Foregut carcinoids
Midgut carcinoids
Hindgut carcinoids
Thymus
Jejunum
Transverse colon
Bronchus
Ileum
Descending colon
Stomach
Ascending colon
Sigmoid colon
Duodenum
Caecum
Rectum
Appendix
Genitourinary tract
The ENETS classification 2006/2007, the 7th American Joint Cancer Committee/Union Internationale Contre le Cancer (AJCC/UICC) classification 2009 and the current WHO classification 2010 all equally define a grading system based upon the proliferation index Ki-67 and/or mitotic index with low-grade G1 tumours (Ki-67 ≤2 %, mitotic count <2 per 10 high-power field; HPF) (9). Well-differentiated NETs are classified together as neuroendocrine tumours (NETs) grade 1 (G1) or G2. The carcinoid term is sometimes used instead of NET G1. The term neuroendocrine carcinoma refers to all poorly differentiated NETs and high-grade (G3) malignant neoplasms. NEC is further subdivided into a small-cell and a large-cell subtype. Mixed adenoneuroendocrine carcinomas (MANEC) and hyperplastic and preneoplastic lesions are termed as special groups. Tumour characteristics as localisation, size, composition, relationship to anatomic structures, resection margins and the presence of metastases should be assessed in order to classify the tumour according to the TNM staging system [9].
11.3 Oesophageal NETs
Oesophageal neuroendocrine tumours are extremely rare. In 1969, an oesophageal carcinoid case was reported [10]. The age of oesophageal NET patients ranged from 44 to 82 (median 64 years). The lesions predominate in males. Dysphagia, weight loss, pain and reflux oesophagitis are the most common symptoms. The diagnosis is based on classical approach as to other oesophageal masses.
Reported cases are poorly differentiated tumours. Immunohistochemical studies revealed positivity for NSE and serotonin, but these tumours lacked argentaffin and argyrophilic staining. Barrett’s oesophagus may be a potential factor for development of oesophageal NETs.
The stage is an important prognostic factor for oesophageal NETs. Stage I (localised disease to mucosa, lamina propria or submucosa) and stage II (involving only the muscularis propria) NETs have a good prognosis after resection. However, patients with stage III (extending through the muscularis propria into adventitia) and IV grade tumours (invading the adventitia, as well as involving a mediastinal structure, most commonly pulmonary vessels) typically succumb to the disease, as such lesions have a propensity for significant local spread and relatively poor outcome. In one series, most of the tumours had already invaded the oesophageal wall and local lymph node metastasis was present [11]. However, there are also few cases reported to be successfully treated with oesophagogastrectomy [12].
The small size of reported patients limits to develop a general therapeutic approach, but most reports indicate oesophagogastrectomy and subtotal excision with gastro-oesophageal anastomosis are the preferred methods [13].
11.4 Gastric NETs
Gastric neuroendocrine tumours are rare neoplasms arising from enterochromaffin cells of the stomach. Gastric NETs are heterogenous neoplasms consisting of 8.7 % of all GI-NETs. The wide application of upper gastrointestinal endoscopic techniques and broader use of proton pump inhibitors lead to increased diagnosis of gastric NETs [14, 15].
Gastric NETs are heterogenous neoplasms with varying histopathology and biological behaviour. A classification system was proposed which distinguishes gastric NETs as four different groups. This classification system which based on mainly clinicopathological features, such as hypergastrinaemia, has prognostic and management implications.
Type 1 NETs are the most frequent type and comprise approximately 70–80 % of all cases. The lesions are usually less than 10 mm, multifocal and localised in the gastric fundus or body [16]. Type 1 is mostly related to atrophic gastritis. Gastrin is the key molecule in pathological process of gastric NETs developing from enterochromaffin-like (ECL) cells. Generally this type has an excellent prognosis after resection; metastatic potential of type 1 tumours is low (5 % to local lymph nodes, <2 % distant metastasis) [14, 17]. Histopathologically these tumours are regular-shaped cells with round nuclei. Mitotic index is low; tumour spread is limited to the submucosa and mucosa. Mostly type 1 gastric NET cells are positive with chromogranin A (CgA) and neuron-specific enolase (NSE). Determination of CgA expression is helpful but neither pathognomonic nor diagnostic since enterochromaffin cells of the stomach express high amounts of CgA.
