bs_bs_banner
doi:10.1111/jgh.12512
GASTROENTEROLOGY
Gastric xanthelasma may be a warning sign for the presence of early gastric cancer Akira Sekikawa,* Hirokazu Fukui,† Takanori Maruo,* Takehiko Tsumura,* Takashi Kanesaka,* Yoshihiro Okabe* and Yukio Osaki* *Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, and †Division of Upper Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
Key words age, atrophic gastritis, gastric cancer, gastric xanthelasma. Accepted for publication 7 December 2013. Correspondence Dr Akira Sekikawa, Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, 5-30, Fudegasaki, Tennoji-ku, Osaka 543-8555, Japan. Email: [email protected] Disclosure: The authors have declared no conflicts of interest.
Abstract Background and Aim: The significance of gastric xanthelasma in relation to gastric disease still remains unclear. We investigated the prevalence and significance of gastric xanthelasma in patients with atrophic gastritis and gastric cancer. Methods: A total of 3238 patients who underwent endoscopic examinations of the upper gastrointestinal tract were enrolled. We retrospectively investigated the presence of gastric xanthelasma, the severity of gastric atrophy, and the presence of gastric cancer, and examined the relationship between gastric xanthelasma and various clinicopathological features. Results: Gastric xanthelasma was detected in 249 (7.7%) of the 3238 patients and was significantly associated with age ≥ 65 years, male gender, open-type atrophy, and the presence of gastric cancer (P < 0.0001, P = 0.0002, P < 0.0001 and P < 0.0001, respectively). Multivariate analysis revealed that the presence of gastric cancer was independently related to the presence of gastric xanthelasma (odds ratio 6.19 [3.95–9.70], P < 0.0001). Age/sex/atrophy-matched control analysis demonstrated that the presence of gastric xanthelasma was significantly associated with the presence of gastric cancer (P < 0.0001). Moreover, the presence of xanthelasma in the upper region of the stomach was significantly associated with gastric cancer (P = 0.002). Gastric xanthelasma was observed in 50 (47.6%) of 105 patients with gastric cancer. Conclusion: Gastric xanthelasma may serve as a warning sign for the presence of gastric cancer.
Introduction Gastric cancer is one of the most common causes of cancer-related death worldwide.1,2 Because the outcome of patients with unresectable gastric cancer is very poor, adequate removal of the lesion at a curable stage by endoscopic or surgical resection remains the most likely curative treatment.3,4 In this context, detection of gastric cancer at an early stage improves the chances of survival. Gastric atrophy, which reflects the chronic gastritis induced by Helicobacter pylori (H. pylori) infection, is known to be a risk factor for gastric cancer.5–9 Although gastric atrophy is an important finding that should alert endoscopists to the possible presence of early gastric cancer, additional findings may be also helpful for this purpose. Gastric xanthelasma, also known as xanthoma or lipid island, is a small yellowish-white plaque or nodule characterized by accumulation of lipid, including oxidized low-density lipoprotein (LDL), in histiocytic foam cells.10 The reported incidence of gastric xanthelasma is 0.018–7%.11–14 Several investigators have suggested that xanthelasma may be the result of an inflammatory
response to mucosal damage or aging, although its developmental mechanism remains to be elucidated.13,15 Gastric xanthelasma has received little attention, as its benign nature has been considered to have little clinical significance. Accordingly, the prevalence and clinical significance of gastric xanthelasma in relation to gastric diseases, especially gastric cancer, still remain unclear. In the present study, we investigated the prevalence rate of gastric xanthelasma and its relationship to clinicopathological and endoscopic features. We then investigated whether gastric xanthelasma would be a useful marker for the presence of early gastric cancer.
