Cereus. 2024 Aug 15;16(8):e66910. doi: 10.7759/cureus.66910.
Introduction
Accurately diagnosing AIG cases without H. pylori infection
1) Exclude cases with a history of eradication by performing a detailed evaluation
2) Confirm negative H. pylori test results using two or more modalities to exclude current cases of H. pylori infection
3) Confirm corpus-restricted histologic gastritis with spared antrum to exclude cases of current and past H. pylori infection
Case presentation
70세 여자
Upper gastrointestinal endoscopy: flat whitish lesion in the prepylorus (Figure 1A) - Endoscopically resected
Pathology: adenoma (background mucosa exhibited reactive gastropathy), pyloric atrophy/intestinal metaplasia (-/-) (Figure 1B)
Figure 1. Endoscopic and histologic findings of intestinal-type adenoma in the gastric antrum
A) White light endoscopy reveals an elevated round lesion in the gastric antrum adjacent to the pylorus ring.
B) Histological findings of the endoscopically resected specimen. The pyloric mucosa surrounding the intestinal type adenoma with low-grade dysplasia shows no atrophy or intestinal metaplasia with corkscrew-like foveolar hyperplasia, suggesting reactive gastropathy (hematoxylin and eosin staining; magnification, ×40).
“Corpus-dominant advanced atrophy”
Antrum: normal (Figure 2A), Corpus: severely atrophy (Figure 2B)
Figure 2. Endoscopic findings of background mucosa suggestive of autoimmune gastritis
A) Conventional white light endoscopic findings of the gastric antrum showing no atrophy.
B) Conventional white light endoscopic findings of the gastric body showing severe atrophy with marked vascular visibility on the entire great curvature of the gastric body and scattered hyperplastic polyps. Endoscopy of the gastric antrum and body reveals “corpus-dominant advanced atrophy,” which is a typical feature of autoimmune gastritis (AIG).
* Serologic findings
Anti-parietal cell antibodies (40-fold positive), Anti-intrinsic antibodies (negative)
Gastrin: 2950 pg/ml (normal range: 37-172 pg/ml)
Pepsinogen I: 6.3 ng/ml, Pepsinogen II: 5.7 ng/ml, Pepsinogen I/II ratio: 1.1
Vitamin B12: 135 pg/ml (normal range: 233-914 pg/ml)
* Histologic findings
Greater curvature of the body: Loss of parietal cells and intestinal metaplasia (Figure 3A)
Chromogranin A staining: Extraglandular micronodular hyperplasia of enterochromaffin-like cells (Figure 3B)
Antrum: No pyloric gland atrophy and no inflammatory cell infiltration (Figure 3C)
Background mucosa of the corpus in the resected specimen: Complete intestinal metaplasia (Figure 3D)
Figure 3. Histological findings of background mucosa compatible with autoimmune gastritis (AIG) without current and past H. pylori infection
A) Histological findings of the oxyntic mucosa biopsy reveal a marked reduction in the oxyntic gland, including the absence of parietal cells, intestinal metaplasia, pseudopyloric metaplasia, and thickened muscularis mucosae (hematoxylin and eosin staining; magnification, ×100).
B) Immunohistochemical staining with chromogranin A identifies enterochromaffin-like cells that line the long portion of the gastric pit, indicating “linear hyperplasia,” and form small clusters, indicating an endocrine cell micronest (arrowhead) (Chromogranin A staining; magnification, ×100).
C) Histological findings of the pyloric mucosa biopsy reveal no pyloric gland atrophy or intestinal metaplasia with foveolar hyperplasia, suggesting reactive gastropathy. Histological findings in the body and antrum are typical of end-stage AIG (hematoxylin and eosin staining; magnification, ×100).
D) Complete intestinal metaplasia is recognized in the background mucosa of the corpus (hematoxylin and eosin staining; magnification, ×200).
