Atrophic gastritis can be classified into two types based on etiology: type A (autoimmune) and type B (environmental). Type B gastritis, with Helicobacter pylori being the most common agent of gastritis, is much more common and is characterized by antrum-predominant atrophy.¹ On the other hand, autoimmune gastritis (AIG; type A gastritis) exhibits a corpus-predominant atrophy due to the destruction of parietal cells by antiparietal cell antibody (APCA) and/or anti-intrinsic factor antibody.¹ Worldwide, the frequency of AIG is estimated to be approximately 0.5% to 2%.¹ In Asia, the frequency of AIG is considered rare and was previously underestimated; however, its frequency has steadily increased with the rising awareness of this condition.^2,3 Additionally, AIG concurrent with previous or current H. pylori infection has been reported in various ranges, and potential links between the two conditions are suggested.⁴ Therefore, AIG in H. pylori-prevalent countries draws significant clinical attention.

Although the symptoms of AIG are nonspecific, several factors are clinically significant. The complications of AIG include iron deficiency anemia, pernicious anemia, and neurologic symptoms due to decreased acid secretion, intrinsic factors, and vitamin B₁₂ deficiency.³ In addition, reduced acid secretion leads to hypergastrinemia as a negative feedback mechanism and consequent enterochromaffin-like (ECL) neuroendocrine cell hyperplasia in the corpus.³ Accordingly, there is an increasing risk of neuroendocrine tumor (NET).¹ While the risk of developing NET is well-established, the risk of gastric cancer (GC) in AIG remains controversial. Chronic atrophic gastritis, mostly caused by H. pylori gastritis, is a known risk factor for GC.¹ Patients with AIG, particularly those with a long-staining disease, are known to have a 2- to 4-fold increased risk of developing GC than the normal population.¹ However, older studies did not consider the possible concurrence of H. pylori infection and are inadequate in providing accurate information on the risk of GC in AIG.⁵ Recently, Rugge et al.⁵ revealed no excess risk of GC for highly selected 211 patients with H. pylori-negative AIG over a mean follow-up period of 7.5 years. Nevertheless, it still remains inconclusive in that longer follow-up is required, and GC development in AIG in association with H. pylori needs to be elucidated.^6,7

The frequency of AIG in patients with GC is even less well-established, with reported incidences ranging from 2% to 7.5% in GC cohorts.^2,8-10 However, reliable frequency data remain scarce due to the limited number of studies and the inconsistent criteria applied to AIG. In this study, we assessed the frequency of AIG in Korean patients with gastric tumors (n=624) using stringent diagnostic criteria. We also detail the clinicopathological features of AIG in patients with gastric tumors in a country where both H. pylori-associated atrophic gastritis and GC are common, with the detailed diagnostic criteria.

1. Study design and population

This was a retrospective observational study conducted at a single academic hospital in Korea. Without selecting specific patients, serum APCA was tested in all patients who visited J.H.L.’s Outpatient Clinic of Gastroenterology in Samsung Medical Center between January 2021 and June 2023 for the management of gastric tumors. The inclusion criteria for this study were as follows: (1) patients who had serum APCA results; (2) histologically confirmed GC or NET; and (3) availability of a review of endoscopy and histology for AIG. A total of 624 patients met the inclusion criteria (612 GC and 12 NET). All GCs were histologically confirmed as carcinoma, and other malignancies such as lymphoma were excluded from the final analyses. Serum anti-Helicobacter IgG antibody (HpAb) and pepsinogen (PG) I/II levels were tested in all patients, along with APCA. Serum gastrin levels were measured in 23 patients (11 GC and 12 NET).

Among the 624 patients, those with positive APCA were selected, and endoscopy and histology were comprehensively reviewed to diagnose AIG in the background. The preoperative endoscopic findings were reviewed by T.S.K. and J.H.L. We reviewed endoscopic images of 37 APCA-positive patients to assess the presence of reverse atrophy. In addition, we examined endoscopic images of 133 HpAb-negative patients to determine whether the regular arrangement of collecting venules (RAC) in the gastric angle was maintained. Histology was assessed by S.A. and K.M.K. The histological diagnosis of AIG was confirmed by R.K., a knowledgeable expert in AIG pathology among Asian patients. The flowchart of this study is illustrated in Fig. 1. Clinical information, including laboratory results, was retrieved from medical records. This study was approved by the Institutional Review Board of Samsung Medical Center (IRB number: SMC 2024-03-057). The requirement for informed consent was waived because of the retrospective nature of the study.

