**2.4. Gastric apudoma type 1**

mainly in relation to the nonendocrine carcinomas. Concerning the apudomas, this parameter, as an isolated element, has little value. Differently, the well-differentiated apudoma can present unpredictable clinical behavior. However, when the tumor is histologically poorly differentiated, the prognosis is often worse. In this respect, this criterion of cellular differentiation may be helpful. In addition, apudomas present varying densities of membrane receptors for different regulatory peptides, including somatostatin. And, a high density of these receptors in apudoma cells acquires current medical importance for the patient treatment. Some data indicate that the

**Figure 4.** Well-differentiated type 1 (A) and poorly differentiated type 2 (B) gastric apudomas. Although the degree of tumor differentiated could have some importance regarding the degree of malignancy, the proliferative activity remains

Under the view of histopathological diagnosis, the malignancy potential of a particular apudoma rests mainly on the degree of tumor cell proliferation. This criterion can be applied to all apudomas regardless of their origin. There are two histopathological tools to assess the degree of cell proliferation: (i) the number of observable mitoses in the routine preparations stained by *hematoxylin* and *eosin* and (ii) the index of cell immunoreactivity for Ki-67 antibody. The Ki-67 reactive protein is only expressed in the nucleus of cells that are in the various phases of the active cell replication cycle. This protein is not expressed in resting cells, that is, the cells that have not yet entered the active mitotic cycle. Moreover, there is not always any correspondence between the

somatostatin receptor density would be dependent on the degree of tumor grade [20].

degree of differentiation of a given apudoma and the degree of cell proliferation [21, 22].

two extremes are considered to be G2.

as a better histopathological indicator for this purpose.

34 Gastric Cancer

**2.3. Gastric apudomas**

Concerning proliferative activity, the low-grade (G1) tumors present very few numbers of mitosis in routine HE preparation or otherwise less than 3% of neoplastic cells stained by Ki-67 antibody. The high-grade (G3) tumors should present more than 20 mitoses per 10 microscopic high-power field (hpf) or more than 20% of the neoplastic cells positive to Ki-67 antibody. Finally, tumors with intermediate degree of cell proliferation that lie between these

Almost all apudomas of the stomach are derived from the endocrine cells of the body mucosa and rarely from the endocrine cells of the antral mucosa. They represent approximately 2–4%

of all gastric neoplasias and 7.2% of all apudomas of the gastrointestinal tract [10].

These are the most frequent gastric neuroendocrine tumors. They are characteristically associated with atrophic body gastritis (ABG) and are the most frequent of the gastric apudomas constituting about 70–80% of them. The criterion adopted for the classification of these tumors in type 1 is the recognition of the presence of established chronic autoimmune gastritis, with or without pernicious anemia, or just the presence of atrophic body gastritis confirmed by histopathology. This type of tumor appears to be more prevalent in women as well as the prevalence of the underlying disease (**Figure 5**).

**Figure 5.** Distribution of 196 consecutive patients with atrophic body gastritis according to the age and gender. Patients were from a general hospital in Belo Horizonte, Brazil [26].

Therefore, it can be assumed that this type of tumor is a direct consequence of the atrophic body gastritis. According to this diagnostic criterion, we can conclude that the different types of apudomas of the stomach cannot be diagnosed based only on their endoscopic and histopathological pattern. Therefore, for the inclusion or exclusion of a gastric apudoma as type 1, it is necessary that in addition to histological samples of the tumor itself we also have samples of the gastric mucosa of the antral and body regions of the stomach to confirm or rule out the possibility of atrophic body gastritis. Recognizing an endocrine tumor as type 1 opens a range of possibilities to better understand the set of pathophysiological changes that may be occurring in the patient:


#### **2.5. Gastric apudoma type 2**

Type 2 gastric apudomas are those associated with sporadic or familial Zollinger-Ellison syndrome. They account for only 5–6% of the gastric apudomas. Almost always these tumors

#### Neuroendocrine Tumors of the Stomach: Gastric Apudomas http://dx.doi.org/10.5772/intechopen.69722 37


**Table 4.** Differential profiles between the three groups of gastric apudomas.

**a.** Gastric apudoma type 1 occurs in the mucosa of the fundus or the gastric body generally as multiple nodules, smaller than 1 cm in most cases. As they are generally multiple, they may occur according to an irregular distribution in the gastric body, the gastric fundus, or in the two regions simultaneously (**Table 4**). Usually, these nodules are projected into the lumen of the stomach and are frequently diagnosed by endoscopy as "gastric polyps." This diagnosis is not always incorrect because in ABG hyperplastic polyps are relatively