* H. pylori antibodies test, stool test of H. pylori antigens, H. pylori culture, H. pylori histology obtained using Giemsa staining: negative
--> These H. pylori test results and pathological findings of the antrum without atrophy (Figures 1B, 3C) suggested that current and past H. pylori infections were unlikely; therefore, we suspected pure AIG without H. pylori infection.
4 years later, endoscopy:
Lesser curvature of the antrum: flat lesion (Figure 4A)
Lower body: depressed lesion (Figure 4B)
Figure 4. Endoscopic findings of gastric cancers in the angle and body
A) Conventional white light endoscopy of the gastric angle. A whitish-raised lesion is observed in the angle. The biopsy results indicate differentiated adenocarcinoma.
B) Conventional white light endoscopy of the gastric body. An erythematous depressed lesion with a nodule at the margins is observed in the lower corpus of the greater curvature, where a poorly cohesive carcinoma is detected (arrowhead). At this angle, a whitish-raised lesion (A) is observed (arrow).
Surgery was performed
(Final pathological stage: stage I (T1b, N0, M0) according to the 8th edition of the AJCC)
* Lesion at the gastric angle: intramucosal differentiated adenocarcinoma (Figures 5A-5B)
Figure 5. Histological findings of the resected specimen of gastric cancer in the angle
A) Microscopic findings of the resected specimen of the lesion in the gastric angle. Differentiated adenocarcinoma localized in the mucosa without invasion into the submucosal layer is observed (hematoxylin and eosin staining; magnification, ×40).
B) Highly magnified image. The right side of the specimen shows a well-differentiated adenocarcinoma with minimal glandular alterations, whereas the left side shows severe glandular alterations (hematoxylin and eosin staining; magnification, ×200).
* Lesion at the gastric body: poorly cohesive carcinoma with a signet ring cell component invading the deep layer of the submucosa (>1 mm) with lymphovascular involvement (Figures 6A-6D)
Figure 6. Histological findings of the resected specimen of gastric cancer in the body
A) Microscopic findings of the resected specimen of the lesion in the gastric body. Poorly cohesive carcinoma invading the submucosal layer is observed (hematoxylin and eosin staining; magnification, ×40).
B) Highly magnified image. Classic signet ring cell carcinoma is observed in the superficial layer. Poorly cohesive carcinoma is observed in the deep layer (hematoxylin and eosin staining; magnification, ×200).
C) Cytokeratin AE1/AE3 staining indicates that the tumor has invaded the deeper submucosal layers just above the muscle layer (arrowhead) (Cytokeratin AE1/AE3 staining; magnification, ×12.5).
D) Elastica van Gieson staining of the vein reveals intravascular invasion of tumor cells, suggesting positive lymphovascular invasion (Elastica van Gieson staining; magnification, ×200).
Discussion
Severe hypoacidity & Marked hypergastrinemia: risk of gastric carcinogenesis
Microbe overgrowth d/t hypoacidity: induces N-nitrosation
Complete intestinal metaplasia is not rare in patients with AIG accompanied by gastric cancer (5/26 (19%) cases in their study)
In our case, the background mucosa showed complete intestinal metaplasia
During this study, we collected cases of strict H. pylori-negative AIG-associated gastric cancer (as in our case) (Table 1: 5 cases)
Following Criteria:
(1) No history of eradication and two or more H. pylori tests with negative results
(2) Either positive anti-parietal cell antibodies or positive anti-intrinsic factor antibodies
(3) Pathological findings of the gastric body compatible with AIG (severe atrophy of oxyntic glands, metaplasia, diffuse lymphoplasmacytic infiltration, enterochromaffin-like cell hyperplasia etc.) without pyloric gland atrophy, metaplasia and inflammatory cell infiltration in the antrum
Table 1. Gastric cancer accompanied by autoimmune gastritis without current and past H. pylori infections
M: mucosal layer; SM: submucosal layer; SAT: stool antigen test; UBT: urea breath test
* Autoantibodies: more than 40-fold positive for anti-parietal cell antibodies in four patients and positive for anti-intrinsic factor antibodies in two patients
* Gastrin: high (>2500 pg/ml) in all patients
* Pepsinogen: <10 ng/ml in three patients
* Vitamin B12: only 4 patients could be measured. Of these four patients, three had vitamin B12 levels less than 200 pg/ml
* Endocrine cell micronests: 4 patients
* Gastric cancers: one case of a hyperplastic polyp that progressed to carcinoma / one case of fundic type gastric adenocarcinoma / two cases of differentiated adenocarcinoma
* 3 cases remained in the mucosa --> high-grade dysplasia according to the 8th AJCC
* Submucosal invasion: 2 cases
* Location: 4 lesions were located in the corpus. 2 lesions were located in the antrum.