Figure 1. Flowchart of study and frequency of autoimmune gastritis (AIG). APCA, antiparietal cell antibody; GC, gastric cancer; NET, neuroendocrine tumor. *Two of three patients: concurrent AIG and Helicobacter pylori gastritis; ^†All two patients: concurrent AIG and H. pylori gastritis.

2. Laboratory tests

Serum APCA was tested with indirect immunofluorescence, using NOVA Lite^Ⓡ ANA KSL Mouse Kidney/Stomach/Liver Kit (Inova Diagnostics, San Diego, CA, USA), and a titer >1:20 was reported positive. PG I and PG II were tested with CIAS Latex PG I and II kit (Kanto Chemical, Tokyo, Japan) and analyzed by Cobas^Ⓡ c702 (Roche Diagnostics, Indianapolis, IN, USA). Serum HpAb titer was determined using PLATELIA H. pylori IgG (Bio-Rad, Hercules, CA, USA).

3. Histology examination

For patients with positive APCA results, hematoxylin and eosin-stained slides of the biopsy and resection were retrieved. Corpus tissue apart from the tumor was reviewed for the diagnosis of AIG and scored according to the updated Sydney scoring.¹¹ Non-tumor antral tissue was reviewed in available cases, and updated Sydney scoring was performed.¹¹

Representative formalin-fixed paraffin-embedded blocks of the corpus were selected for each case, and chromogranin A and gastrin immunohistochemistry (IHC) were performed. Gastrin IHC of the corpus confirmed that the tissue was from the corpus and not the antrum.¹² H. pylori IHC was conducted in cases where H. pylori presence was equivocal on hematoxylin and eosin-stained slides. IHC employed the following antibodies: Chromogranin A mouse monoclonal antibody (1:800 dilution, DAKO, Glostrup, Denmark; clone DAK-A3, cat. No. M0869), gastrin rabbit polyclonal antibody (1:250 dilution, Cell Marque, Rocklin, CA, USA; cat. No. 256A-1), and H. pylori rabbit polyclonal antibody (1:1000 dilution, Cell Marque; cat. No. 215A-76) using the Bond-RX autoimmunostainer (Leica Biosystems, Melbourne, Australia) with Bond™ Polymer Refine Detection, DS9800 (Vision Biosystems, Melbourne, Australia).

ECL cell hyperplasia in the corpus was assessed using chromogranin IHC staining. The presence of ECL cell hyperplasia was defined when linear ECL cell hyperplasia (a series of five adjacent chromogranin-expressing ECL cells lining the glandular neck region) or micronodular hyperplasia (clusters of neuroendocrine cells <150 µm) were identified.¹³ Areas of intestinal metaplasia were excluded from the evaluation of ECL cell hyperplasia.¹⁴

4. Diagnostic criteria for AIG

For the diagnosis of AIG, we applied the Japanese diagnostic criteria for AIG established by the “Study Group on the establishment of diagnostic criteria for type A gastritis.”³ The cases were considered compatible with AIG if they met both criteria: (1) either the endoscopic and/or histological findings, and (2) positivity for gastric autoantibodies using APCA and/or anti-intrinsic factor tests.³

On endoscopy, typical advanced AIG is characterized by corpus-dominant atrophy, wherein uniform mucosal blood vessels are visible in the corpus with an intact antrum (so-called reserve atrophy), which was used as the main diagnostic criterion.³ In addition, endoscopic findings of early AIG include erythematous and edematous fundic mucosa and subepithelial capillary network expansion despite the absence of reverse atrophy.^3,15

Histological diagnosis of AIG was based on a combination of hematoxylin and eosin findings and chromogranin IHC and classified as early, florid, and end-stage for definite AIG cases.³ The diagnostic criteria for early AIG include multifocal, dense lymphoplasmacytic infiltration of the oxyntic mucosa with accentuation in the deeper portion and pseudohypertrophy of oxyntic glands.³ ECL cell hyperplasia is either mild or absent.³ The florid stage of AIG is diagnosed when there is a marked decrease of oxyntic glands with pseudopyloric and/or intestinal metaplasia, accompanied by ECL cell hyperplasia.³ The end stage of AIG shows marked loss of oxyntic glands with moderate-to-severe intestinal metaplasia, and ECL cell hyperplasia is present in most cases.³

For the diagnosis of AIG in a background of H. pylori gastritis, the criteria of full-thickness inflammation combined with oxyntic gland loss and ECL cell hyperplasia were used.¹⁶

5. Statistical analyses

All statistical analyses were performed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA). Clinicopathological characteristics were compared between two groups of interest using the Student t-test or Mann-Whitney test for continuous variables and the chi-square test or Fisher exact test for categorical variables. Statistical significance was set at p<0.05.

1. Clinicopathological characteristics of 624 patients with gastric tumors according to the APCA positivity

The average age of 624 patients was 63 years, ranging from 31 to 90, with 408 (65.4%) being males. A total of 584 patients (93.6%) underwent resection for a gastric tumor (199 endoscopic submucosal dissection, 339 operation, and 46 endoscopic submucosal dissection followed by operation). All patients were Korean.

Of the 624 patients with gastric tumors, 37 (5.9%) tested positive for APCA. The comparison of clinicopathologic features between APCA positive group and APCA negative group are summarized in Table 1. APCA positivity was significantly more frequent in female sex (p=0.043), and in NET diagnosis (p=0.029). The PG I level was significantly lower in the APCA positive group than in the APCA negative group (median: 42.1 vs 59.9, p=0.007). Serum gastrin was tested in 23 patients, and no significant difference was observed between two groups.

Table 1 . Clinicopathological Characteristics of 624 Patients with Gastric Tumors According to Their Antiparietal Cell Antibody Results.

Antiparietal cell antibody	Negative (n=587)	Positive (n=37)	Total (n=624)	p-value
Sex				0.043
Female	197 (33.6)	19 (51.4)	216 (34.6)
Male	390 (66.4)	18 (48.6)	408 (65.4)
Age, yr	63.0 (54.0–71.0)	61.0 (52.0–68.0)	63.0 (54.0–70.5)	0.102
H. pylori antibody				0.799
Negative	124 (21.1)	9 (24.3)	133 (21.3)
Positive	463 (78.9)	28 (75.7)	491 (78.7)
H. pylori antibody titer	62.1 (25.6–135.7)	57.6 (29.7–117.4)	61.6 (26.4–135.6)	0.877
Diagnosis				0.029
Gastric cancer	578 (98.5)	34 (91.9)	612 (98.1)
Neuroendocrine tumor	9 (1.5)	3 (8.1)	12 (1.9)
Pepsinogen I	59.9 (37.8–92.2)	42.1 (27.1–75.1)	58.8 (37.0–91.6)	0.007
Pepsinogen II	23.9 (14.8–38.7)	22.3 (12.5–32.0)	23.9 (14.6–38.0)	0.072
Pepsinogen I/II ratio	2.5 (1.8–3.5)	2.4 (1.6–2.9)	2.5 (1.8–3.5)	0.142
Gastrin	70.0 (62.2–147.7)	397.0 (58.3–867.5)	70.0 (59.8–195.0)	0.611
Hemoglobin	13.8 (12.7–14.9)	13.6 (13.2–14.7)	13.8 (12.8–14.9)	0.804
Vitamin B12	687.0 (547.0–933.0)	854.0 (641.0–970.0)	697.5 (547.0–937.0)	0.177

Data are presented as the number (%) or median (interquartile range)..

H. pylori, Helicobacter pylori..

Serum HpAb was positive in 491 of 624 patients (78.7%), and the median HpAb titer was 61.6 (interquartile range, 26.4 to 135.6). The APCA positivity did not significantly differ based on the HpAb positivity (p=0.799), and HpAb titer (p=0.877). Upon reviewing the endoscopic images of 133 HpAb-negative patients, we found that the RAC was maintained in 17 patients (12.8%).

2. Frequency of AIG

Endoscopy and histology were reviewed for the diagnosis of AIG in 37 patients with positive APCA results. Endoscopically, eight patients showed reverse atrophy compatible with advanced AIG (Figs 2-4), and one patient showed partial corpus atrophy and reddening compatible with early AIG. Of the nine patients whose endoscopic findings were compatible with AIG, five were also histologically compatible with AIG, and four were histologically not definite for AIG. Among cases where endoscopic findings were not specific for AIG (pan-atrophy) (Fig. 5), histological review identified two additional cases of concurrent AIG and H. pylori gastritis. Ultimately, 11 patients (1.8%) were diagnosed with AIG when the diagnostic criteria for AIG (1: either endoscopic and/or histological findings compatible with AIG, and 2: positivity for the antibodies) were applied (Fig. 1).

