World J Gastrointest Oncol. 2023 Aug 15; 15(8): 1451–1460. doi: 10.4251/wjgo.v15.i8.1451
1. Introduction
AIG는 immune-mediated destruction of gastric parietal cells 을 특징으로 하는 organ-specific disease 입니다. 이러한 destruction of the oxyntic mucosa은 hypo 및 achlorhydria를 초래하고, high circulating gastrin levels 로 이어지게 됩니다(hallmarks of AIG). Hypergastrinemia는 위체부의 enterochromaffin-like (ECL) cells의 hyperplasia 및 neoplasia의 원인이 되고, 결국 type I gNENs 발생에 중요한 위험인자 입니다.
Type I gNENs에 대한 정확한 prevalence와 incidence를 확인하는 것은 AIG 환자의 monitoring, 효과적인 검사 및 치료에 도움이 됩니다. 또한, AIG와 관련된 risk factors에 대한 연구는 high risk patients를 구분하는데 유용하고, Type I gNENs의 조기 발견과 치료로 이어져 질환의 진행을 예방할 수 있습니다. Autoimmune diseases와 cancer 사이의 복잡한 상호작용을 이해하는 것은 AIG 환자에서 type I gNENs에 대한 효과적인 검사와 치료 전략을 향상시킬 수 있을 것입니다.
2. Materials and methods
From January 2020 to June 2022까지 AIG 확진된 환자
(진단기준: Atrophic gastritis on the fundus , APCA or AIFA 양성인 경우 진단)
Retrospectively하게 환자들의 January 1990 부터 June 2022 까지의 임상 기록을 후향적으로 분석 하였습니다.
* Endoscopic examinations
- 최소 15일 이상 PPI 중단
- update Sydney system을 이용하여 5곳 biopsies
- Polypoid mucosal lesions: 발생년도, 위치(antrum, body, or fundus), size, treatment, 그리고 histological characterization
- Patients (uncomplicated chronic AIG): 3년 간격, Patients (gNENs): 1년 간격, Patients (adenocarcinoma): case-by-case
* Histological findings
- OLGA score: the stage of mucosal atrophy & the risk of gastric cancer, OLGIM score: the stage of intestinal metaplasia
- Pseudopyloric metaplasia: presence & severity
- Hyperplasia of ECL cell: proliferation > 150 µm in diameter / classification: simple, linear, micronodular, or macronodular
- Hematoxylin-eosin stain (routine exam), Alcian blue/periodic acid–Schiff stain (intstinal metaplasia), Chromogranin A (CgA) & Synaptophysin (gNENs), MIB-I antibody (Ki-67 level 측정)
* Laboratory investigations
- Hemoglobin level was < 12 g/dL in women and < 13 g/dL in men, Mean corpuscular volume > 99 fL (macrocytic anemia)
- APCA, AIFA: dilution and direct immunofluorescence techniques, and positivity was defined as ≥ 1:80
- Gastrin: quantitative chemiluminescence immunoassay, normal range < 115 pg/mL
- Circulating CgA levels: IF TRACE kit, normal range < 84.7 ng/mL (2010년 sample: CgA levels were measured using the radioimmunoassay method)
3. Results
<Characteristics of the patients, Table 1>
- 176 patients (Female: 142, 80.7%) / Median BMI: 24.6 kg/m2
- 72% of the patients had at least one autoimmune endocrine disease (autoimmune thyroid disease: most common (35.8%))
- H. pylori infection: 20.4% (eradicated in all cases)
<Esophagogastroduodenoscopy, EGDs>
176명의 내시경 건수는 total 507건이 수행되었습니다.