Material and methods Patients. A total of 3238 patients who underwent endoscopic examinations of the upper gastrointestinal tract at Osaka Red Cross Hospital between 2007 and 2008 were enrolled. All the patients were recruited from this tertiary care center. This study was based on retrospective analysis conducted at this single
Journal of Gastroenterology and Hepatology 29 (2014) 951–956 © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
951
Gastric xanthelasma and gastric cancer
A Sekikawa et al.
institution. Gastric xanthelasma, gastric atrophy, and the presence of gastric cancer were evaluated endoscopically. We also examined the relationship between gastric xanthelasma and various clinicopathological features, including age, sex, presence of gastric atrophy, presence of gastric cancer, tumor location, tumor depth, Lauren’s histological classification, lymph node metastasis, and tumor size in the gastric cancer patients. Controls matched with the patients for age, sex, and atrophy severity were also examined. Patients who had undergone gastrectomy previously were excluded from this study. The gastric cancer specimens obtained by endoscopic or surgical resection were fixed in 10% formalin and embedded in paraffin. Multiple HE-stained sections of the lesions were examined. This study was carried out with the approval of the Osaka Red Cross Hospital Ethics Committee, and informed consent was obtained from all patients.
between two groups were analyzed using unpaired two-tailed t-test or by Mann–Whitney U-test when the data were not parametric. Chi-squared analyses were performed to investigate the relationships between groups and the various clinicopathological features. Multivariate stepwise logistic analysis was performed to identify variables that were related to the presence of gastric xanthelasma. Differences at P < 0.05 were considered to be statistically significant.
Results
Endoscopic procedure. Endoscopic examination was performed using panendoscopes (GIF-Q260 or GIF-H260; Olympus Medical Systems, Tokyo, Japan) equipped with an electronic endoscopy system (EVIS LUCERA system; Olympus Medical Systems). Briefly, 30 min before the endoscopic procedure, patients were given a mixture of 100 mL of water with 20 000 units of pronase (Pronase MS; Kaken Pharmaceutical Co., Ltd, Tokyo, Japan) and 10 mL of dimethylpolysiloxane (20 mg/dL; Horii Pharmaceutical Ind., Osaka, Japan). Basically, all patients were examined under conscious sedation using 1–3 mg of midazolam (Dormicum; Astellas Pharma, Inc., Tokyo, Japan). Ten experienced endoscopists performed each examination, carefully observing the esophagus, the entire stomach, and the bulbar portion of the duodenum. Endoscopic images were reviewed by two experienced endoscopists (A.S. and T.K.), respectively. The interobserver variability for detecting gastric xanthelasma was very small (kappa value = 0.937). Patients were diagnosed by endoscopic examinations as follows: gastric cancer (n = 105), esophageal cancer (n = 17), gastric malignant lymphoma (n = 4), gastric submucosal tumor (n = 26), gastric hyperplastic polyps (n = 74), gastric ulcer (n = 55), duodenal ulcer (n = 28), reflux esophagitis (n = 45), esophago-gastric varices (n = 49), atrophic gastritis (n = 1285), and no lesion (n = 1550). We classified the severity of gastric atrophy according to the criteria of Kimura and Takemoto, as reported previously.16,17 Briefly, by identifying the location of the borderline between the fundic and pyloric gland regions, the stage of atrophy was divided into three types: open type, closed type, and antral type. If the borderline between the fundic and pyloric regions was located in the angular part of the lesser curvature, it was defined as the antral type. If the borderline was located on the lesser curvature of the stomach, it was defined as the closed type. If the entire aspect of the lesser curvature was pyloric in nature, and the border was shifted orally, it was defined as the open type. Tumor location was classified according to the Japanese classification of gastric carcinoma.18
Relationship of gastric xanthelasma to age, gastric atrophy, and the presence of gastric cancer. The clinical features of the patients evaluated in the present study are summarized in Table 1. A total of 3238 patients underwent endoscopic examination. Gastric cancer was detected in 105 (3.2%) of the patients overall. The prevalence of gastric xanthelasma in these patients was then investigated. Gastric xanthelasma was detected in 249 (7.7%) of the 3238 patients. The patients were then divided into two groups based on the presence of gastric xanthelasma, and differences between these two groups were examined. Patients with gastric xanthelasma were significantly older than those without (P < 0.0001). The proportion of males was significantly higher in patients with than in those without xanthelasma (P = 0.0002). Moreover, a significantly higher proportion of patients with gastric xanthelasma had open-type atrophy than was the case for patients without (P < 0.0001, Table 1): gastric xanthelasma was observed in 244 (14.7%) of the 1660 patients with atrophic gastritis compared with only 5 (0.3%) of 1578 patients without gastric atrophy. Interestingly, the proportion of patients with gastric cancer was significantly higher among those with gastric xanthelasma than in those without (20.1% vs 1.8%, P < 0.0001, Table 1). Conversely, gastric xanthelasma was observed in 50 (47.6%) of the 105 patients with gastric cancer compared with 199 (6.4%) of the 3133 patients without gastric cancer (Fig. 1). Univariate analysis showed that the prevalence of gastric xanthelasma was significantly related to clinical features including, age, sex, gastric atrophy, and the presence of gastric cancer (Table 1). Therefore, these factors were evaluated by multivariate analysis in 3238 patients. This revealed that age ≥ 65 years, opentype atrophy, and the presence of gastric cancer were each factors independently related to the presence of gastric xanthelasma (Table 2). In addition, we examined the factors related to gastric cancer. Univariate analysis revealed that gastric cancer was significantly related to age ≥ 65 years, male gender, gastric atrophy, and the presence of gastric xanthelasma (Supporting Information Table S1). Furthermore, multivariate analysis indicated that age ≥ 65 years, male gender, open-type atrophy, and the presence of gastric xanthelasma were independently related to gastric cancer (Supporting Information Table S2).
