**4.1. Neuroendocrine tumours (NETs)**

or mixed adenomas and into low-grade or high-grade intraepithelial neoplasia. A minor group of gastric adenomas shows gastric gland differentiation like foveolar (so-called type II dysplasia) or pyloric gland differentiation, a mixture of foveolar/intestinal like differentiation or (very

Pyloric gland-adenoma usually arises in women and has a background of atrophic autoimmunegastritis. This type of adenoma is polypoid and show closely packed pyloric gland-like tubuli. The epithelia are cuboidal with round nuclei and pale cytoplasm. Immunohistochemically

Adenomas must be removed with clear margins. Large adenomas (more than 2 cm) show a

Especially in the stomach, intraepithelial neoplasia is flat and demonstrates endoscopically with only slight, uncharacteristic abnormalities. Frequently flat intraepithelial neoplasia arises in a background of chronic gastritis later in life (beyond the fifth decade). By conven-

Microscopically, the main characteristics of intraepithelial neoplasia consider cytology and

Low-grade intraepithelial neoplasia preserves more or less the normal glandular differentiation, the epithelia show enlarged hyperchromatic nuclei, the nucleoli are not prominent, and

High-grade intraepithelial neoplasia demonstrates with crowding of glands, including budding and branching of some glands. The nucleoli are prominent and often intense eosinophilic.

Flat low-grade intraepithelial neoplasia: re-endoscopy to exclude concurrent carcinoma is suggested. The risk of carcinoma is low (about 25%). Re-endoscopy twice a year and annual

Flat high-grade intraepithelial neoplasia: the risk of accompanied carcinoma is high (about

Geographic differences in interpretation of gastric epithelial tumours exist (generally between Western pathologists and Japanese pathologists). The Vienna classification of (pre-)cancerous

tion, the intraepithelial neoplasia has to divide into either low grade or high grade.

pyloric gland-adenoma shows common gastric mucin (MUC 5A/C and MUC6).

rare) a predominant Paneth-cell differentiation.

**3.2. Pyloric gland-adenoma**

276 Gastric Cancer

*3.2.1. Clinical significance*

higher risk of malignancy.

**3.3. Flat intraepithelial neoplasia**

architecture (like in adenoma):

*3.3.1. Clinical significance*

cell pleomorphism and cell stratification are limited.

after two negative endoscopies is suggested.

85%). An excision of the whole lesion/region is necessary [2, 11].

lesions of the GI-tract tries to harmonize both interpretations (**Table 5**).

*3.3.2. Vienna classification of gastrointestinal epithelial neoplasia*

NETs in total represent about 2% of all gastric malignancies.

Gastric neuroendocrine tumours (formerly 'carcinoid tumours') are mostly asymptomatic small 'polyps' on a background of hypergastrinemia-associated hyperplasia of endocrine cells in the gastric corpus of middle age adults (the 'classical' type 1 gastric NET, compare **Table 6**). But rarely they also can be associated with syndromes or unrelated to hypergastrinemia —these rare manifestations are usually correlated to unusual locations (e.g. antrum, more aggressive behaviour) [2, 16].

According to clinico-pathophysiological characteristics, three types of gastric NETs have been proposed (**Table 6**). These types share the same histological pattern. The great majority are tumours of enterochromaffin-like (ECL) cells induced by hypergastrinemia and caused by chronic atrophic corpus gastritis due to autoimmune gastritis and consecutive hypochlorhydria (type 1 NET) [3, 13, 17, 18].

Pathophysiologically, NETs start with ECL-cell hyperplasia (scattered or linear ECLhyperplasia), which may confluent to micronodules. More than five micronodules in a group are called adenomatoid ECL-hyperplasia. Enlargement of adenomatoid ECL-hyperplasia with


**Table 6.** Typing of gastric neuroendocrine tumours.

invasion and accompanied stroma reaction, the term dysplastic ECL-hyperplasia can be used. If the dysplastic ECL-nodules exceed 0.5 mm or invade the submucosa, the correct term is NET [2].

NETs of all types are composed of uniform cuboidal cells with round nuclei with stippled ('salt and pepper-like') chromatin and eosinophilic, granular cytoplasm. Nuclear pleomorphism, nucleoli and mitosis are unusual/infrequent in typical NETs (unlike neuroendocrine carcinoma). Growth pattern of NETs can be quite different and even quite heterogeneous in the same tumour forming nests, trabecular, tubules, rosettes or solid structures of tumour cells. Immunohistochemically, gastric NETs are consistent chromogranin A positive and have by definition a low Ki67 (up to 2%) [19, 20].

#### **4.2. Neuroendocrine carcinomas (NECs)**

Gastric neuroendocrine carcinomas are very rare (separated into small-cell and large-cell NECs). These poorly differentiated tumours are highly proliferative active (>20 mitosis/10 hpf or Ki67 >20%) and show an aggressive biological behaviour [3, 21].

Rare (atypical), NETs coexist with adenocarcinoma ('adenocarcinoid)—so-called MANEC (mixed adeno-neuroendocrine carcinoma, according to WHO). MANECs have the similar prognosis to that of conventional adenocarcinoma [2].

Clinical significance:

