Jpn J Clin Oncol 2014;44(1)65 – 71 doi:10.1093/jjco/hyt167 Advance Access Publication 11 November 2013

Different Histological Status of Gastritis in Superficial Adenocarcinoma of the Esophagogastric Junction Masayoshi Yamada1,2, Ryoji Kushima2,*, Ichiro Oda1, Kaveh Mojtahed3, Satoru Nonaka1, Haruhisa Suzuki1, Shigetaka Yoshinaga1, Akiko Matsubara2, Hirokazu Taniguchi2, Shigeki Sekine4, Yutaka Saito1 and Tadakazu Shimoda5 1

Endoscopy Division, National Cancer Center Hospital, Tokyo, 2Pathology Division, National Cancer Center Hospital, Tokyo, Japan, 3Internal Medicine Division, Scripps Green Hospital, La Jolla, CA, USA, 4Molecular Pathology Division, National Cancer Center Research Institute, Tokyo and 5Center for Cancer Control and Information Services, National Cancer Center Hospital, Tokyo, Japan

Received December 20, 2012; accepted October 11, 2013

Objective: Although many gastric cancers arise in chronic gastritis, the association between adenocarcinoma of the esophagogastric junction and the status of background gastritis remains unclear. We aim to investigate the histological status of gastritis in the background fundic gland mucosa of adenocarcinoma of the esophagogastric junction. Methods: The present study included 121 consecutive patients with superficial adenocarcinoma of the esophagogastric junction obtained by surgical and/or endoscopic resection. We reevaluated the histogenesis of adenocarcinoma of the esophagogastric junction, including the background fundic gland mucosa using the Updated Sydney System. The prevalence of histologic atrophic gastric mucosa with gastritis ( positive gastritis), non-atrophic gastric mucosa without gastritis (negative gastritis) and Barrett’s adenocarcinoma was examined. Results: Histologic-positive gastritis was found in 67 (55%) of all patients, in 24 (38%) of 63 Barrett’s adenocarcinoma patients and in 43 (74%) of 58 non-Barrett’s adenocarcinoma patients (P , 0.01). A higher female ratio in non-Barrett’s adenocarcinoma with gastritis patients ‘and younger age in non-Barrett’s adenocarcinoma without gastritis patients were shown. There were no differences in clinicopathological features related to the gastritis status in Barrett’s adenocarcinoma patients. Reflux esophagitis was observed in most (81%) of all patients, and 32 (74%) of the non-Barrett’s adenocarcinoma with gastritis patients. In the 67 positive gastritis patients, the mean Updated Sydney System scores of glandular atrophy and intestinal metaplasia were 1.45 and 1.10, respectively, and these scores were higher in the non-Barrett’s adenocarcinoma patients than in the Barrett’s adenocarcinoma patients. Conclusions: This study suggests that about half of the patients with adenocarcinoma of the esophagogastric junction harbor histological gastritis. Adenocarcinoma of the esophagogastric junction is considered to be a heterogeneous entity, including Barrett’s esophagus-related, positive gastritis-related, and Barrett’s esophagus and gastritis-unrelated adenocarcinoma of the esophagogastric junction. Key words: adenocarcinoma of the esophagogastric junction – Barrett’s adenocarcinoma – Helicobacter pylori – gastritis – Updated Sydney System

# The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]

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*For reprints and all correspondence: Ryoji Kushima, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. E-mail: [email protected]

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Histological status of adenocarcinoma of EGJ

INTRODUCTION

HISTOPATHOLOGICAL EVALUATION

We reviewed the histopathology of 210 consecutive patients with AEGJ obtained by surgical and/or endoscopic resection at the National Cancer Center Hospital Tokyo, from January 1980 to December 2010. Of these 210 patients, 74 patients whose tumor invaded into the muscularis propria ( pT2) or deeper were excluded, as were 15 patients, including four patients with past history of upper gastrointestinal surgeries, where the mucosa could not be fully evaluated. After these exclusions, 121 patients remained with superficial AEGJ ( pT1). AEGJ is defined as Type II in accordance with the Siewert classification (1). Sixty-three of the patients underwent surgical resection and 58 had endoscopic resection. None of the patients had findings of peptic ulcers and none received preoperative radiotherapy or chemotherapy.