Statistical analysis. Statview 5.0J statistical software (Abacus Concepts Inc., Berkeley, CA, USA) was used for all analyses. Data for age, number of gastric xanthlasmas, and the sizes of gastric xanthelasmas and tumors were expressed as the mean ± standard error of the mean. Differences in these values
Significant association of gastric xanthelasma with the presence of gastric cancer as demonstrated by age/sex/atrophy-matched control analysis. To clarify the value of gastric xanthelasma as an indicator of the presence of gastric cancer, an age/sex/atrophy-matched control
952
Journal of Gastroenterology and Hepatology 29 (2014) 951–956 © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
A Sekikawa et al.
Table 1
Gastric xanthelasma and gastric cancer
Comparison of clinical features between patients with and without gastric xanthelasma
Characteristics
Total patients (n = 3238)
Patients with GX (n = 249)
Patients without GX (n = 2989)
P value
Age (years) Age ≥ 65 < 65 Sex Male Female Atrophy Open type Closed type Antral type No atrophy Gastric cancer Present Absent
60.4 ± 0.3
69.2 ± 0.6
59.6 ± 0.3
< 0.0001†
1408 (43.5%) 1830 (56.5%)
180 (72.3%) 69 (27.7%)
1228 (41.1%) 1761 (58.9%)
< 0.0001‡ —
1660 (51.3%) 1578 (48.7%)
156 (62.7%) 93 (37.3%)
1504 (50.3%) 1485 (49.7%)
0.0002‡ —
1146 (35.4%) 341 (10.5%) 173 (5.3%) 1578 (48.8%)
222 (89.2%) 19 (7.6%) 3 (1.2%) 5 (2.0%)
924 (30.9%) 322 (10.8%) 170 (5.7%) 1573 (52.6%)
< 0.0001‡ — — —
105 (3.2%) 3133 (96.8%)
50 (20.1%) 199 (79.9%)
55 (1.8%) 2934 (98.2%)
< 0.0001‡ —
†
Mann–Whitney U-test. Chi-squared analysis. GX, gastric xanthelasma.
‡
a
b
Figure 1 Representative images showing gastric xanthelasmas occurred in patients with early gastric cancer. (a) Two gastric xanthelasmas are observed at the greater curvature of the lower body (arrows). Early gastric cancer is detected at the greater curvature of the antrum (arrow head). (b) Gastric xanthelasma is observed at the posterior wall of the upper body (arrow). Early gastric cancer is detected at the lesser curvature of the upper body (arrow head).