Type 1 gastric NETs are diagnosed incidentally during upper GI endoscopy. Chronic atrophic gastritis may lead to reduced intrinsic factor secretion, achlorhydria, vitamin B12 deficiency and macrocytic anaemia.
In diagnosis and staging, endoscopic ultrasonography is helpful for local staging and for resection of lesions. Abdominal computed tomography scan can aid to diagnosis of metastatic stage [18]. Netazepide is a potent and selective cholecystokinin 2 receptor antagonist which has an oral antagonistic effect on gastrin receptors. Netazepide was reported to regression of tumour and decrease in chromogranin A levels [19, 20].
Annual endoscopic surveillance along with annual abdominal ultrasonography is recommended in type 1 GNET patients [21]. In patients with lesions of >10 mm, CT and somatostatin receptor scintigraphy may be offered.
Type 2 gastric NETs are less common tumours with similar characteristics of type 1 tumours with increased gastrin levels but no achlorhydria or atrophic gastritis. Type 2 tumours are usually associated with multiple endocrine neoplasm (MEN-1) type 1 or Zollinger-Ellison syndrome [22, 23]. Peak incidence of type 2 tumours is 45 and there is no gender predominance. Type 2 lesions are small (10–20 mm) multiple well-differentiated lesions scattered multifocally throughout the stomach, limited to the mucosa and submucosa. Type 2 tumours also express CgA, but levels do not correlate with malignancy [23]. A moderate level of atypia and a slight increased of mitotic index may be encountered in type 2 lesions when compared to type 1 lesions. A practical test to differentiate type 1 GNET with type 2 is to determine fasting gastric PH. It is high in type 1 and low in type 2 as expected.
Type 2 tumours are diagnosed endoscopically, if amenable endoscopic resection is curative. But due to the multifocality, endoscopic resection may not be optimal. In such cases, somatostatin analogues may be used, to induce tumour regression, decrease plasma gastrin levels and relieve symptoms [24]. Besides removal of the gastric lesions, the source of hypergastrinaemia should be considered, such as gastrinoma according to the location as defined in the related chapter of the book.
Type 3 NETs are usually sporadic; 14–20 % of gastric NETs are classified as type 3. Type 3 gastric NETs are observed more frequently in men with a peak incidence at the age of 50. They are usually solitary and large tumours occurring in any part of the stomach. They are usually well differentiated, larger than 1 cm in size but with invasion of the muscularis propria. Mitotic index is higher (>2 %) and focal necrosis is common. These types of tumours are not gastrin dependent [25]. Type 3 tumours are more aggressive and usually negative for CgA and have a poor prognosis. These tumours are likely to have lymph node involvement and liver metastases at the time of diagnosis [26]. If amenable, surgical resection with lymph node dissection is necessary; depending on local growth features, radical gastric resection may be included [27].
Type 4 NETs are solitary tumours with larger size which are poorly differentiated neuroendocrine carcinomas. They can occur in any part of the stomach with a peak incidence over age 60. These tumours are more frequently seen in men. They are gastrin-independent tumours. Histopathology is characteristic of a grade 3 carcinoma with abundant atypia, mitosis and necrosis. Chromogranin A is absent, whereas neuron-specific enolase is strongly expressed [28]. Type 4 NETs have a poor prognosis; at the time of diagnosis, lymph node invasion, angioinvasion and deep wall invasion usually exist in type 4 tumours. Therefore, type 4 tumours are likely to be diagnosed at the advanced stage [29]. Surgical resection is the most appropriate treatment for this type of tumour. Type 4 gastric NET demands an aggressive surgical approach followed by chemotherapy and multimodality adjuvant therapy [30].
A brief overview of characteristics and treatment strategies of gastric NETs is done in Table 11.2.
