Answer: Carcinoid tumor most likely arising in the setting of autoimmune metaplastic atrophic gastritis (AMAG)

Histology: This biopsy shows a tumor composed of small round blue cells with “salt-and-pepper” nuclei. The cells form nests and cords, and the tumor is therefore best designated a carcinoid tumor. Synaptophysin and chromogranin stains were positive within the tumor cells. In addition to the tumor, areas of intestinal metaplasia are seen in this biopsy. The gastric mucosa seen around the tumor shows some parietal cells, indicative of the biopsy’s origin in the body of the stomach, but the majority of the mucosa has an “antralized/atrophic” appearance. That is, the mucosa is composed primarily of mucus cells without intervening parietal cells, and there is loss of gastric foveolae and pits. This appearance—an atrophic mucosa showing intestinal metaplasia within the body of the stomach—is most consistent with autoimmune metaplastic atrophic gastritis. Therefore, this patient has a carcinoid tumor arising in the setting of autoimmune metaplastic atrophic gastritis (AMAG).

Discussion: AMAG is an autoimmune disorder in which a patient develops antibodies against his or her parietal cells, housed in the body of the stomach. Clinically, this disorder is known as pernicious anemia, since destroyed parietal cells cannot produce the intrinsic factor that is needed for B12 absorption. The antibodies attack the parietal cells, and thus the mucosa in the body becomes atrophic and fibrotic. Intestinal metaplasia occurs as the stomach tries to regenerate itself. Because the parietal cells produce acid, the patient’s stomach becomes hypochlorhidric, and a negative inhibition on gastrin cells in the antrum is removed. This negative inhibition is removed because acid turns off the antral gastrin cells, since it is gastrin that stimulates the parietal cells in the body to produce acid. The gastrin cells there proliferate in the setting of AMAG, with the aim of increasing acid production by the parietal cells. Unfortunately, the parietal cells in the body have been destroyed by the patient’s own antibodies. The increase in gastrin also has another effect: it causes the proliferation of neuroendocrine cells in the body by way of a feedback loop. This proliferation results in neuroendocrine hyperplasia and neuroendocrine neoplasms (i.e., carcinoid tumors). One way to reduce these neuroendocrine proliferations is to remove the patient’s antrum because it is the source of the gastrin causing the neuroendocrine proliferations.

AMAG is not the only cause of neuroendocrine proliferations in the stomach. Other causes include Zollinger-Ellison (ZE) syndrome or sporadic carcinoids. In ZE syndrome, gastrin overproduction causes neuroendocrine proliferations in the stomach, just like in AMAG. However, unlike in AMAG, the gastrin overproduction itself results from an independent neoplasm, a gastrinoma. Before the diagnosis of AMAG is made, these possibilities of ZE syndrome and sporadic carcinoid should be excluded. One way to verify that an atrophic biopsy with intestinal metaplasia originates in the body (and thus may represent an AMAG) is to perform a gastrin stain. If an antralized piece of mucosa truly represents the body, a gastrin stain will be negative. This is an important test because AMAG never involves the antrum of the stomach.