Most reported cases of H. pylori-negative AIG with gastric cancer complications were accompanied by pathological endocrine cell micronests. Endocrine cell micronests arise from intraductal linear enterochromaffin-like cell hyperplasia and are observed during late-stage AIG; therefore, the reported cases of AIG can be interpreted as both serologically and histologically advanced. Most gastric cancers in AIG are thought to be associated with H. pylori infection; however, in H. pylori-negative AIG, the absence of H. pylori carcinogenic risk may require a high degree of gastric mucosal atrophy.
Conclusions
Our case of H. pylori-negative AIG was complicated by both differentiated adenocarcinoma and poorly cohesive carcinoma. Based on previous case reports of gastric cancer in patients with H. pylori-negative AIG, advanced-stage AIG may be associated with a high risk of gastric cancer. Therefore, surveillance for gastric cancer in patients with H. pylori-negative AIG is particularly necessary, especially for those with advanced atrophy. Discussions of the clinical characteristics of H. pylori-negative AIG complicated with gastric cancer and risk factors for gastric cancer have been limited to case reports. Therefore, large cohort studies that include more H. pylori-negative AIG cases diagnosed according to an unbiased and strict definition are necessary to confirm these findings.
Abstract
Recent studies have suggested that gastric cancer does not occur in patients with Helicobacter pylori-negative autoimmune gastritis (AIG); however, this notion is controversial. We encountered a case of gastric cancer associated with AIG in which H. pylori infection was excluded. A woman in her 70s was referred to our hospital for endoscopic resection of an antral adenoma. An H. pylori antibodies test, stool antigens test, H. pylori culture, and histological analysis using Giemsa staining yielded negative results. AIG was suspected because the antrum was endoscopically normal but the body was severely atrophic, which are typical findings of AIG. Anti-parietal cell antibodies were 40-fold positive, the gastrin level was 2950 pg/ml, and the pepsinogen I level, pepsinogen II level, and pepsinogen I/II ratio were 6.3 ng/ml, 5.7 ng/ml, and 1.1, respectively. A pathological examination of the gastric body revealed severe oxyntic atrophy with hyperplasia of enterochromaffin-like cells, whereas the antrum showed no pyloric gland atrophy or inflammation. These findings indicated that the patient had H. pylori-negative AIG. Four years later, a depressed lesion in the lower body and a flat lesion at the angle were observed; the former was a poorly cohesive carcinoma, and the latter was a differentiated adenocarcinoma. Surgical resection revealed that the lesion in the lower body was a poorly cohesive carcinoma invading the submucosa with vascular involvement, whereas the lesion in the angle was an intramucosal differentiated adenocarcinoma. A review of previous studies of gastric cancer with H. pylori-negative AIG suggested that patients with histologically and serologically advanced gastritis are at high risk for carcinogenesis. Even in H. pylori-negative cases, severe gastric mucosal atrophy in AIG cases may indicate a carcinogenic risk; therefore, surveillance for gastric cancer is especially recommended for these cases. Large cohort studies on the association between H. pylori-negative AIG and gastric cancer are warranted.
