Net of the stomachD44.9

Epithelial tumor, starting from the enterochromaffin cells (EC cells) of the DENS (diffuse neuroendocrine system), which are characterized by the production of tissue hormones and enzymes such as serotonin, kallikrein, tachykinins and prostaglandins.

A distinction is made between 4 types of neuroendocrine gastric neoplasias. The starting point for the classification of gastric NETs is that all NETs have a malignant potential with the possibility of metastasis. There is a direct relationship between their histological differentiation, size, invasiveness, proliferative activity and their cell biology and clinical sympomatics.

This classification was supplemented by the introduction of a stage classification according to TNM and a grading of neuroendocrine neoplasias on the basis of their proliferative activity in G1 to G3

Type 1

About 70-80% of all NETs of the stomach. Type 1 always occurs in connection with (autoimmune) chronic atrophic corpus gastritis and occasionally associated pernicious anaemia. The majority (>80%) of women between 40 and 60 years of age are affected.

Clinical presentation: multiple polyposis of the mucosal protrusions in the body and fundus <1cm. A hormone hypersecretion syndrome does not develop. Microscopically, there are well differentiated tumors with a trabecular to acinar structure. In > 90% of cases only the mucosa and submucosa are infiltrated. The proliferation index (Ki67/MIB1 index) < 2% (G1). Immunohistologically (and also ultrastructurally) ECL (histamine) cells and only single EC(serotonin) cells or somatostatin cells can be detected. The ECL cells are strongly chromogranin A positive, express VMAT2 (vesicular monoamine transporter 2) and are usually also positive for the somatostatin receptor SSTR2.

In tumors > 1cm, lymph node metastases are detected in 2-9% of cases at the time of diagnosis. Deaths as a result of type 1 NET have not been described so far. The 5- and 10-year survival rates do not differ from those of the general population (Borch K et al. 2005; Hou W et al. 2007).

Type 2

About 5-6% of all gastric NETs are of this type. It is associated with multiple endocrine neoplasia type 1 (MEN1) and Zollinger-Ellison syndrome (ZES) as a result of duodenal gastrinoma.

Clinical: Detection of multiple polypoid tumours in the corpus and fundus region. Tumor sizes often > 1 cm. Men and women are equally affected; the mean age is 45 years. Microscopically well differentiated and trabecular tumors are found. Proliferation index mostly < 2% (G1). Immunohistologically they consist of ECL cells (VMAT2-positivity). Corpus mucosa without atrophy (in contrast to type 1). Due to the simultaneously existing duodenal gastrinoma u , and the associated hypergastrinemia of the simultaneously existing duodenal gastrinoma, there is hyperplasia of the main and secondary cells.

The risk of lymph node metastases is high if the tumours are > 1 cm, angioinvasion is present and/or infiltrate the muscular wall layer.

Deaths as a result of type 2 NET have been described in < 10% of cases.

type 3

About 14-25% of gastric NETs. This type is not associated with any other disease. The mean age of the patients is 50 years. M:w=1:1.

Clinical presentation: Solitary polypoid tumour > 1cm (time of diagnosis). No special localisation in the stomach. Solid and trabecular patterns are found microscopically. Proliferation rate > 2% (G2). Tumor cells infiltrate the muscularis propria early and/or show angioinvasion. Often lymph node and liver metastases.

Immunohistologically, most tumor cells are reactive to VMAT2 (ECL cells). In contrast to type 1 and type 2, there is no ECL cell hyperplasia in the corpus mucosa of the stomach. Deaths as a result of type 3 NET were observed in 25-30% of patients. 5-year overall survival < 50% (Ruszniewski P et al. 2006)

Type 4

Rare, poorly differentiated, sporadic neuroendocrine tumor of the stomach (neuroendocrine carcinoma of the stomach = NEK). NEKs can occur in all areas of the stomach.

Clinical presentation: Mostly at the time of diagnosis ulcerated and metastasized sporadic tumor of 5-7 cm in size (Rindi G et al. 1999). Mostly older (>60 years) men are affected.

