Volume 123, Issue 1, Pages 68-85 (July 2002) Effect of chronic hypergastrinemia on human enterochromaffin-like cells: Insights from patients with sporadic gastrinomas  Paolo L. Peghini, Bruno Annibale, Cinzia Azzoni, Massimo Milione, Vito D. Corleto, Fathia Gibril, David J. Venzon, Gianfranco Delle Fave, Cesare Bordi, Robert T. Jensen  Gastroenterology  Volume 123, Issue 1, Pages 68-85 (July 2002) DOI: 10.1053/gast.2002.34231 Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 1 Gastric biopsy specimens showing different degrees of ECL cell changes on chromogranin A staining (A, C, E, and G) or α-hCG expression (B, D, F, and H) in different patients. (A) Qualitatively normal pattern of distribution of chromogranin A–positive immunoreactive cells (in black) in the oxyntic mucosa. (B) Consecutive section of the same area as in A, showing no cells immunoreactive for α-hCG (α-hCG 0). (C) Diffuse hyperplasia of ECL cells (in black). (D) Consecutive section of the same area as in C, showing sparse, discrete cells expressing α-hCG (α-hCG ≥1; arrows). The cell indicated by the long arrow is shown in detail in the inset. (E) Linear hyperplasia of ECL cells (in black). (F) Consecutive section of the same area as in E, showing a moderate number of α-hCG–positive cells (in black; α-hCG 2+). (G) Micronodular hyperplasia of ECL cells (in black). (H) Consecutive section of the same area as in G, showing diffuse immunostaining for α-hCG (in black; α-hCG 3+). Gastroenterology 2002 123, 68-85DOI: (10.1053/gast.2002.34231) Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 2 Correlation of increased α-hCG expression with the presence of dysplasia in patients with mild ECL cell changes. (A) Diffuse hyperplasia of ECL cells (in black) in a biopsy specimen from a patient without ECL dysplasia. (B) Consecutive section of the same area as in A, showing sparse α-hCG–immunoreactive cells (α-hCG 1+). The cell shown by an arrow is illustrated in detail in the inset. (C) Diffuse and linear hyperplasia of ECL cells (in black) in a biopsy sample from a patient with ECL cell dysplasia. (D) Consecutive section of the same area as in C, showing an abundance of α-hCG–immunoreactive cells (α-hCG 3+). Gastroenterology 2002 123, 68-85DOI: (10.1053/gast.2002.34231) Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 3 Correlation of the magnitude of the ECL index, the most advanced ECL change, and the α-hCG–immunoreactive intensity in each patient. In the 773 biopsy specimens from 106 patients, 4 patients had as their most advanced ECL change a normal ECL pattern, 54 had diffuse hyperplasia (DH), 32 had linear hyperplasia (LH), 10 had micronodular hyperplasia (MH), and 6 had dysplasia. No patient had either adenomatoid hyperplasia or a gastric carcinoid. Each dot represents data from 1 patient. The left upper panel shows the correlation between the ECL cell index for each patient and the most advanced qualitative ECL cell change. The left lower panel shows the correlation between the ECL cell index per patient and the most intense α-hCG staining. The right panel shows the correlation between the most advanced ECL cell change and the most intense α-hCG staining per patient. The mean and SEM are shown by the vertical and horizontal bars, respectively. The correlation coefficient was calculated by using a least-square analysis (left upper panel). The significance in the left lower panel and right panel was calculated from the correlation coefficient. Gastroenterology 2002 123, 68-85DOI: (10.1053/gast.2002.34231) Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 4 Effect of disease activity on the distribution of the most advanced ECL cell change and intensity of α-hCG staining. The frequency of the most advanced qualitative ECL cell changes per patient (top) or the most intense staining for α-hCG per patient (bottom) of the gastric biopsy specimens in patients with active disease (n = 90) or after curative resection (n = 16) are represented by the bar graphs. Results are expressed as the percentage of patients with the indicated degree of qualitative ECL