Table 11.2
Classification and characteristics of gastric neuroendocrine tumours
Type 1 | Type 2 | Type 3 | Type 4 | |
|---|---|---|---|---|
Incidence (among gastric NETs) | 70–80 % | 5–6 % | 14–25 % | Rare |
Pathological features | Multiple, small, intramucosal lesions | Multiple, small, intramucosal lesions | Single, large lesion, more extensive stage lesions | Single, large |
<1 % MI | <1 % MI | >2 % MI | Severe, grade 3 histology | |
CgA and NSE positive | CgA and NSE positive | CgA positive | >30 % MI | |
CgA negative | ||||
NSE positive | ||||
Prognosis | Very good | Good | Less good | Poor |
Metastatic potential very low | 10–30 % metastatic potential | 50–100 % metastatic potential | 100 % metastatic potential | |
Treatment strategy | Endoscopic resection | Endoscopic resection or limited surgery | Radical surgery | Radical surgery if amenable |
Chemotherapy | NN | NN | Usually NN | Combination chemotherapy: |
Cisplatin-etoposide | ||||
Carboplatin-octreotide/pasireotide | ||||
Somatostatin analogues | ||||
Radiotherapy | NN | NN | Usually NN | Targeted radiotherapy with 177Lu-octreotate (177Lu) and 90Y-labelled somatostatin analogue |
Biological treatment and targeted treatment | NN | NN | Usually NN | Interferon |
Sunitinib | ||||
Everolimus |
11.5 Duodenal Neuroendocrine Tumours
Foregut NETs include those arising in the oesophagus, stomach, pancreas and duodenum [31]. Primary duodenal NETs account for less than 2 % of all gastrointestinal NETs [32].
Duodenal NETs are usually solitary, small lesions restricted to duodenal submucosa at the time of diagnosis. They are usually located in the first and second part of the duodenum [33]. They are relatively benign lesions with slow growth pattern and low metastatic potential which lead to broad classification of duodenal NETs as carcinoids [34, 35].
Five major types of NETs may be seen in the duodenum:
Type 1 tumours are gastrinomas which are the most frequent form and usually seen in the proximal duodenum. One third of duodenal gastrinomas are associated with MEN-1 and Zollinger-Ellison syndrome (ZES) [36, 37]. They are small lesions rarely exceeding 10 mm.
Type 2 duodenal tumours are somatostatinomas. They are the second common duodenal NETs which may be periampullary located. They may be associated with von Recklinghausen disease [38]. They are often fairly large, deeply invasive and metastatic to local lymph nodes at the time of diagnosis.
Type 3 tumours are benign gangliocytic paragangliomas which are found at the ampulla or periampullary region.
Type 4 tumours are rare. These tumours may secrete serotonin and calcitonin.
Type 5 tumours are extremely rare tumours located at the ampulla of Vater. They are highly aggressive, malignant tumours [39].
Duodenal NETs are mostly asymptomatic and non-functional. They are usually detected incidentally during upper GI endoscopy. And also upper GI endoscopy is the preferred method of detection of duodenal NEs. In retrospective analysis of duodenal NETs, tumour size (>20 mm), tumour depth of invasion (muscularis propria) and presence of mitotic figures have been defined as independent risk factors [40, 41].
Duodenal NETs can be considered as early lesions if tumours are less than 10 mm in size with grade 1 features and without lymphovascular invasion and no muscularis propria invasion [29]. There is no consensus on optimal management strategy of duodenal NETs. According to retrospective case series, tumours with “early lesions” characteristics can be safely removed endoscopically. Treatment of locally advanced and metastatic lesions does not differ from other intestinal NETs.
11.6 Neuroendocrine Tumours of the Gall Bladder and Extrahepatic Bile Ducts
Gall bladder neuroendocrine tumours (GB-NETs) represent only 0.5 % of all NETs [42]. GB-NETs were hypothesised to derive from multipotent stem cells or from neuroendocrine cells of intestinal or gastric metaplasia of gall bladder epithelium [43, 44]. They are usually poorly differentiated, aggressive, large-cell or small-cell NECs [42]. The symptomatology of GB-NETs is nonspecific, and their diagnosis is often made at the cholecystectomy for cholecystolithiasis or polyps. For well-differentiated tumours, simple cholecystectomy may be adequate. The vast majority of GB-NETs, however, require cholecystectomy and regional lymphadenectomy combined with a hepatic resection to obtain adequate clear margins [42].