Figure 2. Representative images from patient No. 2 with a neuroendocrine tumor. Endoscopic images showing (A) a relatively preserved mucosa with patchy redness in the antrum and (B) diffuse atrophy in the corpus, consistent with the reverse atrophy sign. (C) Histology of a neuroendocrine tumor (hematoxylin and eosin [H&E] staining, ×4). (D) Histology of autoimmune gastritis, florid stage in the corpus. The gastric pit is elongated, oxyntic glands have disappeared and are replaced by pyloric metaplasia (H&E staining, ×4) and (E) pancreatic metaplasia (H&E staining, ×10, arrow). (F) Chromogranin immunohistochemistry showing linear and nodular enterochromaffin-like cell hyperplasia (×10, arrow).

Figure 3. Representative images from patient No. 6 with gastric cancer. Endoscopic images showing (A) a relatively preserved mucosa in the antrum and (B) diffuse atrophy in the corpus, consistent with the reverse atrophy sign. (C) Histology of the antrum showing atrophy and intestinal metaplasia (hematoxylin and eosin [H&E] staining, ×4). (D) Histology showing concurrent autoimmune gastritis and Helicobacter pylori gastritis in corpus. The mucosa shows full-thickness inflammation (H&E staining, ×4) and (E) the degeneration of oxyntic glands (H&E staining, ×10). (F) Chromogranin immunohistochemistry showing linear enterochromaffin-like cell hyperplasia (×10).

Figure 4. Representative images from patient No. 3 with a neuroendocrine tumor. Endoscopic images showing (A) a relatively preserved mucosa in the antrum and (B) diffuse atrophy in the body, consistent with the reverse atrophy sign. (C) Histology of the corpus, showing a normal appearance (hematoxylin and eosin [H&E] staining, ×4). (D) Histology of the corpus, showing foveolar hyperplasia and the loss of oxyntic glands as well as (E) the degeneration of oxyntic glands (arrow) in the focal area (H&E staining, ×4). (F) Chromogranin immunohistochemistry showing no enterochromaffin-like cell hyperplasia (×10). Overall, the histological findings are indefinite for autoimmune gastritis.

Figure 5. Representative images from patient No. 11 with gastric cancer. Endoscopic images of (A) the antrum, (B) mid-body, and (C) high body. Whitish metaplastic nodules are scattered in the atrophic background mucosa of the antrum. Diffuse atrophy and hyperemic spots are noticed in the mid-body and high body, respectively. Overall, endoscopic findings are indefinite for autoimmune gastritis (AIG); AIG findings are possibly obscured by the extensive Helicobacter pylori-associated gastritis. (D) Histology of concurrent AIG and H. pylori gastritis in the corpus. The mucosa shows full-thickness inflammation with intestinal metaplasia (hematoxylin and eosin [H&E] staining, ×4). (E) Chromogranin immunohistochemistry showing linear enterochromaffin-like cell hyperplasia (×10). (F) Histology of the antrum showing focal atrophy and intestinal metaplasia (H&E staining, ×4).

The frequency of AIG was evaluated according to tumor type (Fig. 1). Of the 612 GCs, 34 patients (5.6%) were positive for APCA, and finally, eight patients (1.3%) met the criteria for AIG (3 both endoscopy and histology, 3 endoscopy only, and 2 histology only). Of the 12 patients with NET, three (25.0%) were positive for APCA, and all three met the criteria for AIG (2 both endoscopy and histology, 1 endoscopy only).

3. Clinicopathologic characteristics of patients with AIG

The clinicopathological information of the 11 patients with AIG is summarized in Supplementary Table 1. Eight patients (72.7%) were female, and the mean age was 61, ranging from 42 to 80. Three patients had NET, and eight had GC. The tumors were located in the body in nine patients and the antrum in two. Patient No. 11 had multiple GCs in both the body and antrum. The histological types of GC were moderately differentiated tubular adenocarcinoma (patients No. 5, 6, 8, and 11), poorly differentiated tubular adenocarcinoma (patients No. 7 and 9), and poorly cohesive carcinoma (patients No. 4 and 10). Serum HpAb was positive in six patients (54.5%), all of whom had GC. None of these patients had undergone H. pylori eradication at the time of diagnosis. Serum PG I levels were below 70 in nine patients (81.8%), and the PG I/II ratio was below 3 in 10 patients (90.1%). Serum gastrin results were available for three patients with NET, two of whom had elevated levels. Hemoglobin levels decreased in eight patients (72.7%). Vitamin B₁₂ levels, available for five patients, ranged from 259 to 2,125. Two patients with NET had a history of thyroiditis and thyroid cancer.