The surgically resected specimens were opened longitudinally, stretched out, pinned on a flat board and fixed in 10% buffered formalin. The esophagus and EGJ, including the tumor of the specimens, were cut serially into 5 mm thick sections. A section was also taken along the lesser curvature of the stomach to assess the gastritis status of the background mucosa. The endoscopically resected specimens, after being fixed in formalin, were sectioned serially at 2 – 3 mm intervals. All the paraffin-embedded sections were stained with haematoxylin and eosin (H&E). We evaluated the histological type of the tumor, depth of invasion, presence of Barrett’s esophagus (BE) and histological status of gastritis. The histological classification of adenocarcinoma was made by Japanese classification of gastric carcinoma (11). Papillary and tubular adenocarcinomas were classified as ‘differentiated-type’, and other histological types were classified as ‘undifferentiated-type’. Mixed type included both differentiated type and undifferentiated type within one lesion. Tumor invasion was subclassified as mucosa (pT1a) and submucosa (pT1b). BE was defined according to the previous reports not requiring the presence of goblet cells in esophageal columnar epithelium (14 – 16). BA was defined as a tumor arising within or adjacent to an area of BE. The Updated Sydney System (USS) score was independently graded in the fundic gland mucosa by two investigators (M.Y. and R.K.). The evaluated features included glandular atrophy, IM, chronic inflammation (mononuclear cells), neutrophil activity and HP density on a scale of 0 (normal), 1 (mild), 2 (moderate) and 3 (marked) (17). In this USS scoring, IM was defined as the presence of goblet cells regardless of Paneth cells on H&E staining, which were seen in the surrounding fundic gland mucosa. All specimens of stomach were evaluated. We defined histological non-atrophic gastric mucosa without gastritis (negative gastritis) as mucosa graded with glandular atrophy, 0; chronic inflammation, 0 or 1; neutrophil activity, 0; IM, 0; and HP density, 0; according to the report of Kakinoki et al. (Fig. 1A – H) (18). All the patients who did not fulfill this definition were classified into atrophic gastric mucosa with gastritis (positive gastritis).

CLINICOPATHOLOGICAL CHARACTERISTICS

STATISTICAL ANALYSIS

Clinicopathological characteristics of patients with AEGJ, including age, sex, tumor size and macroscopic type, were

The extended Fisher’s exact test, Welch’s t-test and one-way ANOVA test were used for statistical analysis for comparison

PATIENTS ANS METHODS PATIENTS

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Adenocarcinoma of the esophagogastric junction (AEGJ) is defined by the anatomical location of the tumor center (1); therefore, AEGJ includes Barrett’s adenocarcinoma (BA) and adenocarcinoma derived from cardiac gland mucosa or fundic gland mucosa. A stepwise progression of chronic inflammation, intestinal metaplasia (IM) and dysplasia leading to adenocarcinoma is believed to be the mechanism for developing BA (2,3). Although this mechanism is also believed to play a role in the development of AEGJ, there have been a few reports of small AEGJ lesions arising from mucosa without IM (4–6). Siewert et al. (7) classified adenocarcinomas arising in the vicinity of the esophagogastric junction (EGJ) into three distinct entities. In this widely used classification scheme, Type I tumors (adenocarcinoma of the distal esophagus) mainly include BA. Type II tumors (true carcinoma of the cardia), which have their center within 1 cm proximal or 2 cm distal to the cardia, include both carcinoma arising from cardiac and fundic gland mucosa and BA. Type III tumor (subcardial gastric cancer) includes carcinoma arising from fundic gland mucosa. Helicobacter pylori (HP) infection is thought to increase the risk of a Type III tumor (8). While it is believed that HP infection protects against Type I tumors (9), the association between HP infection and the risk of Type II tumors, indicating AEGJ, is still controversial. Wu et al. (10) reported that HP infection did not affect the development of AEGJ, evidenced by an odds ratio that was only 1.26 (95% CI 0.82 – 1.94) in Western populations. In the present study, we retrospectively reviewed the histological status of gastritis in 121 patients of AEGJ to clarify the histological status of gastritis in the background fundic gland mucosa of AEGJ.