* Atrophy (모두 corpus-fundus atrophy가 관찰됨)
: Mild (16.2%), Moderate (44%), Severe (39.8%)
* Intestinal metaplasia (126 patients (71.5%))
: Mild (32.9%), Moderate (28.9%), Severe (9.6%)
* Pseudopyloric metaplasia: 27 patients (15.3%)
* OLGA IV stage: 3명 (severe gastric atrophy in corpus-fundus & moderate atrophy in antrum)
* ECL cell hyperplasia (116 of 176 patients (65.9%))
: simple/linear (29.5%), micronodular (30.7%), macronodular patterns (5.7%)
<Median follow-up duration: 5 years (range from 3 to 7.5 years)>
- 1032 person-years (follow-up period), 33 patients developed a total of 50 type I gNENs
: annual cumulative incidence of 5.7%, incidence rate of 0.057 person-years
<Patients with and without type I gNEN, similar characteristics. Table 2>
<Circulating CgA levels>
: Not significantly differ between the two groups
<Gastrin levels, Figure 1>
: AIG patients with gNENs showed higher levels (median 992 pg/mL, IQR = 449–1500 vs 688 pg/mL, IQR = 423–1200, P = 0.03)
Figure 1. Differences in circulating gastrin levels in patients with chronic atrophic autoimmune gastritis with or without gastric neuroendocrine tumors. gNENs: Gastric neuroendocrine neoplasms.
* Calculated gastrin sensitivity (90.9%), specificity (1.4%)
* Calculated overall diagnostic accuracy: 30%
* Receiver operating characteristic (ROC) curve in terms of gNENs detection
: calculated area under the gastrin ROC curve (AUROC or AUC): 0.53 (0.45–0.61)
: Youden index J of 0.14 corresponding to a circulating gastrin cutoff value: 857 pg/mL (sensitivity: 53.1%, specificity: 61.2%)
CONCLUSION
Our study confirms that type I gNENs represent a non-negligible complication in patients with AIG and that they are related to hypergastrinemia. Gastrin has only moderate diagnostic accuracy; therefore, it cannot be a noninvasive marker of early diagnosis of gNEN in AIG because of its low specificity. Given these findings, further efforts must be made to identify new noninvasive early markers of aberrant ECL cell proliferation so as to identify effective strategies for individualizing endoscopic follow-up of AIG patients, for early diagnosis and treatment of superimposed neuroendocrine lesions. Further studies are needed to explore the potential clinical implications of these results in managing AIG patients.
Abstract
Background: The incidence of type I gastric neuroendocrine neoplasms (gNENs) has increased significantly over the past 50 years. Although autoimmune gastritis (AIG) increases the likelihood of developing gNENs, the exact incidence and prevalence of this association remain unclear.
Aim: To evaluate the incidence and prevalence of type I gNENs in a cohort of patients with a histological diagnosis of AIG.
Methods: Patients with a histological diagnosis of AIG were enrolled between October 2020 and May 2022. Circulating levels of CgA and gastrin were assessed at enrollment. Included patients underwent regular endoscopic follow-up to detect gastric neoplastic lesions, enterochromaffin-like (ECL) cell hyperplasia, and the development of gNEN.
Results: We included 176 patients [142 women (80.7%), median age 64 years, interquartile range (IQR) 53-71 years] diagnosed with AIG between January 1990 and June 2022. At enrollment. One hundred and sixteen patients (65.9%) had ECL hyperplasia, of whom, 29.5% had simple/linear, 30.7% had micronodular, and 5.7% had macronodular type. The median follow-up time was 5 (3-7.5) years. After 1032 person-years, 33 patients developed a total of 50 type I gNENs, with an incidence rate of 0.057 person-years, corresponding to an annual cumulative incidence of 5.7%. Circulating CgA levels did not significantly differ between AIG patients who developed gNENs and those who did not. Conversely, gastrin levels were significantly higher in AIG patients who developed gNENs [median 992 pg/mL IQR = 449-1500 vs 688 pg/mL IQR = 423-1200, P = 0.03]. Calculated gastrin sensitivity and specificity were 90.9% and 1.4%, respectively, with an overall diagnostic accuracy of 30% and a calculated area under the gastrin receiver operating characteristic curve (AUROC or AUC) of 0.53.
Conclusion: Type I gNENs are a significant complication in AIG. Gastrin's low diagnostic accuracy prevents it from serving as a marker for early diagnosis. Effective strategies for early detection and treatment are needed.
