Reportedly, the overall risk of developing a carcinoid tumor in patients with pernicious anemia is 4% (1). The incidence of endocrine cell hyperplasia is less clear in atrophic gastritis (AG) patients without pernicious anemia. Moreover, the progression sequence of endocrine cell hyperplasia on one end of the spectrum to an unequivocal gastric carcinoid at the opposite end is a problematic and confusing pathologic and clinical dilemma.

Solcia et al. has proposed a classification schema for proliferative endocrine cell lesions in patients with AG (2). This system seems to be intuitive and relevant. The proposed sequence features three basic categories of hyperplasia, dysplasia and neoplasia. The three basic categories each have a number of patterns or types as listed below:

Figure 1: H and E stain showing endocrine cell clusters 

Figure 2: Chromogranin immunohistochemical stain showing
same cell clusters
 

Hyperplasia - diffuse, linear (chain-forming),
micronodular and adenomatoid

Dysplasia – enlarged, adenomatous or fused
micronodules; microinfiltration, and nodular
growth with newly formed stroma

Neoplasia – intramucosal or invasive carcinoids

A progression of this sequence from endocrine cell hyperplasia to dysplasia and ultimately to neoplasia has been observed in multiple endocrine neoplasia (MEN)-Zollinger Ellison syndrome and chronic atrophic gastritis. Although hyperplastic endocrine cell changes have been noted to occur in chronic gastritis associated with Helicobacter pylori and ulcer disease/dyspepsia, progression to dysplasia and/or neoplasia has not been observed.

Nodular endocrine cell hyperplasia can, uncommonly, lead to the development of a carcinoid tumor (3-5). However, those carcinoid tumors that do result from nodular endocrine cell hyperplasia do not typically behave like more prototypical mid-gut carcinoids in that they usually lack excessive catecholamine production and a clinical carcinoid syndrome. When these gastric carcinoids are “small” (<2 cm) they behave in a nonaggressive or benign fashion. When they exceed 2 cm, they possess a slight potential for aggressive or malignant behavior. Hypergastrinemia, regardless of the source, is the source of stimulation that can prod the enterochromaffin- like cells to hyperplasia and ultimately neoplasia (3-6).

The details of the subheadings of the Solcia derived system is based on subjective histological appearance and less subjective size measurements. However, it is important to remember that perhaps the biggest and most important distinction lies in knowing the background in which the endocrine hyperplasia is arising. Specifically, is the proliferation, regardless of the stage of the hyperplasia- dysplasia-neoplasia sequence it is in, occurring in the setting of a chronic atrophic gastritis secondary to an autoimmune process/MEN or in a setting of Helicobacter pylori/dyspepsia/ulcer disease? This is critical in that both can produce endocrine cell proliferations but the latter category does not progress to neoplasia (carcinoid tumor) while the former can, albeit uncommonly.

A 1992 study by McCloy (7) focused on a review of a number of studies of endoscopic monitoring of patients with long term omeprazole therapy. A total of 646 patients were included who underwent routine endoscopic evaluation with gastric biopsy for up to 5.5 years. He found that in patients receiving treatment for peptic ulcer disease/reflux esophagitis, routine endoscopic surveillance demonstrated no neoplastic changes. Four of 184 patients with ZES were found to have macroscopic lesions and one patient with MEN 1 developed multiple gastric endocrine tumors and another showed a gastric carcinoid following seven years of omeprazole therapy. In evaluating the studies of patients with pernicious anemia and/or low acid state secondary to gastric resections, he concluded routine endoscopic surveillance other than for clinical indications was not justified to simply evaluate for neoplastic developments. His article does not address monitoring of patients once they have shown endocrine cell hyperplasia/neoplasia on biopsy as in this case.

Clearly, this area represents an area of difficulty amongst pathologists in assigning the precisely correct pathologic diagnosis. Furthermore, the appropriate clinical followup of patients showing hyperplasic or neoplastic endocrine processes is also problematic.

REFERENCES:
1. Borch K. Epidemiologic, clinicopathologic, and economic aspects of gastroscopic screening of patients pernicious anemia. Scand J Gastroenterol 1986;21:21- 30.

2. Solcia E, Fiocca R, Villani L et al. Hyperplastic, dysplastic and neoplastic enterochromaffin-like cell proliferations of the gastric mucosa. Classification and histogenesis. Am J Surg Pathol. 1995;19 Suppl 1:S1-7. Review.

3. Carney JA, Go VL, Fairbanks VF, et al. The syndrome of gastric argyrophil carcinoid tumor and non-antral gastric atrophy. Ann Intern Med 1983; 99:761-6.

4. Borch K, Renvall H, Liedberg G. Gastric endocrine cell hyperplasia and carcinoid tumors in pernicious anemia. Gastroenterology 1985;88:638-48.

5. Muller J, Kirchner T, Muller-Hermelink HK. Gastric endocrine cell hyperplasia and carcinoid tumors in atrophic gastritis type A. Am J Surg Pathol 1987; 11:909-17.

6. Moyles K, Owen DA, Scudamore CH and Bogoch A. Hypergastrinemia, gastric endocrine cell hyperplasia, and intractable diarrhea. Gastroenterolo 1990; 12(6):675-80.

7. McCloy R. Is endoscopy helpful in patient monitoring? Digestion 1992; 51 (suppl 1): 115-119.