reviewed. We used the Japanese classification of gastric cancer for defining gross tumor morphology (11). To identify the presence of reflux esophagitis, we reviewed all preoperative endoscopic images. The endoscopic diagnosis of reflux esophagitis, including the severity of reflux esophagitis, was made based on the modified Los Angeles (LA) classification (Grade M, A – D) (12). If reflux esophagitis was not observed, we evaluated irregularity of the Z-line (squamocolumnar junction line), which indicates previous reflux esophagitis. The irregular Z-line was assessed for the zigzag pattern, tongue-like protrusion and columnar epithelium islands (13,14).

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Downloaded from http://jjco.oxfordjournals.org/ by guest on March 26, 2015 Figure 1. Representative histology of background fundic gland mucosa and Barrett’s esophagus in the adenocarcinoma of the esophagogastric junction (AEGJ) [original magnifications (A – H) 40, HE staining]. (A) Adenocarcinoma without Barrett’s esophagus. Subepithelial extension of the tumor can be seen. (B) Background fundic gland mucosa of A. Moderate atrophic gastritis can be seen, while intestinal metaplasia (IM) seems to be mild. (C) Adenocarcinoma without Barrett’s esophagus. Tumor infiltrates muscularis mucosae. (D) Background fundic gland mucosa of C. Non-atrophic mucosa without gastritis can be seen. (E) Adenocarcinoma with Barrett’s esophagus. Columnar epithelium is contiguous to the tumor. Double layer of muscularis mucosae can be seen under the columnar epithelium. (F) Background fundic gland mucosa of E. Atrophic gastritis with lymphoid follicle and IM can be seen. (G) Adenocarcinoma with Barrett’s esophagus. Columnar glands with IM are contiguously spread to the tumor. Double layer of muscularis mucosae can be seen. (H) Background fundic gland mucosa of G. Non-atrophic gastric mucosa without gastritis can be seen.

between each group. All statistical tests were two-sided and the alpha level was set at 0.05.

RESULTS CLINICOPATHOLOGICAL CHARACTERISTICS OF THE 121 SUPERFICIAL AEGJ PATIENTS Table 1 summarizes the results of clinicopathological characteristics. There was a marked male predominance. About half

of the lesions were described as having a protruded gross feature, 0-I or 0-IIa, and were detected in mucosal lesions. Histologically, most of the lesions were differentiated-type carcinoma. In the BA patients, 62 (98%) of the lesions were associated with short-segment Barrett’s esophagus (SSBE) and only one patient (2%) was associated with long-segment Barrett’s esophagus. More than 80% (98/121) of the AEGJ patients, at the time of diagnosis, were diagnosed as having endoscopic reflux esophagitis, irrespective of having gastritis (Tables 1 and 2).

Histological status of adenocarcinoma of EGJ

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Table 1. Clinicopathological characteristics of the 121 patients with superficial adenocarcinoma of the esophagogastric junction Age (years) at diagnosisa

65 + 11

Sex (M/F ratio)

103/18 (5.7:1)

Tumor size (mm)a

25 + 16

Macroscopic type 0-I

19 (16%)

0-IIa

46 (38%)

0-IIb

3 (2%)

0-IIc

53 (44%)

Depth of invasion pT1a

56 (46%)

pT1b

65 (54%)

Histological type

Undifferentiated Mixed type Diff. predominant Undiff. Predominant

98 (81%) 1 (1%) 22 (18%) 18 (82%) 4 (18%)

Barrett’s esophagusb Presence

63 (52%)

Absence

58 (48%)

Reflux esophagitis Presence

98 (81%)

Absence

23 (19%)

M, male; F, female; M, mucosa; MM, muscularis mucosae; SM, submucosa; Diff., differentiated-type adenocarcinoma; Undiff., undifferentiated-type adenocarcinoma. a Data are expressed as mean + SD. b Barrett’s esophagus surrounding the tumor.