4. Comparison of GC patients with and without AIG

The clinicopathologic characteristics of GC patients with and without AIG are shown in Table 2. The PG I level was significantly lower in GC with AIG than GC without AIG (median: 35.2 vs 59.8, p=0.042). The PG I/II ratio was also significantly lower in GC with AIG than GC without AIG (median: 1.5 vs 2.5, p=0.016). There was no significant difference of other clinicopathologic factors including tumor histology and multiplicity between two groups. Serum gastrin was tested in only 11 patients with GC, and all were without AIG. The median gastrin level was 88.0 with ranging from 41.5 to 202.8 (normal range, 25 to 110).

Table 2 . Clinicopathologic Characteristics of the 612 Gastric Cancer Patients with and without AIG.

Characteristic	AIG (n=8)	Non-AIG (n=604)	Total (n=612)	p-value
Sex				0.131
Female	5 (62.5)	205 (33.9)	210 (34.3)
Male	3 (37.5)	399 (66.1)	402 (65.7)
Age, yr	65.5 (59.5–72.5)	63.0 (54.0–71.0)	63.0 (54.0–71.0)	0.506
H. pylori antibody				0.675
Negative	2 (25.0)	126 (20.9)	128 (20.9)
Positive	6 (75.0)	478 (79.1)	484 (79.1)
H. pylori antibody titer	57.7 (47.5–113.5)	62.0 (26.5–136.8)	61.8 (26.6–136.8)	0.939
Pepsinogen I	35.2 (12.1–67.7)	59.8 (37.4–92.5)	59.3 (37.2–91.9)	0.042
Pepsinogen II	24.6 (15.7–27.2)	23.9 (14.8–38.6)	23.9 (14.8–38.3)	0.536
Pepsinogen I/II ratio	1.5 (0.9– 2.5)	2.5 (1.8– 3.5)	2.5 (1.8– 3.5)	0.016
Hemoglobin	13.3 (13.1–14.4)	13.8 (12.8–14.9)	13.8 (12.8–14.9)	0.798
Vitamin B12	484.0 (280.0–854.0)	697.0 (548.5–928.5)	695.0 (547.0–928.5)	0.210
Multiplicity				0.295
Multiple	1 (12.5)	25 (4.1)	26 (4.2)
Single	7 (87.5)	579 (95.9)	586 (95.8)
Location				0.606
Lower third	2 (25.0)	236 (39.1)	238 (38.9)
Middle third	5 (62.5)	295 (48.8)	300 (49.0)
Upper third	1 (12.5)	73 (12.1)	74 (12.1)
Histology				1.000
Tubular adenocarcinoma	6 (75.0)	416 (68.9)	422 (69.0)
Papillary adenocarcinoma	0	10 (1.7)	10 (1.6)
PCC, non-signet ring cell type	1 (12.5)	74 (12.3)	75 (12.3)
PCC, signet ring cell type	1 (12.5)	88 (14.6)	89 (14.5)
Others	0	16 (2.6)	16 (2.6)
pT stage				1.000
pT1	7 (87.5)	466 (81.5)	473 (81.6)
pT2, 3, 4	1 (12.5)	106 (18.5)	107 (18.4)
pN stage				0.566
pN0	3 (75.0)	309 (81.3)	312 (81.2)
pN1, 2, 3	1 (25.0)	71 (18.7)	72 (18.8)

Data are presented as the number (%) or median (interquartile range)..

AIG, autoimmune gastritis; H. pylori, Helicobacter pylori; PCC, poorly cohesive carcinoma..

5. Comparison of GC patients with single lesion and multiple synchronous lesions

The clinicopathologic characteristics of GC patients with single lesion and multiple synchronous lesions were compared in Supplementary Table 2. The frequency of AIG in patients with single lesion and multiple synchronous lesions were 1.2% and 3.8%, respectively (p=0.295). PG I level was significantly lower in patients with multiple synchronous lesions compared to those with single lesion (median: 45.5 vs 60.3, p=0.039).

