Table 2.

Clinical histopathological features of early onset and development of gastric signet-ring cell carcinoma.

Histopathological type	Histopathological features
Foveal epithelial hyperplasia of gastric mucosa	When the gastric mucosa was affected by infection, chemical irritation, autoimmune disease, heredity, and other factors, especially H. pylori infection, it resulted in foveal epithelial hyperplasia of the gastric mucosa. Histological findings: the height of gastric fovea was ≥0.05–0.55 mm. The cytoplasm and nucleus of the proliferating surface mucous cells showed a hazy basophilic degeneration, and the nucleus volume was increased, which was 1 time the volume of normal nucleus, with small nucleolus available. Foveal epithelial hyperplasia of gastric mucosa is a reactive hyperplasia, and is also referred to as compensatory hyperplasia. Upon eradication of H. pylori, the surface epithelial hyperplasia of gastric mucosa in this stage may be restored, therefore it is also referred to as reversible lesion.
Proliferative dysfunction of stem cells in proliferative zone	The gastric mucosa was continuously affected by infection, chemical irritation, autoimmune disease, heredity, and other factors, resulting in proliferative dysfunction of stem cells in the proliferative zone. While there was an insufficient upward migration of the proliferative zone, resulting in a reduction of gastric foveal epithelium; on the other hand, there was an insufficient downward migration of the proliferative zone, resulting in extensive atrophy of the laminar propria glands of the gastric mucosa. Lastly, it resulted in obstructed upward migration of the stem cells in the zone from top of the fundus gland to deep gastric fovea; due to changes in physiologic regularity or polarity of stem cell proliferation in the zone from top of the fundus gland to deep gastric fovea, a disordered proliferation state was formed.
Abnormal proliferation and transformation of stem cells in the proliferative zone	Continuous dysfunction of stem cells in the proliferative zone resulted in mass proliferation and accumulation of the cells in the proliferative zone of the deep gastric fovea, isthmus of the gastric gland, and superior glandular neck, thus forming a lamellar heteromorphic cell nest-like structure, which is referred to as abnormal proliferation and transformation of stem cells in the proliferative zone. This refers to epithelial cells of the gastric mucosa which are deviated from normal differentiation, and pathologically speaking, refers to the occurrence of atypia features of cell morphology and tissue structure to different degrees. Such proliferated and transformed cells showed a prolonged nucleus, mild to moderate atypia, and increased nuclear chromatin, with a small to medium-sized nucleolus visible in approximately 20%~30% of the nucleus.
Signet-ring-like heterocysts	This refers to the single cell, multiple cells, or lumpy signet-ring-like cells in the proliferative zone of the isthmus of the gastric gland, and superior glandular neck at the time of continuous abnormal proliferation and transformation. It is at a certain distance from the gland within the stroma. Such cells were 1~2 times the number of cells on the peripheral columnar epithelium in quantity, and their nucleus showed a crescent shape or an irregularly oval shape, forming the signet-ring cell carcinoid cells in cytology, therefore, they are referred to as signet-ring-like heterocysts in deep gastric fovea. Such cells were originally found between normal cervical mucus gland cells, and then gradually migrated to outside of the gland, and then entered the re-differentiation and proliferation stage, thus forming an independent monoclonal or neoplastic proliferation.
Micro signet-ring carcinoid lesion	After the re-differentiation and proliferation stage, signet-ring-like heterocysts formed into classical signet-ring cells. These cells were round in shape, with a diameter of 15~30 μm, and had light-red stained mucous substances; the nucleus was deviated and showed a signet-ring or crescent shape. Such signet-ring-like heterocysts and classical signet-ring cells formed proliferative nodes jointly, with the node size ≤ 0.5 mm. These nodes were free of hyperplasia of fibrous connective tissues, extracellular mucus, or glandular structure, and are thus referred to as micro signet-ring carcinoid lesion.
Gastric foveolar-type signet-ring cell carcinoma	The signet-ring-like heterocysts and the classical signet-ring cells made a horizontal expansion within 1/3rd of the opening side of the fundus gland mucosa jointly, at the length of 3~6 mm, therefore, they are referred to as gastric foveolar-type signet-ring cell carcinoma. Gastric foveolar-type signet-ring cell carcinoma was often accompanied by H. pylori infection, gastric mucosal erosion, or mucosal ulcer change. Or it formed local mucosal depression due to the thinning of local mucosa.
Adenocarcinoma with signet-ring cell differentiation
Undifferentiated adenocarcinoma with signet-ring cell differentiation	When gastric foveolar-type signet-ring cell carcinoma makes an invasive growth towards the mucous lamina propria or sub-mucosa, the signet-ring cells can be differentiated into undifferentiated adenocarcinoma with signet-ring cell differentiation. In terms of the tumor histology composition, it is a tumor composed of a mixture of undifferentiated cancer cells and signet-ring cells. Undifferentiated cancer cells are small in volume, and show an irregular small round shape, an oval shape, have less cytoplasm, and involve a very big proportion between the nucleus and cytoplasm, and are bare nucleus-like, and slight basophilic staining. Signet-ring carcinoma has rich cytoplasm, full of mucus, and the nucleus is pressed to one side of the cytoplasm, showing a “signet-ring” shape.
Mucinous adenocarcinoma with signet-ring cell differentiation	In terms of tumor histology composition, it is composed of signet-ring carcinoma and mucous tissues. Signet-ring carcinoma cells account for 20%~80% of the tumor. Signet-ring cancer cells are distributed in the mucous tissues in a single or diffuse way, and separate the mucous and signet-ring carcinoma cells into irregular lumps at different sizes using fibrous connective tissues. As for invasion characteristics of the tumor, it could invade spaces of the surrounding tissues to infiltrate and destroy them.
Adenoid adenocarcinoma with signet-ring cell differentiation	In terms of tumor histology composition, it is made of signet-ring carcinoma and adenocarcinoma tissues. Adenocarcinoma cells are arranged in an adenoid, fascicular, nest-like structure, and are in a staggered distribution with signet-ring cells. Signet-ring carcinoma cells can either be distributed singularly or with multiple ones close to each other, or form an adenoid, fascicular, nest-like structure together with adenocarcinoma tissues.
Fundus gland adenocarcinoma with signet-ring cell differentiation	In terms of tumor histology composition, it is composed of the signet-ring carcinoma and fundus gland adenocarcinoma tissues. Fundus gland adenocarcinoma tissues show irregular tubular and branching structures, with less stroma. In cytology, the glandular epithelial cells are columnar, the cytoplasm is basophilic, the nucleus shows an irregular round or oval shape, the cells are irregularly arranged, with significant atypia, the nucleus volume is approximately more than 2 times than that of normal master cells, and exhibits significantly visible nucleolus in the nucleus. The signet-ring cancer cells are distributed singularly or diffusely in the fundus gland adenocarcinoma tissues.