study was performed. A total of 240 patients with gastric xanthelasma and 240 age/sex/atrophy-matched controls without gastric xanthelasma were examined. The clinical features of these two groups are shown in Table 3. Interestingly, gastric cancer was detected in 50 (20.8%) of the 240 patients with gastric xanthelasma, whereas it was detected in 8 (3.3%) of the 240 age/sex/atrophy-matched controls without gastric xanthelasma (P < 0.0001, Table 3). Thus, the presence of gastric xanthelasma was significantly associated with the presence of gastric cancer independently of age and gastric atrophy, suggesting that gastric xanthelasma may serve as a biomarker for the presence of gastric cancer. Presence of xanthelasma in the upper region of the stomach is associated with gastric cancer. A total of 249 patients with gastric xanthelasma were then divided
into two groups based on the presence of gastric cancer, and differences between these two groups were examined. Patients with xanthelasma who had gastric cancer were significantly older than those without. Among the xanthelasma patients, a significantly higher proportion of those with cancer were males compared with those without cancer. Interestingly, a significantly higher proportion of patients with cancer had xanthelasma in the upper region of the stomach compared with patients who did not have cancer (50.0% vs 23.1%, P = 0.002, Table 4). None of the other parameters, including gastric atrophy, presence of xanthelasma in the middle region, presence of xanthelasma in the lower region, and the number and size of xanthelasma lesions, was significantly related to the presence of gastric cancer (Table 4). Moreover, we classified the xanthelasma into three grades: grade 1 (one xanthelasma), grade 2 (two xanthelasmas), and grade 3 (more than three xanthelasmas). Thereafter, we examined the relationship between the grade of xanthelasma and the presence of gastric cancer. Gastric cancer was present in 25 (18.4%) of 136 grade 1 patients, 11 (17.2%) of 64 grade 2 patients, and 14 (28.6%) of 49 grade 3 patients (P = 0.249). These findings showed that no correlation was present between the grade of xanthelasma and the presence of gastric cancer.
Comparison of clinicopathological features between gastric cancer patients with and without xanthelasma. We next investigated the clinicopathological features of the 105 patients with gastric cancer in relation to the presence or absence of gastric xanthelasma; the data are summarized in the Supporting Information Table S3. Gastric xanthelasma was present in 50 (47.6%) of the gastric cancer patients. We then examined the relationship between gastric xanthelasma and clinicopathological features in these patients. Gastric cancer patients with gastric xanthelasma included a significantly higher proportion of individuals older than 65 years than those without (86.0%
Journal of Gastroenterology and Hepatology 29 (2014) 951–956 © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
953
Gastric xanthelasma and gastric cancer
Table 2
A Sekikawa et al.
Multivariate analysis of factors related to gastric xanthelasma
Age Sex Atrophy GC
≥ 65 years Male Open type Present
Crude odds ratio
P value
Adjusted odds ratio
P value
3.74 (2.81–4.98) 1.66 (1.27–2.16) 18.38 (12.23–27.61) 13.40 (8.90–20.18)
< 0.0001 0.0002 < 0.0001 < 0.0001
1.78 (1.30–2.44) 1.32 (0.99–1.77) 13.22 (8.70–20.12) 6.19 (3.95–9.70)
0.0003 0.0616 < 0.0001 < 0.0001
GC, gastric cancer.
Table 3 Comparison of the presence of gastric cancer between patients with gastric xanthelasma and age/sex/atrophy-matched controls without gastric xanthelasma Characteristics
Patients with GX (n = 240)
Controls without GX (n = 240)
P value
Age (years) Age ≥ 65 < 65 Sex Male Female Atrophy Open type Closed type Antral type No atrophy Gastric cancer Present Absent
69.5 ± 0.4
69.5 ± 0.4
175 (72.9%) 65 (27.1%)
175 (72.9%) 65 (27.1%)
1.0‡ —
151 (62.9%) 89 (37.1%)
151 (62.9%) 89 (37.1%)
1.0‡ —
215 (89.5%) 17 (7.1%) 3 (1.3%) 5 (2.1%)
215 (89.5%) 17 (7.1%) 3 (1.3%) 5 (2.1%)
1.0‡ — — —
50 (20.8%) 190 (79.2%)
8 (3.3%) 232 (96.7%)
1.0†
< 0.0001‡ —
†
Mann–Whitney U-test. Chi-squared analysis. GX, gastric xanthelasma.
‡
vs 65.5%, P = 0.015). None of the other parameters, including sex, the proportion of patients with open-type atrophy, tumor location, tumor depth, Lauren’s classification, lymph node metastasis, and tumor size, was significantly correlated with the presence of gastric xanthelasma in gastric cancer patients (Supporting Information Table S3).