Gastritis (þ)

Gastritis (2)

P value

Number of patients

67 (55%)

54 (45%)

Age (y) at diagnosisa

69 + 10

61 + 12

Sex (M/F (ratio))

53/14 (3.8:1)

50/4 (12.5:1)

0.043

Tumor size (mm)a

28 + 18

21 + 12

0.014

Protrudedb

36 (54%)

29 (54%)

0.998

Flat and depressed

31 (46%)

25 (46%)

pT1a

34 (5%)

22 (41%)

pT1b

33 (49%)

32 (59%)

Differentiated

56 (84%)

42 (78%)

Undifferentiated and mixed

11 (16%)

12 (22%)

,0.001

Macroscopic type

Depth of invasion 0.359

Histological type 0.488

Barrett’s esophagusb Presence

24 (36%)

39 (72%)

Absence

43 (64%)

15 (28%)

Presence

54 (81%)

44 (81%)

Absence

13 (19%)

10 (19%)

,0.001

Reflux esophagitis 0.821

Gastritis (þ), positive gastritis group; gastritis (2), negative gastritis group. a Data are expressed as mean + SD. b Protruded type includes 0-I and 0-IIa. c Barrett’s esophagus surrounding the tumor.

CLINICOPATHOLOGICAL DIFFERENCES BETWEEN THE FOUR GROUPS SUPERFICIAL AEGJS

OF

In the 23 patients without reflux esophagitis, seven patients had taken antacid agent (histamine receptor antagonist or proton pump inhibitor). Severity of the reflux esophagitis was evaluated as follows: 59 grade M, 34 grade A, 5 Grade B and none with Grades C and D. An irregular Z-line was observed in 52% (12/23) patients without reflux esophagitis (Table 3). HISTOLOGICAL STATUS OF GASTRITIS IN THE PATIENTS WITH SUPERFICIAL AEGJS Histological-positive gastritis was found in 67 (55%) patients with AEGJ. The clinicopathological differences between positive and negative histological gastritis are shown in Table 2. Both age at diagnosis and tumor size were significantly higher and the ratio of male to female was significantly lower in the positive gastritis group than in the negative gastritis group. No significant differences were seen in the macroscopic type, depth of invasion and histological type. The presence of BE was significant in the negative gastritis group.

The AEGJs were subclassified into four groups by the histopathological status of the background mucosa: presence or absence of BE surrounding the tumor, and histologicalpositive or -negative gastritis. The prevalence and clinicopathological features of each group are shown in Table 3. The ages of patients within the non-BA group with positive gastritis were significantly higher, and the sex ratio (male to female) in this group was significantly lower than that of other groups. There was no significant difference in the tumor size, although the tumor sizes of the non-BA group with positive gastritis were larger than that of other groups. HISTOLOGICAL STATUS OF THE BACKGROUND FUNDIC GLAND MUCOSA CONFINED TO SUPERFICIAL AEGJS WITH THE HISTOLOGICAL-POSITIVE GASTRITIS The mean USS scores of gastritis in the background fundic gland mucosa were as follows: glandular atrophy 0.81, IM 0.61, chronic inflammation 0.87, and neutrophil activity 0.31. Scores of the group with histological positive gastritis are

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Differentiated

Table 2. Comparison of clinicopathological features of the patients with superficial adenocarcinoma of the esophagogastric junction between positive and negative histological gastritis

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Table 3. Comparison of clinicopathological characteristics between each group of the 121 patients with superficial adenocarcinoma of the esophagogastric junction (AEGJ) BA (52%, 63/121)

Non-BA (48%, 58/121)

P value

Gastritis (þ)

Gastritis (2)

Gastritis (þ)

Gastritis (2)

(38%, 24/63)

(62%, 39/63)

(74%, 43/58)