Keywords: histology, endoscopy, pepsinogen, gastric cancer, helicobacter pylori, autoimmune gastritis
Cereus. 2024 Aug 15;16(8):e66910. doi: 10.7759/cureus.66910.
Introduction
Accurately diagnosing AIG cases without H. pylori infection
1) Exclude cases with a history of eradication by performing a detailed evaluation
2) Confirm negative H. pylori test results using two or more modalities to exclude current cases of H. pylori infection
3) Confirm corpus-restricted histologic gastritis with spared antrum to exclude cases of current and past H. pylori infection
Case presentation
70세 여자
Upper gastrointestinal endoscopy: flat whitish lesion in the prepylorus (Figure 1A) - Endoscopically resected
Pathology: adenoma (background mucosa exhibited reactive gastropathy), pyloric atrophy/intestinal metaplasia (-/-) (Figure 1B)
Figure 1. Endoscopic and histologic findings of intestinal-type adenoma in the gastric antrum
A) White light endoscopy reveals an elevated round lesion in the gastric antrum adjacent to the pylorus ring.
B) Histological findings of the endoscopically resected specimen. The pyloric mucosa surrounding the intestinal type adenoma with low-grade dysplasia shows no atrophy or intestinal metaplasia with corkscrew-like foveolar hyperplasia, suggesting reactive gastropathy (hematoxylin and eosin staining; magnification, ×40).
“Corpus-dominant advanced atrophy”
Antrum: normal (Figure 2A), Corpus: severely atrophy (Figure 2B)
Figure 2. Endoscopic findings of background mucosa suggestive of autoimmune gastritis
A) Conventional white light endoscopic findings of the gastric antrum showing no atrophy.
B) Conventional white light endoscopic findings of the gastric body showing severe atrophy with marked vascular visibility on the entire great curvature of the gastric body and scattered hyperplastic polyps. Endoscopy of the gastric antrum and body reveals “corpus-dominant advanced atrophy,” which is a typical feature of autoimmune gastritis (AIG).
* Serologic findings
Anti-parietal cell antibodies (40-fold positive), Anti-intrinsic antibodies (negative)
Gastrin: 2950 pg/ml (normal range: 37-172 pg/ml)
Pepsinogen I: 6.3 ng/ml, Pepsinogen II: 5.7 ng/ml, Pepsinogen I/II ratio: 1.1
Vitamin B12: 135 pg/ml (normal range: 233-914 pg/ml)
* Histologic findings
Greater curvature of the body: Loss of parietal cells and intestinal metaplasia (Figure 3A)
Chromogranin A staining: Extraglandular micronodular hyperplasia of enterochromaffin-like cells (Figure 3B)
Antrum: No pyloric gland atrophy and no inflammatory cell infiltration (Figure 3C)
Background mucosa of the corpus in the resected specimen: Complete intestinal metaplasia (Figure 3D)
Figure 3. Histological findings of background mucosa compatible with autoimmune gastritis (AIG) without current and past H. pylori infection
A) Histological findings of the oxyntic mucosa biopsy reveal a marked reduction in the oxyntic gland, including the absence of parietal cells, intestinal metaplasia, pseudopyloric metaplasia, and thickened muscularis mucosae (hematoxylin and eosin staining; magnification, ×100).
B) Immunohistochemical staining with chromogranin A identifies enterochromaffin-like cells that line the long portion of the gastric pit, indicating “linear hyperplasia,” and form small clusters, indicating an endocrine cell micronest (arrowhead) (Chromogranin A staining; magnification, ×100).
C) Histological findings of the pyloric mucosa biopsy reveal no pyloric gland atrophy or intestinal metaplasia with foveolar hyperplasia, suggesting reactive gastropathy. Histological findings in the body and antrum are typical of end-stage AIG (hematoxylin and eosin staining; magnification, ×100).
D) Complete intestinal metaplasia is recognized in the background mucosa of the corpus (hematoxylin and eosin staining; magnification, ×200).