6. Detailed histologic findings of AIG in patients with gastric tumors

The histology of the 11 AIG cases is summarized in Supplementary Table 3. The corpus mucosa revealed absence of neutrophilic infiltration in all, more than moderate degree of mononuclear cell infiltration in nine (81.8%), atrophy of various degrees in eight (72.7%), and metaplasia in seven (63.6%) patients. Pseudopyloric, intestinal, and pancreatic metaplasias were identified in five (45.5%), five (45.5%), and two (18.2%) patients, respectively. All intestinal metaplasias were of the complete type. Pancreatic metaplasia was identified in two of the 37 APCA-positive cases, and both cases were associated with AIG.

Of the 11 patients, three (patients No. 1 and 2 with NET, No. 5 with GC) exhibited pure AIG histology (Fig. 2), while four (patients No. 6, 9, 10, 11, all with GC) demonstrated histology of concurrent AIG and H. pylori gastritis with full-thickness inflammation and degenerated oxyntic glands (Figs 3 and 5). Antral tissue was available in three of the four cases with concurrent AIG and H. pylori gastritis, with the degree of antral atrophy and metaplasia being more severe than the corpus. In the four cases of concurrent AIG and H. pylori gastritis, all were serum HpAb-positive, and two had H. pylori confirmed in their tissues. All cases of histologically definite AIG showed ECL cell hyperplasia, more pronounced in patients with NET (patients No. 1 and 2).

Meanwhile, four patients appeared endoscopically compatible with AIG, but histologically not definite for AIG. Patient No. 3 underwent a proximal gastrectomy for the NET (Fig. 4). The majority of the corpus mucosa was normal, with foveolar hyperplasia, disorganization of oxyntic glands, and intestinal metaplasia observed in less than 10% of the total area (Fig. 4). ECL cell hyperplasia was not noted. The overall histological findings were not definite for AIG. However, the possibility of early AIG with residual oxyntic gland mucosa is present because inflammation and atrophy in AIG occur heterogeneously. In patient No. 4 with GC, diffuse atrophy and intestinal metaplasia were identified in both the corpus and antrum. Although the possibility of end-stage AIG was present, ECL cell hyperplasia was not identified, and the histology itself was not definitive for AIG. However, AIG remains a possible scenario given the negative H. pylori status. Patient No. 7 underwent a subtotal gastrectomy for GC. The corpus mucosa exhibited H. pylori gastritis with superficial lymphocytic infiltration and lymphoid follicles. ECL cell hyperplasia was absent. Parietal cell hypertrophy and protrusions, possible features of early AIG, were noted. However, distinguishing this effect from that of the proton pump inhibitors was challenging; thus, it was histologically not definite for AIG. Patient No. 8 showed H. pylori gastritis in the corpus biopsy, and the resected antrum specimen showed diffuse atrophy with intestinal metaplasia. ECL cell hyperplasia was not observed in the corpus. In this instance, the AIG area may not have been biopsied.

7. Histologic findings of APCA-positive, but non-AIG cases

Of the 37 APCA-positive patients, 26 patients were positive for APCA, but did not meet the diagnostic criteria for AIG (Fig. 1). All were patients with GC. Among them, 22 (84.6%) were positive for serum HpAb. Histologically, the majority of the available cases showed marked antral atrophy, indicating past or present H. pylori gastritis. Antral tissue was available for 16 patients, with atrophy and intestinal metaplasia identified in 15 of them.

Among the 26 APCA-positive, but non-AIG cases, 13 (50%) displayed normal corpus histology. Antral tissue was available from eight patients of them, revealing atrophy with intestinal metaplasia in seven.

In this study, we assessed the frequency of AIG in 624 Korean patients with gastric tumors. The frequency of AIG in GC was 1.3% (8/612), and in NET, it was 25.0% (3/12). Although the development of GC in H. pylori-associated atrophic gastritis is well-documented, its occurrence in AIG remains controversial.^5,6,17 AIG, particularly that associated with pernicious anemia, has been considered a precancerous lesion. However, Rugge et al.⁵ indicated a virtual absence of risk of GC in H. pylori-negative pure AIG in a recent prospective study, suggesting that the elevated risk of GC observed in AIG could be attributed to unrecognized or concurrent H. pylori infection.⁵ This may affect the clinical surveillance of AIG for the secondary prevention of GC;⁵ therefore, it has sparked a discussion on the risk of GC in AIG.^6,17-19 Similarly, other recent studies revealed no or very low frequency of GC in AIG.^20,21 In the present study, the frequency of AIG in patients with GC was low (1.3%), and 75% of AIG had past/present H.pylori infection, which may support the very low risk of GC in pure AIG. AIG appeared to be more related to NET than GC in Korea due to higher frequency in NET.