Solid carcinomas are found microscopically; remind of small or large cell bronchial carcinomas; tumour parenchyma is rich in mitoses; proliferation rate > 20-30% (G3). Angioinvasion and deep wall infiltration are detectable. Immunohistologically the tumor cells stain positively for synaptophysin, occasionally for chromogranin A. Reactivity for VMAT2 is not detectable.

Poorly differentiated NEK of the stomach occasionally contain a squamous cell and/or adenocarcinoma component in addition to the neuroendocrine component, so that the transition to mixed exocrine endocrine carcinomas may be fluid.

Prognosis is poor. Tumours are often only detected in the advanced metastatic stage.50% of patients die of the disease within 12 months (Ruszniewski P et al. 2006).

Exocrine endocrine mixed tumours

Carcinomas of the stomach which, in addition to their glandular mucus-producing (exocrine) component, contain an endocrine cell population that makes up more than 30% of the tumour tissue, or which consist of a glandular mucus-producing adenocarcinoma in addition to a neuroendocrine carcinoma ("collision tumour"), are called exocrine endocrine mixed tumours.

Most of the type 1 and type 2 NET of the stomach are asymptomatic and are discovered by chance during a gastroscopy (Landry CS et al. 2009). The symptomatic NETs are predominantly of type 3 and type 4 and are conspicuous by upper abdominal pain, gastroduodenal bleeding, diarrhoea, loss of appetite and weight loss. A carcinoid syndrome with protracted flush seizures and diarrhoea is a rarity associated with a sporadic NET of the stomach and is due to the secretion of serotonin, histamine and possibly 5-hydroxytryptophan by the tumor cells.

Determination of serum gastrin and serum chromogranin A.

Clinic, histology, evidence of possible metastasis.

Well differentiated NET of the stomach of type 1, type 2 or type 3

Well differentiated NET of the stomach of type 1, type 2 or type 3, which are restricted to the mucosa/submucosa, have a diameter of up to 1 cm, show low proliferative activity (<2%, G1) and are not angioinvasive, can be described as NET without risk factors. They can be ablated endoscopically or only monitored endoscopically and bioptically. In either case, control gastroscopies are recommended every 12 months.

If type 1 and type 2 NET are between 1 and 2 cm in size and show no other risk factors, endoscopic ablation by mucosectomy is recommended (current guideline). Prognostic tumor recurrences after polypectomy or mucosectomy have not been observed so far. If risk factors in the form of angioinvasion, infiltration of the muscular wall layer, lymph node metastases and/or a proliferation of more than 2% (G2 or G3) are present, surgery is recommended.

Well differentiated NET with risk factors

In the USA, well-differentiated (G1 and G2), non-metastatic gastric NETs (carcinoids) of type 1 and type 2 up to a diameter of 3 cm are often treated conservatively or minimally invasively. In Europe and Japan, surgical procedures are preferred for well differentiated gastric NETs that exceed the submucosa or are larger than 2 cm in size and in most cases show angioinvasion and increased proliferation (>2%) simultaneously ("NET with risk factors") (Hou W et al. 2007).

Surgical procedures are indicated for well differentiated gastric NET with > 2 cm and lymph node metastases. Here, total gastrectomy is preferable to partial gastric resection. In the presence of a metastasis of the liver, a palliative situation exists in which "debulking surgery" and ablation/resection of the liver metastases should be performed.

Poorly differentiated neuroendocrine stomach carcinomas

Poorly differentiated (G3) NEK of the stomach must be resected according to oncological standards if the stage still allows it, or receive chemotherapy equivalent to the treatment of a small cell carcinoma of the lung (Nilsson O et al. 2006) .

Postoperative chemotherapy is usually recommended for poorly differentiated neuroendocrine carcinomas that have been resected primarily (Nilsson O et al. 2006) . Whether the G3 carcinoma is nodally positive or negative is not decisive for the indication for chemotherapy. Liver metastases can occur even in nodal-negative neuroendocrine G3-NEK.