(26%, 15/58)

Age at diagnosisa

68 + 10

63 + 11

69 + 10

55 + 13

Sex (M/F)

22/2

36/3

31/12

14/1

0.047

26 + 15

21 + 11

30 + 19

23 + 15

0.077

a

Tumor size

,0.001

Macroscopic type Protrudedb

15 (63%)

22 (56%)

21 (49%)

7 (47%)

9 (38%)

17 (44%)

22 (51%)

8 (53%)

pT1a

14 (58%)

18 (46%)

20 (47%)

4 (27%)

pT1b

10 (42%)

21 (54%)

23 (53%)

11 (73%)

22 (92%)

31 (80%)

34 (79%)

11 (73%)

2 (8%)

8 (21%)

9 (21%)

4 (27%)

22 (92%)

32 (82%)

32 (74%)

12 (80%)

2 (8%)

7 (18%)

11 ((26%)

3 (20%)

1 (50%)

5 (71%)

4 (36%)

2 (67%)

Flat and depressed

0.662

Depth of invasion

Histological type Differentiated Undifferentiated and mixed

0.454

Reflux esophagitis Presence Absence Irregular Z-linec

0.386

BA, Barrett’s adenocarcinoma; gastritis (þ), positive gastritis group; gastritis (2), negative gastritis group; M, male; F, female; M, mucosa; SM, submucosa. Patient age is given in years. a Data are expressed as mean + SD. b Protruded type includes 0-I and 0-IIa. c Data shows in the absence group of reflux esophagitis.

shown in Table 4, including the scores for the BA and non-BA groups. Scores of IM were significantly higher in the non-BA group than in the BA group, while there were no significant differences in scores of chronic inflammation, neutrophil activity and glandular atrophy.

DISCUSSION We found that 55% of patients with superficial AEGJ harbor histological positive gastritis in their background fundic gland mucosa. This proportion is higher than the 25% rate of HP infection with cytotoxin-associated antigen A positive strains (CagAþ) of similar patients in Western countries, but lower than the 98% infection rate of patients in Japan who have gastric cancer (10,19). Furthermore, the rate of positive gastritis in those with BA was only 38% (Table 3). This rate is a little higher than the CagAþ HP infection rate in the BA patients of Western countries (9). The prevalence of gastritis was significantly lower in BA patients than that in non-BA (Table 2). The female ratio was significantly higher in non-BA with the gastritis group, resembling characteristics of gastric cancer. Age was significantly

younger in non-BA without the gastritis group. However, no difference was shown between positive and negative gastritis in the BA group. Regarding reflux esophagitis, the prevalence was higher in the BA group and non-BA without gastritis group than that in the non-BA with gastritis group (Table 3). Therefore, AEGJ is considered to be a heterogeneous entity, including three groups: BE-related, positive gastritis-related, and BE and gastritis-unrelated AEGJ. We confirmed that the clinical characteristics of the patients with positive gastritis in the non-BA group were significantly different from the other groups, and those characteristics, relatively high patient age and female preponderance resembled that of reported adenocarcinoma of the distal stomach (18). However, we found that the tumors had common pathological characteristics regardless of the positive or negative gastritis in the fundic gland mucosa. Our findings agree with those of Nunobe et al., who also investigated AEGJ and reported common clinicopathological characteristics regardless of the presence or absence of IM (4). From an evaluation of the histogenesis of gastric carcinomas, Kakinoki et al. reported that most differentiated adenocarcinomas develop in mild to moderate atrophic mucosa with HP infection, which is called ongoing atrophy, and concluded

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0.302

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Histological status of adenocarcinoma of EGJ

Table 4. Updated Sydney System Scores of the background fundic gland mucosa confined to the histological gastritis positive superficial AEGJ Score

BA (n ¼ 24)

Non-BA (n ¼ 43)

Total (n ¼ 67)