World J Gastrointest Oncol. 2023 Aug 15; 15(8): 1451–1460. doi: 10.4251/wjgo.v15.i8.1451
1. Introduction
AIG는 immune-mediated destruction of gastric parietal cells 을 특징으로 하는 organ-specific disease 입니다. 이러한 destruction of the oxyntic mucosa은 hypo 및 achlorhydria를 초래하고, high circulating gastrin levels 로 이어지게 됩니다(hallmarks of AIG). Hypergastrinemia는 위체부의 enterochromaffin-like (ECL) cells의 hyperplasia 및 neoplasia의 원인이 되고, 결국 type I gNENs 발생에 중요한 위험인자 입니다.
Type I gNENs에 대한 정확한 prevalence와 incidence를 확인하는 것은 AIG 환자의 monitoring, 효과적인 검사 및 치료에 도움이 됩니다. 또한, AIG와 관련된 risk factors에 대한 연구는 high risk patients를 구분하는데 유용하고, Type I gNENs의 조기 발견과 치료로 이어져 질환의 진행을 예방할 수 있습니다. Autoimmune diseases와 cancer 사이의 복잡한 상호작용을 이해하는 것은 AIG 환자에서 type I gNENs에 대한 효과적인 검사와 치료 전략을 향상시킬 수 있을 것입니다.
2. Materials and methods
From January 2020 to June 2022까지 AIG 확진된 환자
(진단기준: Atrophic gastritis on the fundus , APCA or AIFA 양성인 경우 진단)
Retrospectively하게 환자들의 January 1990 부터 June 2022 까지의 임상 기록을 후향적으로 분석 하였습니다.
* Endoscopic examinations
- 최소 15일 이상 PPI 중단
- update Sydney system을 이용하여 5곳 biopsies
- Polypoid mucosal lesions: 발생년도, 위치(antrum, body, or fundus), size, treatment, 그리고 histological characterization
- Patients (uncomplicated chronic AIG): 3년 간격, Patients (gNENs): 1년 간격, Patients (adenocarcinoma): case-by-case
* Histological findings
- OLGA score: the stage of mucosal atrophy & the risk of gastric cancer, OLGIM score: the stage of intestinal metaplasia
- Pseudopyloric metaplasia: presence & severity
- Hyperplasia of ECL cell: proliferation > 150 µm in diameter / classification: simple, linear, micronodular, or macronodular
- Hematoxylin-eosin stain (routine exam), Alcian blue/periodic acid–Schiff stain (intstinal metaplasia), Chromogranin A (CgA) & Synaptophysin (gNENs), MIB-I antibody (Ki-67 level 측정)
* Laboratory investigations
- Hemoglobin level was < 12 g/dL in women and < 13 g/dL in men, Mean corpuscular volume > 99 fL (macrocytic anemia)
- APCA, AIFA: dilution and direct immunofluorescence techniques, and positivity was defined as ≥ 1:80
- Gastrin: quantitative chemiluminescence immunoassay, normal range < 115 pg/mL
- Circulating CgA levels: IF TRACE kit, normal range < 84.7 ng/mL (2010년 sample: CgA levels were measured using the radioimmunoassay method)
3. Results
<Characteristics of the patients, Table 1>
- 176 patients (Female: 142, 80.7%) / Median BMI: 24.6 kg/m2
- 72% of the patients had at least one autoimmune endocrine disease (autoimmune thyroid disease: most common (35.8%))
- H. pylori infection: 20.4% (eradicated in all cases)
<Esophagogastroduodenoscopy, EGDs>
176명의 내시경 건수는 total 507건이 수행되었습니다.