For diagnosis, we applied the Japanese diagnostic criteria of AIG, which provide details on endoscopy and histology for each stage.³ Of the 11 patients with AIG, five met both the histologic and endoscopic criteria for AIG. Additionally, four patients only met the endoscopic diagnostic criteria. The reasons why AIG was not definitively diagnosed histologically are presumed to be as follows: (1) the possibility of early histologic changes (patient No. 3); (2) the inability to determine etiology due to end-stage atrophy (patient No. 4)–late stages of AIG may not exhibit ECL cell hyperplasia;¹⁴ and (3) sampling errors or AIG obscured by active H. pylori gastritis (patients No. 7, 8).²² Finally, two cases were endoscopically not specific for AIG, but met the histological criteria. Both patients had concurrent AIG and H. pylori gastritis with endoscopically pan-atrophy pattern. These patterns may account for a significant proportion of AIG in H. pylori-prevalent countries. It cannot be diagnosed by simple criteria that consider only corpus-restricted atrophy alone. Comprehensive understanding of both AIG and H. pylori gastritis is essential for diagnosing AIG in H. pylori-prevalent countries. In fact, the RAC was maintained in the angle in only 12.8% (17/133) of HpAb-negative patients in the present study. These results indicate that in countries with a high prevalence of H. pylori, the number of true H. pylori-naiive patients could be very low even if they test negative for HpAb. Therefore, when diagnosing AIG in patients with extensive atrophy, it is crucial to take a detailed history of H. pylori treatment and employ various methods, in addition to HpAb testing, to determine the infection status and current condition of H. pylori.

Of the 11 patients with AIG, six tested positive for serum HpAb, and four exhibited proven H. pylori infection in their tissues. The H. pylori positivity in AIG has been reported to range from 7.8%²³ to 45.2%²⁴ in Asian studies and from 14.9%²⁵ to 50%⁹ in European studies. According to a case series reporting four AIG patients in Korea, three of four had past H.pylori infection.²⁶ All were female with age ranging from 54 to 62, and one had NET.²⁶ In countries where the H. pylori prevalence is high, the diagnosis of AIG is often challenging.¹⁸ Generally, AIG is characterized by corpus atrophy with antrum remaining normal. However, concurrent AIG and H. pylori gastritis had antral atrophy, and 42.3% of patients with AIG presented with various extents of antral atrophy, according to a Japanese study on endoscopy of AIG.²³ In our study, antral atrophy with intestinal metaplasia was confirmed in all patients with AIG for whom histological evaluation was available. In addition to the endoscopy, a pathological diagnosis of concurrent AIG- H. pylori gastritis presents challenges.²⁷ It is crucial for pathologists to discern full-thickness inflammation from superficial inflammation in H. pylori gastritis and to confirm ECL cell hyperplasia using chromogranin IHC. However, several caveats exist. In early AIG, histologic changes can be subtle, lacking atrophy or ECL cell hyperplasia, and may precede endoscopic changes.^3,28 Next, in the end stage, the degree of inflammation can decrease, and ECL cell hyperplasia may not be present.³ What makes diagnosis more difficult is that ECL cell hyperplasia may also be present in H. pylori gastritis²⁹ or after administration of a proton pump inhibitor.¹⁴ In difficult cases, histologic assessment after H. pylori eradication is even recommended.³⁰ Importantly, interpreting ECL cell hyperplasia requires caution. Paneth cells and goblet cells may stain non-specifically.^14,31 Therefore, areas distant from intestinal metaplasia are essential for histologic evaluation.¹⁴ We also experienced diagnostic difficulty in some cases, and diagnosis was confirmed by a Japanese expert in AIG pathology. In this article, we have detailed the histology to share our experience.