P valuea

Chronic inflammation 0

0

0

0

1

13

23

36

2

10

16

26

3

1

4

5

Mean

1.50

1.56

1.54

0.857

Neutrophil activity 11

22

33

1

13

18

31

2

0

3

3

3

0

0

0

Mean

0.54

0.56

0.55

0.435

Glandular atrophy 0

7

3

10

1

7

17

24

2

7

19

26

3

3

4

7

Mean

1.25

1.56

1.45

0.095

IM 0

13

8

21

1

4

20

24

2

5

11

16

3

2

4

6

Mean

0.83

1.26

1.10

0.015

IM, intestinal metaplasia. a BA vs non-BA group.

that IM is a paracancerous lesion (18). In the present study, positive gastritis affected about half of superficial AEGJ patients, although the degree of glandular atrophy and IM seems to be mild. Ongoing atrophic mucosa may preserve gastric acid secretion, which has been reported to be a key factor for the development of AEGJ (20). Furthermore, regarding the prevalence of reflux esophagitis in the present study, the ratio was lowest in the non-BA with the gastritis group. Comparing the prevalence, ongoing atrophic mucosa may play a more important role than reflux esophagitis in the development of AEGJ with gastritis. This is similar to distal gastric cancer. The prevalence of AEGJ with negative gastritis in the non-BA group accounted for only 12% (15 of 121) of patients in the present study. It has been suggested that confirmation of BE is difficult in advanced AEGJ, because BA might overgrow and obliterate the BE (21). Despite this theory, tumors in non-BA without the gastritis group are considered to derive

Conflict of interest statement None declared.

References 1. Siewert JR, Stein H. Adenocarcinoma of the gastroesophageal junction: classification, pathology and extent of resection. Dis Esophagus 1996;9:173–82. 2. Correa P. Human gastric carcinogenesis: a multistep and multifactorial process—First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res 1992;52:6735–40. 3. Spechler SJ, Goyal RK. Barrett’s esophagus. N Engl J Med 1986;315:362– 71.

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from BE-unrelated factors and negative gastritis. This is possibly because the subjects of our investigation included only superficial AEGJ, and the mean tumor size of this group was relatively small. IM limited to EGJ is thought to be one of the risk factors in the development of AEGJ and may be included in this group (4). In fact, given the irregularity of Z-line as a finding of reflux esophagitis, reflux esophagitis was observed in 93% (14 of 15). Reflux esophagitis is related to the IM limited to EGJ and Barrett’s esophagitis. Therefore, in our speculation, reflex esophagitis is considered to be strongly associated with the etiology of this type of AEGJ. We also encountered some limitations. First, the present study did not provide the history of HP infection, eradication and other causes of gastritis representing autoimmune gastritis and non-specific chronic gastritis. Despite carefully reviewing medical records, we could not fully identify these etiologies of the positive gastritis. Notably, in Japan, the etiology of positive gastritis is mostly HP, particularly in the gastric cancer. Second, because the materials included total gastorectomy, proximal partial gastric resections and endoscopically resected specimens, the present study could not fully evaluate the influence of gastritis of the pyloric glands mucosa, which causes hypergastric acid secretion (22). However, we confirmed that none of the patients with negative gastritis had endoscopic findings of HP-related gastritis, such as swelling of area gastrica, diffuse redness and lack of a regular arrangement of collecting venules, in the preoperative endoscopic images (data not shown) (23). Third, based on the definitions used in the present study, IM seen in the fundic gland mucosa did not reflect IM limited to EGJ. Fourth, there was some subjectivity to the evaluation of the degree of the scores determined by the experienced gastrointestinal pathologists. However, the scoring method of the USS has been used widely and evaluation by this method for resected specimens should be more precise than for biopsied specimens. In conclusion, about half of the patients with AEGJ harbor histological gastritis. AEGJ is considered to be a heterogeneous entity arising in various backgrounds, including BE-related, positive gastritis-related, and BE- and gastritisunrelated AEGJ.

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Different histological status of gastritis in superficial adenocarcinoma of the esophagogastric junction.

Although many gastric cancers arise in chronic gastritis, the association between adenocarcinoma of the esophagogastric junction and the status of bac...
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