Discussion The incidence of gastric xanthelasma has been reported to be 0.018% in the European population and 0.2% in Turkey compared with 7% in Korea.11,13,14 In the present series, the prevalence of gastric xanthelasma was 7.7%, consistent with the report by Yi.14 In addition, we found that gastric xanthelasma was associated with not only age but also the severity of gastric atrophy. These data suggest that differences in the reported incidence of xanthelasma may be due mainly to differences in the prevalence of atrophic gastritis, the prevalence of H. pylori infection, and its associated atrophic gastritis being higher in the Asian adult population.19–21 On the other hand, we found that 3.2% of total patients had gastric cancer in the endoscopic examinations. This rate is relatively high when compared with that in western countries.22,23 However, we consider it reasonable because in Japan, 954
the prevalence of H. pylori infection is higher, the H. pylori virulence is stronger, and high salt intake is possible to promote gastric cancer development. The most interesting finding of this study was that the incidence of gastric cancer was significantly higher in patients with gastric xanthelasma than in those without. Multivariate analysis showed that gastric cancer was an independent factor related to the presence of gastric xanthelasma. Moreover, it is noteworthy that gastric xanthelasma was significantly associated with the presence of gastric cancer in controls matched for age, sex, and gastric atrophy. Previous reports have indicated that both age and severe gastric atrophy are risk factors for gastric cancer.24–27 We found that the presence of gastric xanthelasma, in addition to age and severe gastric atrophy, was a risk factor for gastric cancer. Although it is still unclear whether gastric xanthelasma would be a useful feature for indicating the possible presence of gastric cancer, our data suggest that this might be the case in patients with atrophic gastritis. Why is gastric cancer present more frequently in patients with gastric xanthelasma than in those without? We found in the present study that the presence of gastric xanthelasma was associated with patient age and/or the presence of severe atrophy; however, it was independently associated with gastric cancer. Thus, gastric xanthelasma may reflect not only gastric atrophy and aging but also
Journal of Gastroenterology and Hepatology 29 (2014) 951–956 © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
A Sekikawa et al.
Table 4
Gastric xanthelasma and gastric cancer
Comparison of the features of gastric xanthelasma between patients with and without gastric cancer
Characteristics
Total GX patients (n = 249)
GX patients with GC (n = 50)
GX patients without GC (n = 199)
Age (years) Age ≥ 65 < 65 Sex Male Female Atrophy Open type Closed type Antral type No atrophy GX in upper region Present Absent GX in middle region Present Absent GX in lower region Present Absent Number of GXs Size of GXs (mm)
69.2 ± 0.6
72.5 ± 1.0
68.4 ± 0.7
P value
0.002†
180 (72.3%) 69 (27.7%)
43 (86.0%) 7 (14.0%)
137 (68.8%) 62 (31.2%)
0.015‡ —
156 (62.7%) 93 (37.3%)
38 (76.0%) 12 (24.0%)
118 (59.3%) 81 (40.7%)
0.029‡ —
221 (88.7%) 20 (8.1%) 3 (1.2%) 5 (2.0%)
44 (88.0%) 6 (12.0%) 0 0
177 (88.9%) 14 (7.0%) 3 (1.5%) 5 (2.6%)
0.356‡ — — —
71 (28.5%) 178 (72.5%)
25 (50.0%) 25 (50.0%)
46 (23.1%) 153 (76.9%)
0.002‡ —
120 (48.2%) 129 (51.2%)
29 (58.0%) 21 (42.0%)
91 (45.7%) 108 (54.3%)
0.121‡ —
139 (56.4%) 110 (43.6%) 1.9 ± 0.1 4.8 ± 0.1
23 (46.0%) 27 (53.0%) 2.2 ± 0.2 4.6 ± 0.1
116 (58.3%) 83 (41.7%) 1.8 ± 0.1 4.9 ± 0.1
0.118‡ — 0.259† 0.154†
†
Mann–Whitney U-test. Chi-squared analysis. GC, gastric cancer; GX, gastric xanthelasma.