We evaluated clinicopathologic features of GC with AIG compared with GC without AIG. According to Angerilli et al.,³² AIG-associated GCs were associated with low stage, neuroendocrine differentiation, and microsatellite instability status. Kitamura et al.² reported that early GCs in AIG were more frequent in the upper location, and had larger tumor size and papillary type. However, we did not find the distinct histologic features in GC with AIG, possibly due to the small number of AIG cases. Further studies are warranted in a larger number of GC patients with AIG.

Serological tests for APCA, gastrin, and PG I/II can aid in screening for AIG. In this study, the positivity rate for APCA was 5.9% (n=37) among patients with gastric tumors, and 11 of these 37 patients with APCA-positive status were ultimately confirmed to have AIG. APCA serves as a diagnostic criterion for AIG, demonstrating 81% sensitivity and 90% specificity.^3,33 APCA positivity can range from 7.8% to 19.5% in the healthy population.³⁴ In our study, PG I was significantly lower in APCA positive group than in APCA negative group. This result is consistent with recent study showing that APCA positivity was strongly associated with chronic atrophic gastritis irrespective of etiology.³⁵ Regarding the assessment of PG, it is proposed as a non-invasive method to grade gastric atrophy.²⁵ Low levels of PG I and low PG I/II ratio are associated with atrophy and may also distinguish AIG from H. pylori gastritis.^25,36 Likewise, PG I and PG I/II ratio were significantly lower in GC with AIG compared to GC without AIG in our cohort with high H.pylori prevalence (Table 2). It appeared that very low PG I and PG I/II can be used as a supportive tool for the diagnosis of AIG, especially in Korea. In summary, APCA testing is recommended for patients with (1) reverse atrophy,³ (2) very low PG I and PG I/II levels,^25,36 and (3) NET patients together with gastrin level.^36,37

This study has several limitations. Firstly, it was a retrospective study conducted at a single tertiary cancer center, and the number of patients with NET was small. Protocol biopsy was not performed for AIG, and antral tissue was not available for some patients. However, the corpus tissue was reviewed in all cases. Additionally, many cases involved resected specimens, which allowed for the evaluation of a large area of non-tumor corpus tissue. Secondly, there were limitations in obtaining accurate information regarding the H. pylori infection status. Although all patients underwent HpAb testing, in some cases, only the result was reported without the titer. Due to the retrospective nature of the study, previous H. pylori infection or treatment status were could not be collected. To overcome this limitation, we retrospectively reviewed all endoscopic images of patients with HpAb negativity to evaluate for RAC in the angle. Thirdly, APCA titer information was not provided, and tests for anti-intrinsic factor antibodies were not conducted. Gastrin testing was performed on only a limited number of patients. Finally, a small proportion of AIG cases is known to be APCA-negative.³⁸ However, we did not include APCA-negative cases. Because the diagnostic criteria of AIG included only APCA-positive patients, histology and endoscopy for APCA-negative patients were not reviewed. Despite these limitations, this study is the first to evaluate AIG in Korean patients with gastric tumors using strict diagnostic criteria.

In conclusion, the frequency of AIG in Korean patients with GC was low, at 1.3%, compared with a higher incidence of AIG in NET, at 25.0%. Serum tests are useful for the diagnosis of AIG; APCA can screen AIG, and low PG I and PG I/II ratio can be used as a supportive tool. However, diagnosing AIG requires histological evaluation of the gastric mucosa and correlation with endoscopic findings. Concurrent AIG and H. pylori gastritis are commonly observed in AIG patients with GC. Comprehensive understanding of both AIG and H. pylori gastritis is essential for diagnosing AIG in H. pylori-prevalent countries.

This study was supported by the Bio and Medical Technology Development Program of the National Research Foundation (NRF), funded by the Korean government (MSIT) (No. RS-2023-00222838) to S.A.

No potential conflict of interest relevant to this article was reported.

Study concept and design: K.M.K., J.H.L. Data acquisition: S.A., T.S.K. Data analysis and interpretation: all authors. Drafting of the manuscript: S.A., T.S.K. Critical revision of the manuscript for important intellectual content: K.M.K., J.H.L. Statistical analysis: S.A., T.S.K. Obtained funding: S.A. Administrative, technical, or material support; study supervision: K.M.K., J.H.L. Approval of final manuscript: all authors.

The datasets used and/or analyzed in the current study are available from the corresponding author upon reasonable request.

Supplementary materials can be accessed at https://doi.org/10.5009/gnl240223.