Exocrine endocrine differentiated gastric carcinoma

For these tumours, the principle applies that the prognosis is determined by the exocrine part of the carcinoma, unless there is also a low differentiated neuroendocrine carcinoma. This means that the therapeutic procedure is completely in line with the guidelines for the treatment of normal adenocarcinoma of the stomach.

The NETs of the stomach are usually detected at an early, easily treatable stage (with tumor diameter <1 cm). This has led to a significant improvement in the prognosis. Thus, the 5-year survival of these patients increased from 51% in the 1970s to 71% (Landry et al. 2009). The proportion of remotely metastasized carcinomas (at the time of diagnosis) decreased over the same period from about 20% to 6.5-7.9% (Modlin IM et al. 2008).

Endoscopic "en-passant" early detection obviously leads to a significant improvement in prognosis in patients with NET of the stomach.

pTNM classification of neuroendocrine neoplasias of the stomach (NET of the stomach)

T - Primary tumour

• TX Primary tumor cannot be assessed
• T0 No indication of primary tumor
• Tis carcinoma in situ, severe dysplasia (<0.5 cm)
• T1 tumor infiltrates lamina propria or submucosa and ≤1 cm
• T2 Tumor infiltrates Muscularis propria or subserosa or >1 cm
• T3 tumor infiltrates the serosa
• T4 tumor infiltrates other organs. For multiple tumors, add for each T (m)

N - regional lymph nodes

• NX Regional lymph nodes cannot be assessed
• N0 No regional lymph node metastases
• N1 Regional lymph node metastases

M - Remote metastases

• MX Remote metastases cannot be assessed
• M0 No remote metastases
• M1 Remote metastases

WHO classification of NETs/proliferation-based grading:

• Highly/well differentiated neuroendocrine tumor (G1) -Ki-67 index: =/<2%
• Highly/well differentiated neuroendocrine tumor (G2) -Ki-67-Index: 3-20%
• Low/well differentiated neuroendocrine tumor (G3) =NEC -Ki-67 index > 20% (large-cell and small-cell variant)

Clinical stages:

• Stage 0 Tis N0 M0
• Stage I T1 N0 M0
• Stage IIa T2 N0 M0 IIb T3 N0 M0
• Stage IIIa T4 N0 M0
• Stage IIIb Each T N1 M0
• Stage IV Every T Every N M1

...for a follow-up. The time intervals of the imaging and laboratory chemical follow-up should be based on the proliferative activity of the tumor. For NET G1 this should initially be every 6-12 months, for NET G2 every 6 months, while for NET/NEC G3 imaging diagnostics should initially be performed at least every 3 months.

1. Borch K et al (2005) Gastric carcinoids: biological behavior and prognosis after differentiated treatment in relation to type. Ann Surg 242:64-73
2. Hou W et al (2007) Treatment of gastric carcinoids. Curr Treat Options Gastroenterol 10:123-133
3. Ito T et al (2007) Preliminary results of a Japanese nationwide survey of neuroendocrine gastrointestinal tumors. J Gastroenterol 42:497-500
4. Landry CS et al (2009) A proposed staging system for gastric carcinoid tumors based on an analysis of 1,543 patients. Ann Surgeon Oncol 16:51-60 11.
5. Modlin IM et al (2008) Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol 9:61-72
6. Nilsson O et al (2006) Poorly differentiated carcinomas of the foregut (gastric, duodenal and pancreatic). Neuroendocrinology 84:212-215

7. Perren A et al (2010): Classification and pathology of gastroenteropancreatic neuroendocrine tumors. Visceralmed 26: 234-240

8. Rindi G et al (1999) ECL cell tumor and poorly differentiated endocrine carcinoma of the stomach: prognostic evaluation by pathological analysis. Gastroenterology 116:532-542
9. Ruszniewski P et al.(2006)Well-differentiated gastric tumors/carcinomas. Neuroendocrinology 84:158-164
10. Scherübl H et al (2003) Neuroendocrine gastrointestinal tumors. Diagnosis and therapy. Dtsch Med Weekly 128: 81-83