* H. pylori antibodies test, stool test of H. pylori antigens, H. pylori culture, H. pylori histology obtained using Giemsa staining: negative
--> These H. pylori test results and pathological findings of the antrum without atrophy (Figures 1B, 3C) suggested that current and past H. pylori infections were unlikely; therefore, we suspected pure AIG without H. pylori infection.
4 years later, endoscopy:
Lesser curvature of the antrum: flat lesion (Figure 4A)
Lower body: depressed lesion (Figure 4B)
Figure 4. Endoscopic findings of gastric cancers in the angle and body
B) Conventional white light endoscopy of the gastric body. An erythematous depressed lesion with a nodule at the margins is observed in the lower corpus of the greater curvature, where a poorly cohesive carcinoma is detected (arrowhead). At this angle, a whitish-raised lesion (A) is observed (arrow).
Surgery was performed
(Final pathological stage: stage I (T1b, N0, M0) according to the 8th edition of the AJCC)
* Lesion at the gastric angle: intramucosal differentiated adenocarcinoma (Figures 5A-5B)
Figure 5. Histological findings of the resected specimen of gastric cancer in the angle
A) Microscopic findings of the resected specimen of the lesion in the gastric angle. Differentiated adenocarcinoma localized in the mucosa without invasion into the submucosal layer is observed (hematoxylin and eosin staining; magnification, ×40).
B) Highly magnified image. The right side of the specimen shows a well-differentiated adenocarcinoma with minimal glandular alterations, whereas the left side shows severe glandular alterations (hematoxylin and eosin staining; magnification, ×200).
* Lesion at the gastric body: poorly cohesive carcinoma with a signet ring cell component invading the deep layer of the submucosa (>1 mm) with lymphovascular involvement (Figures 6A-6D)
Figure 6. Histological findings of the resected specimen of gastric cancer in the body
A) Microscopic findings of the resected specimen of the lesion in the gastric body. Poorly cohesive carcinoma invading the submucosal layer is observed (hematoxylin and eosin staining; magnification, ×40).
B) Highly magnified image. Classic signet ring cell carcinoma is observed in the superficial layer. Poorly cohesive carcinoma is observed in the deep layer (hematoxylin and eosin staining; magnification, ×200).
C) Cytokeratin AE1/AE3 staining indicates that the tumor has invaded the deeper submucosal layers just above the muscle layer (arrowhead) (Cytokeratin AE1/AE3 staining; magnification, ×12.5).
D) Elastica van Gieson staining of the vein reveals intravascular invasion of tumor cells, suggesting positive lymphovascular invasion (Elastica van Gieson staining; magnification, ×200).
Discussion
Severe hypoacidity & Marked hypergastrinemia: risk of gastric carcinogenesis
Microbe overgrowth d/t hypoacidity: induces N-nitrosation
Complete intestinal metaplasia is not rare in patients with AIG accompanied by gastric cancer (5/26 (19%) cases in their study)
In our case, the background mucosa showed complete intestinal metaplasia
During this study, we collected cases of strict H. pylori-negative AIG-associated gastric cancer (as in our case) (Table 1: 5 cases)
Following Criteria:
(1) No history of eradication and two or more H. pylori tests with negative results
(2) Either positive anti-parietal cell antibodies or positive anti-intrinsic factor antibodies
(3) Pathological findings of the gastric body compatible with AIG (severe atrophy of oxyntic glands, metaplasia, diffuse lymphoplasmacytic infiltration, enterochromaffin-like cell hyperplasia etc.) without pyloric gland atrophy, metaplasia and inflammatory cell infiltration in the antrum
Table 1. Gastric cancer accompanied by autoimmune gastritis without current and past H. pylori infections
M: mucosal layer; SM: submucosal layer; SAT: stool antigen test; UBT: urea breath test
* Autoantibodies: more than 40-fold positive for anti-parietal cell antibodies in four patients and positive for anti-intrinsic factor antibodies in two patients
* Gastrin: high (>2500 pg/ml) in all patients
* Pepsinogen: <10 ng/ml in three patients
* Vitamin B12: only 4 patients could be measured. Of these four patients, three had vitamin B12 levels less than 200 pg/ml
* Endocrine cell micronests: 4 patients
* Gastric cancers: one case of a hyperplastic polyp that progressed to carcinoma / one case of fundic type gastric adenocarcinoma / two cases of differentiated adenocarcinoma
* 3 cases remained in the mucosa --> high-grade dysplasia according to the 8th AJCC
* Submucosal invasion: 2 cases
* Location: 4 lesions were located in the corpus. 2 lesions were located in the antrum.