Primary neuroendocrine (carcinoid) tumours of the extrahepatic biliary ducts are extremely rare. Well-differentiated NETs behave less aggressively; only 23 cases were reported as grade 3 NET [45]. The origin of neuroendocrine neoplasms of the biliary tracts is unclear. They may arise from metaplastic epithelia. Metastasis rate is less than 40 %. Clinical symptoms due to hormone production are extremely rare. Tumour size (<2 cm or not) was hypothesised to be the independent risk factor. Accurate preoperative diagnosis is important and can be made by examining brush cytology specimens obtained during endoscopic retrograde cholangiopancreatography and/or endoscopic ultrasound-guided fine-needle aspiration. Immunocytochemical staining properties are important in differential diagnosis especially before operation. Surgery is the mainstay of treatment in well-differentiated, localised tumours. In general, prognosis is poor.
11.7 NETs of the Jejenum and Ileum
NETs of the small intestine are rare tumours in general, but particularly the ileum is the most common NET site in human body. These tumours have a slight male predominance with a peak incidence at the sixth and seventh decades of life [46]. A potential risk factor associated with increased risk of development of NEN of the small bowel is a family history of first-degree relatives with cancer, suggesting a genetic component independent of MEN-1, which is not associated with jejunoileal NEN [46]. Patients with small intestinal NETs may develop symptoms due to effects of the primary tumour, due to enlarging metastases or secondary to hormonal secretion. Small intestinal NETs originate most commonly in the distal ileum, within 60 cm of the ileocaecal valve [47].
Jejunoileal NETs are frequently diagnosed while on a screening colonoscopy. The most frequent symptom is abdominal pain along with other constitutional symptoms. From the clinical point of view, it is important to distinguish between hormonally active and non-active NETs, because the active ones which secrete peptides and hormones cause a characteristic syndrome known as carcinoid syndrome. Tumour-specific, hormone hypersecretion symptoms from carcinoid syndrome in metastatic patients include secretory diarrhoea, flushing and importantly valvular heart disease [48–50]. It is important to note that carcinoid syndrome occurs in patients with liver metastasis, but in rare cases, excess serotonin production/tachykinin production from extraperitoneal metastasis or ovarian metastases can result in carcinoid syndrome without evidence of liver metastasis.
In diagnosis cross-sectional imaging with CT and/or MRI should be followed by somatostatin receptor scintigraphy (SRS), ideally in combination with SPECT/CT. 68Ga-DOTATOC-PET in combination with contrast-enhanced CT may be a more sensitive alternative, and this technique is getting more widely used globally in the last decade.
In 2012, ENETS renewed the guideline for tumours of the lower jejunum and ileum [46]. Jejunoileal NETs are highly prone to metastasise; they tend to be fairly slow growing and are associated with relatively favourable survival durations compared to other metastatic carcinomas. A single-institution analysis of overall survival stratified by TNM stage revealed that 5-year survival rates were 100 % for stage I and II tumours vs. 91 % for stage III (locoregionally advanced) and 72 % for stage IV tumours. The median overall survival for stage IV tumours was 103 months. Among stage III patients, survival differed significantly between patients with resectable mesenteric tumours (95 % 5-year survival) and patients with unresectable mesenteric tumours (78 % 5-year survival) [51].
In localised disease, surgery is the mainstay of treatment. But usually, due to lack of early diagnosis, locally advanced disease or metastatic stage is the area of concern. Therefore, in symptomatic cases, somatostatin analogues are effective. They are also proven to be useful for tumour growth stabilisation. Liver-directed therapies and systemic cytotoxic drugs and targeted agents will be necessary in selected cases.
11.8 Appendix NETs
The appendix is the third common site for development of gastrointestinal tract NETs (small intestine 44.7 %, rectum 19.6 %, appendix 16.7 %) [1, 52]. These tumours develop primarily in the distal part of the appendix and invade deeply into the appendix wall, causing local symptoms and requiring surgical removal of the tumour. Appendix NETs, mostly limited to the appendix, show a benign behaviour and produce serotonin but are non-functional and are usually discovered as an incidental finding at appendectomy for appendicitis. Most appendix NETs are diagnosed in earlier stages. They are usually grade 1 tumours, rarely grade 2, but NECs of the appendix are extremely rare reported only in few case reports [53].
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