cell change or α-hCG intensity in the indicated disease activity category. *P < 0.05; **P < 0.025; ***P < 0.01 compared with cured patients. DH, diffuse hyperplasia; LH, linear hyperplasia; MH, micronodular hyperplasia. Gastroenterology 2002 123, 68-85DOI: (10.1053/gast.2002.34231) Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 5 Influence of disease activity on the ECL cell index and expression of α-hCG. Each dot represents data for 1 patient. The ECL cell index (top) and the most intense α-hCG staining seen in a gastric biopsy per patient (bottom) are shown for each cured patient and each patient with active disease. The mean and SEM are represented by the horizontal and vertical bars, respectively. For cured disease, active disease, and all patients, the mean ECL cell index was 0.76 ± 0.18, 2.73 ± 0.24, and 2.44 ± 0.22, respectively, and the mean α-hCG intensity was 1.50 ± 0.26, 2.34 ± 0.09, and 2.22 ± 0.09, respectively. Gastroenterology 2002 123, 68-85DOI: (10.1053/gast.2002.34231) Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 6 Correlation between fasting serum gastrin level and ECL cell index in all patients (top) and those only with active disease (bottom). Fasting serum gastrin levels are expressed as logarithms to the base 10. Data of all 106 patients with a diagnosis of sporadic ZES (top) and the 90 patients with active disease (bottom) are shown. The correlation coefficient and regression line best fitting the data were calculated by a least-square analysis. Each dot represents data from 1 patient. Gastroenterology 2002 123, 68-85DOI: (10.1053/gast.2002.34231) Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 7 Effect of presence or absence and type of gastritis on ECL cell index. Data from 88 of 90 patients with active disease are shown. Two patients were excluded because of the presence of acute gastritis (n = 1) or because of atrophic gastritis in the antrum only (n = 1). Each dot represents the ECL cell index for a single patient. The mean and SEM of the 3 groups are shown by horizontal bars and vertical lines, respectively. Gastroenterology 2002 123, 68-85DOI: (10.1053/gast.2002.34231) Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 8 Correlation of increased α-hCG staining with the presence of dysplasia in patients with advanced ECL cell changes. (A) Severe diffuse micronodular hyperplasia of ECL cells (in black) in a biopsy sample of a patient without ECL cell dysplasia. (B) Consecutive section of the same area as in A, showing sparse α-hCG–expressing cells (long arrow), whereas the majority of micronodules are unreactive (short arrows; α-hCG 1+). (C) Micronodular and linear hyperplasia of ECL cells (in black) in a biopsy specimen of a patient with ECL cell dysplasia. (D) Consecutive section of the same area as in C, showing an abundance of α-hCG–immunoreactive cells (α-hCG 3+). Gastroenterology 2002 123, 68-85DOI: (10.1053/gast.2002.34231) Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 9 Effect of various clinical, laboratory, and tumoral parameters or gastric biopsy findings on the expression of α-hCG. Shown are the data from 90 patients with active disease. The category “largest tumor size” contains data from the 31 patients without liver metastasis who had tumors ≤1 or ≥3 cm. “Duration of PPI” includes data from the 85 patients with active disease who were treated at any time with a PPI. Gastroenterology 2002 123, 68-85DOI: (10.1053/gast.2002.34231) Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 10 Effect of the presence or absence of dysplasia on α-hCG intensity. Data are from 612 biopsy specimens that were evaluable for both qualitative ECL cell changes and α-hCG staining intensity. Biopsy samples were grouped according to whether they showed mild ECL cell changes (normal pattern [n = 56] or diffuse hyperplasia [n = 392]) or more advanced ECL cell changes (linear hyperplasia [n = 115] or micronodular hyperplasia [n = 49]). Gastroenterology 2002 123, 68-85DOI: (10.1053/gast.2002.34231) Copyright © 2002 American Gastroenterological Association Terms and Conditions