Study on metaplastic lesions in gastric cancerogenesis

Gastric cancer remains the second most frequent cause of cancerrelated deaths and ranks 4th in cancer incidence worldwide [1-9]. Although mortality from gastric cancer has been declining in most countries, it stil represents a major health problem throughout the world, accounting for 7.8% of cancers worldwide [10-13]. Areas where incidence is high at > 60 per 100.000 males include eastern Asia (Republic of Korea and Japan), eastern Europe and Central and Latin America [13-18]. The “intestinal“ type of adenocarcinoma is relatively predominant in high incidence regions of the world, whereas the “diffuse” type is relatively more common in low-incidence areas. The prognosis of GC varies depending on stages [3-7].

From this background, the aim of this review is to provide comprehensive information regarding the diagnosis and management of AG and IM and to establish strategies to prevent gastric cancer.
In most text books metaplasia is defined as "a change from one type of differentiated tissue to another, normally differentiated type". The mechanisms of metaplastic transformation are still obscure.

Materials and methods
During the period from 2013 to 2018, the 50 patients with autoimmune (A) Gastritis, (Figure 1), 50 patients with Helicobacter pylori + infectious (B) Gastritis, (Figure 2), as well as 20 patients in control group, had gastroscopy. Histopathological examinarion was done in  -Basal serum levels of Gastrin ( Figure 9).
-Linear and blackbery ECL cell hyperplasia in fundic mucosa, associated with achlorhydria and hypegastrinaemia ( Figures 10 and 11a,b). endoscopical biopsies of gastric antral and corpus/fundic mucosa and fixed in 10% formaldehyde. Paraffin sections were stained with classic HE, histochemical AB -PAS, HID-AB, Giemsa, argentaffine Masson reaction for analysis of enterochromaffine (EC) and argyrophilic Sevier Munger method for the discover of argirophilic enterochromafine-like (ECL) neuroendocrine cells. Immunohistochemical Avidine Biotin Complex (ABC) method, with antibody to Gastrin, has been applied for the detection of neuuroendocrine Gastrin (G) cells. Basal Gastrin serum levels were examined by using Radio Immuno Assay (RIA) method.

Results
By analysis of endoscopically taken, processed and stained gastric biopsies, we are pointing out the following results:     Type II (incomplete): the crypts are elongated and tortuous. The epithelium is characteriyed by few or absent absorptive cells and the presence of columnar mucous cells in various stage of differentiation ( Figure 12); the goblet cells secrete sialo-and occasionally sulphomucins ( Figure 13). Paneth cells are rarely observed.
Type III (incomplete): distortion of glandular architecture is more pronounced and cell atypia and loss of differentiation is more marked than in type II. (Figure 14). Columnar cells secrete predominantly sulphomucins, and goblet cells contain sialo and/ or sulphomucins (Figures 15, 16 and 17). Paneht cells are usually absent. The highest value of cell heights being seen in type III. The presence of sulphomucin in goblet cells can be seen in any IM type, therefore i s not a criteria for a type III IM [2].
Forms of transition, both in terms of morphology and mucin profiles between these three principal variants are also noted, suggesting that IM heterogeneity and may reflect the stages in a dynamic process in which one form evolves to another, or regress [2]. The incomplete types remain unchanged and correspond to known types II and III. Sulphomucin + incomplete type (type III) is significantly associated with intestinal gastric carcinoma, whereas the sulphomucin negative incomplete type (type II) is more frequentrly seen in benign conditions [2]. By Jarvi and Lauren classification, gastric carcinomas are subclassified into tumours

Rare metaplasias in gastric mucosa
Less knowh the role of Pyloric, and rarer Pancreatic as well as Cilliar metaplasia in the gastric mucosa, requests detailed studied in the future. Except wrong definition that pancreatic acinar metaplasia represents the nodules of normal pancreatic tissue up to 1 cm in gaster or intestinal mucosa. Sometimes these islands presented in submucosa or in muscularis propria, mixing in this way the process of "metaplasia" with hamartomatous "pancreas aberans" [32,33].

Mucin histochemistry
Normal mucinous gastric cells secrete neutral mucins. The goblet cells of the complete and incomplete IM secrete acid mucins. In complete IM this includes N-and O-acylated sialomucin and small amounts of sulphomucins. The columnar cells of complete IM resemble intestinal enterocytes and therefore do not secrete mucus. The columnar cells of incomplete IM secrete mainly neutral mucins or sulphomucins [10,16]. There is generaly an agreement that a variant of IM secreting a sulphomucins shows a selective association with gastric carcinoma, particularly the intestinal type [8,10,11,15,[18][19][20].
Sulphomucins are secreted also by gastric dysplasia and gastric carcinoma. Some authors have adopted the term "colonic" metaplasia to describe the sulphomucin digestion secreting variant of IM [18,19]. The secretion of sulphomucin may not so much indicate early neoplastic transformation, but rarely reflects cellular adaptation to a carcinogenic microenvironment [30][31][32][33][34][35][36][37]. However, the secretion of sulphomucin may represent an important cytoprotective mechanism. Secretion of sulphomucin may be linked in several ways to gastric carcinogenesis. Finally, neoplastic clones which are protected by the secretion of sulphomucin, may be better able to resist gastric acid.

Metaplasia
Metaplasia may be important signal of a potentially cancerogenic environment. In the stomach, metaplasia itself may undergo malignant transformation [1][2][3][4][5][6][7]. The first step involves chronic superficial gastritis, reversible lesion, induced by a variety irritant. Atrophy or loss of pariethal cell mass leads to hypochlorhydria and this allows the growth of bacteria which contain nitrate reductases which transform dietary nitrate to nitrite, a very active molecule which with the appropriate substrates may form N-nitroso compounds in situ. Nitrate is ubiquitous in foods; most diets contain more than adequate amounts to enter in the reactions.

Conclusions
-Gastric cancer is still a major cause of death in our republic.
-H. pylory infection triggers a multistep inflammation from chronic gastritis, atrophic gastritis, IM and funally to gastric cancer.
-As the infection of H. pylory is the most important risk factor of AG and IM, it is important to perform H. pylori eradication to prevent the progression to gastric cancer.
-However, side effects induced by eradication H. pylory therapy, are both mycotic gastritis and ECL-cell type I carcinoid of the corpus/ fundic localisation, requesting further researches.

The proposed protocol
The protocol has been in progress since 1981 in a multicentric study (Filipe et al.). The essential points are: 1. Sampling of various regions and multiple biopsies.
2. Two levels cut from each biopsy.
3. H and E and Alcian blue + PAS stain in each case. If incomplete IM is present, futher HID-AB stain is requested.
4. Report to the clinician to include IM types and advice for follow up according to protocol. A close relationship with the endoscopist is important as clinical as well as histological parameters will determine management.