Most reported cases of H. pylori-negative AIG with gastric cancer complications were accompanied by pathological endocrine cell micronests. Endocrine cell micronests arise from intraductal linear enterochromaffin-like cell hyperplasia and are observed during late-stage AIG; therefore, the reported cases of AIG can be interpreted as both serologically and histologically advanced. Most gastric cancers in AIG are thought to be associated with H. pylori infection; however, in H. pylori-negative AIG, the absence of H. pylori carcinogenic risk may require a high degree of gastric mucosal atrophy.
Conclusions
Our case of H. pylori-negative AIG was complicated by both differentiated adenocarcinoma and poorly cohesive carcinoma. Based on previous case reports of gastric cancer in patients with H. pylori-negative AIG, advanced-stage AIG may be associated with a high risk of gastric cancer. Therefore, surveillance for gastric cancer in patients with H. pylori-negative AIG is particularly necessary, especially for those with advanced atrophy. Discussions of the clinical characteristics of H. pylori-negative AIG complicated with gastric cancer and risk factors for gastric cancer have been limited to case reports. Therefore, large cohort studies that include more H. pylori-negative AIG cases diagnosed according to an unbiased and strict definition are necessary to confirm these findings.
Abstract
Recent studies have suggested that gastric cancer does not occur in patients with Helicobacter pylori-negative autoimmune gastritis (AIG); however, this notion is controversial. We encountered a case of gastric cancer associated with AIG in which H. pylori infection was excluded. A woman in her 70s was referred to our hospital for endoscopic resection of an antral adenoma. An H. pylori antibodies test, stool antigens test, H. pylori culture, and histological analysis using Giemsa staining yielded negative results. AIG was suspected because the antrum was endoscopically normal but the body was severely atrophic, which are typical findings of AIG. Anti-parietal cell antibodies were 40-fold positive, the gastrin level was 2950 pg/ml, and the pepsinogen I level, pepsinogen II level, and pepsinogen I/II ratio were 6.3 ng/ml, 5.7 ng/ml, and 1.1, respectively. A pathological examination of the gastric body revealed severe oxyntic atrophy with hyperplasia of enterochromaffin-like cells, whereas the antrum showed no pyloric gland atrophy or inflammation. These findings indicated that the patient had H. pylori-negative AIG. Four years later, a depressed lesion in the lower body and a flat lesion at the angle were observed; the former was a poorly cohesive carcinoma, and the latter was a differentiated adenocarcinoma. Surgical resection revealed that the lesion in the lower body was a poorly cohesive carcinoma invading the submucosa with vascular involvement, whereas the lesion in the angle was an intramucosal differentiated adenocarcinoma. A review of previous studies of gastric cancer with H. pylori-negative AIG suggested that patients with histologically and serologically advanced gastritis are at high risk for carcinogenesis. Even in H. pylori-negative cases, severe gastric mucosal atrophy in AIG cases may indicate a carcinogenic risk; therefore, surveillance for gastric cancer is especially recommended for these cases. Large cohort studies on the association between H. pylori-negative AIG and gastric cancer are warranted.
Keywords: histology, endoscopy, pepsinogen, gastric cancer, helicobacter pylori, autoimmune gastritis