originate from intestinal enterochromaffin (EC) cells in intestinal crypts. They have been named ‘classical’ midgut carcinoids, and typically display serotonin immunoreactivity in the tumour cells.60 The small-intestinal NETs have increased in frequency, and constitute ∼ 30% of GEP-NETs.1,11,60 Being the most common cause of the carcinoid syndrome, these tumours have often prevailed at referral centres, since this syndrome has required somewhat complicated and often combined medical and surgical treatment.11,60 The small-intestinal NETs account for 25% of small-bowel neoplasms and have been diagnosed at an average age of 65 years, with slight male predominance.
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
Figure 6.2 Small-intestinal NET, unusual entity with liver metastases but no mesenteric tumour. Reproduced from Åkerström G, Hellman P, Öhrvall U. Midgut and hindgut carcinoid tumors. In: Doherty GM, Skogseid B (eds) Surgical endocrinology, 1st edn. Philadelphia: Lippincott Williams & Wilkins, 2001; pp. 448–52. With permission from Lippincott Williams & Wilkins.
Figure 6.3 Computed tomography image of mesenteric metastasis from a small-intestinal NET, typically surrounded by fibrosis (appearing like ‘hurricane centre’). Reproduced from Åkerström G, Hellman P, Öhrvall U. Midgut and hindgut carcinoid tumors. In: Doherty GM, Skogseid B (eds) Surgical endocrinology, 1st edn. Philadelphia: Lippincott Williams & Wilkins, 2001; pp. 448–52. With permission from Lippincott Williams & Wilkins.
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
Figure 6.4 Intestinal venous ischaemia due to small-intestinal NET. Reproduced from Åkerström G, Hellman P, Öhrvall U. Midgut and hindgut carcinoid tumors. In: Doherty GM, Skogseid B (eds) Surgical endocrinology, 1st edn. Philadelphia: Lippincott Williams & Wilkins, 2001; pp. 448–52. With permission from Lippincott Williams & Wilkins.
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.