* Atrophy (모두 corpus-fundus atrophy가 관찰됨)
: Mild (16.2%), Moderate (44%), Severe (39.8%)
* Intestinal metaplasia (126 patients (71.5%))
: Mild (32.9%), Moderate (28.9%), Severe (9.6%)
* Pseudopyloric metaplasia: 27 patients (15.3%)
* OLGA IV stage: 3명 (severe gastric atrophy in corpus-fundus & moderate atrophy in antrum)
* ECL cell hyperplasia (116 of 176 patients (65.9%))
: simple/linear (29.5%), micronodular (30.7%), macronodular patterns (5.7%)
<Median follow-up duration: 5 years (range from 3 to 7.5 years)>
- 1032 person-years (follow-up period), 33 patients developed a total of 50 type I gNENs
: annual cumulative incidence of 5.7%, incidence rate of 0.057 person-years
<Patients with and without type I gNEN, similar characteristics. Table 2>
<Circulating CgA levels>
: Not significantly differ between the two groups
<Gastrin levels, Figure 1>
: AIG patients with gNENs showed higher levels (median 992 pg/mL, IQR = 449–1500 vs 688 pg/mL, IQR = 423–1200, P = 0.03)
Figure 1. Differences in circulating gastrin levels in patients with chronic atrophic autoimmune gastritis with or without gastric neuroendocrine tumors. gNENs: Gastric neuroendocrine neoplasms.
* Calculated gastrin sensitivity (90.9%), specificity (1.4%)
* Calculated overall diagnostic accuracy: 30%
* Receiver operating characteristic (ROC) curve in terms of gNENs detection
: calculated area under the gastrin ROC curve (AUROC or AUC): 0.53 (0.45–0.61)
: Youden index J of 0.14 corresponding to a circulating gastrin cutoff value: 857 pg/mL (sensitivity: 53.1%, specificity: 61.2%)
CONCLUSION
Our study confirms that type I gNENs represent a non-negligible complication in patients with AIG and that they are related to hypergastrinemia. Gastrin has only moderate diagnostic accuracy; therefore, it cannot be a noninvasive marker of early diagnosis of gNEN in AIG because of its low specificity. Given these findings, further efforts must be made to identify new noninvasive early markers of aberrant ECL cell proliferation so as to identify effective strategies for individualizing endoscopic follow-up of AIG patients, for early diagnosis and treatment of superimposed neuroendocrine lesions. Further studies are needed to explore the potential clinical implications of these results in managing AIG patients.
Abstract
Background: The incidence of type I gastric neuroendocrine neoplasms (gNENs) has increased significantly over the past 50 years. Although autoimmune gastritis (AIG) increases the likelihood of developing gNENs, the exact incidence and prevalence of this association remain unclear.
Aim: To evaluate the incidence and prevalence of type I gNENs in a cohort of patients with a histological diagnosis of AIG.
Methods: Patients with a histological diagnosis of AIG were enrolled between October 2020 and May 2022. Circulating levels of CgA and gastrin were assessed at enrollment. Included patients underwent regular endoscopic follow-up to detect gastric neoplastic lesions, enterochromaffin-like (ECL) cell hyperplasia, and the development of gNEN.
Results: We included 176 patients [142 women (80.7%), median age 64 years, interquartile range (IQR) 53-71 years] diagnosed with AIG between January 1990 and June 2022. At enrollment. One hundred and sixteen patients (65.9%) had ECL hyperplasia, of whom, 29.5% had simple/linear, 30.7% had micronodular, and 5.7% had macronodular type. The median follow-up time was 5 (3-7.5) years. After 1032 person-years, 33 patients developed a total of 50 type I gNENs, with an incidence rate of 0.057 person-years, corresponding to an annual cumulative incidence of 5.7%. Circulating CgA levels did not significantly differ between AIG patients who developed gNENs and those who did not. Conversely, gastrin levels were significantly higher in AIG patients who developed gNENs [median 992 pg/mL IQR = 449-1500 vs 688 pg/mL IQR = 423-1200, P = 0.03]. Calculated gastrin sensitivity and specificity were 90.9% and 1.4%, respectively, with an overall diagnostic accuracy of 30% and a calculated area under the gastrin receiver operating characteristic curve (AUROC or AUC) of 0.53.
Conclusion: Type I gNENs are a significant complication in AIG. Gastrin's low diagnostic accuracy prevents it from serving as a marker for early diagnosis. Effective strategies for early detection and treatment are needed.