**b.** The neoplasia usually consists of well-differentiated neuroendocrine cells with a low Ki-67 index (G1) indicating low levels of cell proliferation. This characteristic is in agreement with the indolent evolution of these tumors; only a small number of them present metas-

**c.** Due to atrophy of the oxyntic mucosa these patients present hypochlorhydria or

**d.** Since the gastric mucosa of the corpus is atrophic and the antral mucosa is preserved, the G cells are usually hyperfunctioning, and these patients frequently present hypergastrine-

**e.** Even without the occurrence of high levels of serum gastrin, the constant trophic stimuli of this hormone will lead to hyperplasia of the endocrine cells of the gastric body. These hyperplastic cells are believed to be enterochromaffin-like (ECL) cells. However, other types of neuroendocrine cells may be participating in this hyperplastic process, including ghrelin-producing cells [26]. The areas of neuroendocrine cell hyperplasia can be found in almost all cases of well-established atrophic body gastritis (**Figures 7**–**9**). As we have already said, these areas of endocrine hyperplasia occur along the atrophic mucosa and according to their morphological aspect can be classified as (i) diffuse, (ii) linear, and

**f.** Based on these general aspects of atrophic body gastritis, it is possible to conclude that the areas of neuroendocrine hyperplasia are probably the precursor lesion of type 1 gastric apudoma. However, there are no histological signs that highlight where the hyperplasia ends and where the neoplasm begins. In this regard, the large, confluent hyperplastic nodules with a diameter about 300–500 μm associated with infiltration of mucosa tissues would already be classified as indicative of emerging neoplastic lesion (**Figure 9**). Just for comparison, 500 μm is equivalent, on average, to half thickness of normal oxyntic mucosa

**g.** The infiltration of the submucosa by the hyperplastic endocrine cells is already a sign of malignant behavior. However, for the most part, these type 1 gastric apudomas present indolent evolution, and few of them present metastasis at the time of diagnosis (**Table 4**).

Type 2 gastric apudomas are those associated with sporadic or familial Zollinger-Ellison syndrome. They account for only 5–6% of the gastric apudomas. Almost always these tumors

tases when diagnosed and rarely take the patient to death (**Table 4**).

frequent.

36 Gastric Cancer

achlorhydria.

(iii) nodular [27].

in formalin-fixed histologic sections.

**2.5. Gastric apudoma type 2**

mia (**Table 4** and **Figure 6**).

**Figure6.** Drawing showing the pathogenetic mechanisms of the gastric apudomas type 1 and type 2. The pathophysiological central mechanism associated with these two types of tumors is the occurrence of hypergastrinemia or a persistent suprabasal gastrinemia.

**Figure 7.** Diffuse and linear types of endocrine cell hyperplasia in atrophic body gastritis. The hyperplastic cells are stained for chromogranin.

**Figure 8.** Nodular type of endocrine cell hyperplasia in atrophic body gastritis. The hyperplastic cells form small nodules in the lamina propria. Chromogranin staining.

occur in patients with multiple endocrine neoplasia (MEN) type 1. Rarely, there is also a Zollinger-Ellison syndrome (ZES) not associated with multiple endocrine neoplasia (MEN) which leads to gastric apudoma development. In this case the ZES may be due to the presence of a sporadic gastrinoma, the main location of which is believed to be the tail of the pancreas. Thus, most frequently, the patient presenting a type 2 gastric apudoma may be a carrier of the genetic transmission of MEN syndrome. MEN-1 is an inherited autosomal dominant syndrome caused by an inactivating mutation of the MEN-1 gene, which is a tumor suppressor gene. MEN-1 syndrome may include the development of primary hyperparathyroidism, pancreatic islet tumors, and pituitary adenomas. In addition, some patients may develop other neoplasms such as thyroid tumors, adrenal adenomas, pheochromocytomas, and neuroendocrine tumors mainly of the gastroduodenal area.

**Figure 9.** Endocrine cell forming large hyperplastic nodules in the lamina propria. This type of lesions may be indicative of an emerging gastric apudoma. As these tumors may be multicentric, it is possible that more strongly suspected lesions occur in other areas of the gastric mucosa. Chromogranin staining.