‡
other biological factors. Interestingly, Kaiserling et al. reported that increased release of oxygen-free radicals may be involved in accumulation of oxidized LDL cholesterol and development of gastric xanthelasma.10 On the other hand, oxygen-free radicals are known to cause DNA damage and associated oncogenic changes.28,29 Overall, it is tempting to speculate that excessive production of free radicals may be involved in the development of not only gastric xanthelasma but also gastric cancer, although further studies will be needed to clarify the significance of gastric xanthelasma in relation to gastric cancer. Atrophic gastritis is widely accepted as an important risk factor for gastric cancer.6,7 In Asia, endoscopic examination for detection of early gastric cancer reveals many patients with atrophic gastritis, in view of the high prevalence of H. pylori infection.30 Moreover, although open-type atrophy is associated with a higher risk of cancer development than closed-type atrophy, it may be difficult to distinguish these two types precisely by endoscopic examination. Therefore, in addition to gastric atrophy, it may be necessary to look for other features in order to detect early gastric cancer more effectively. In the present study of patients with atrophic gastritis, we found that gastric cancer was detected more frequently in those with gastric xanthelasma than in those without. Therefore, awareness of gastric xanthelasma in patients with atrophic gastritis may be an effective approach for surveillance of early gastric cancer. Moreover, the presence of xanthelasma in the upper region of the stomach was significantly associated with gastric cancer. Thus, not only the presence of gastric xanthelasma but also its location may be important.
However, our study was limited in the fact that it was based on retrospective analysis conducted at a single institution. Therefore, multicenter prospective studies will be needed to clarify the diagnostic performance of this feature. In summary, we have examined the prevalence of gastric xanthelasma and shown that it is associated with patient age, gastric atrophy, and the presence of gastric cancer. Gastric xanthelasma was significantly associated with the presence of gastric cancer in age/sex/atrophy-matched control analysis. In the context of clinical application, our present data suggest that the presence of gastric xanthelasmas in patients with atrophic gastritis may be an effective approach for surveillance of early gastric cancer and may serve as a marker for alerting clinicians to its possible presence. Therefore, closer attention to gastric xanthelasma seems warranted.
References 1 Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J. Clin. Oncol. 2006; 24: 2137–50. 2 Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer 2010; 127: 2893–917. 3 Chau I, Norman AR, Cunningham D, Waters JS, Oates J, Ross PJ. Multivariate prognostic factor analysis in locally advanced and metastatic esophago-gastric cancer-pooled analysis from three
Journal of Gastroenterology and Hepatology 29 (2014) 951–956 © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
955
Gastric xanthelasma and gastric cancer
4
5
6
7
8
9
10
11
12 13
14 15
16
17
18
A Sekikawa et al.
multicenter, randomized, controlled trials using individual patient data. J. Clin. Oncol. 2004; 22: 2395–403. Sekikawa A, Fukui H, Zhang X et al. REG Iα is a biomarker for predicting response to chemotherapy with S-1 plus cisplatin in patients with unresectable stage IV gastric cancer. Br. J. Cancer 2013; 108: 395–401. Parsonnet J, Friedman GD, Vandersteen DP et al. Helicobacter pylori infection and risk of gastric carcinoma. N. Engl. J. Med. 1991; 325: 1127–31. Nomura A, Stemmmermann GN, Chyou PH, Kato I, Perez-Perez GI, Blaser MJ. Helicobacter pylori infection and risk of gastric carcinoma among Japanese Americans in Hawaii. N. Engl. J. Med. 1991; 325: 1132–6. Uemura N, Okamoto S, Yamamoto S et al. Helicobacter pylori infection and the development of gastric cancer. N. Engl. J. Med. 2001; 345: 784–9. De Vries AC, van Grieken NC, Looman CW et al. Gastric cancer risk in patients with premalignancy lesions: a nationwide cohort study in the Netherlands. Gastroenterology 2008; 134: 945–52. Yamaji Y, Mitsushima T, Ikuma H et al. Inverse background of Helicobacter pylori antibody and pepsinogen in reflux oesophagitis compared with gastric cancer: analysis 5732 Japanese subjects. Gut 2001; 49: 335–40. Kaiserling E, Heine H, Itabe H, Takano T, Remmele W. Lipid islands in human gastric mucosa: morphological and immunohistochemical findings. Gastroenterology 1996; 110: 369–74. Petov S, Churtchev J, Mitova R, Boyanova L, Tarassov M. Xanthoma of the stomach-some morphometrical peculiarities and scanning electron microscopy. Hepatogastroenterology 1999; 46: 1220–2. Chen YS, Lin JB, Dai KS et al. Gastric xanthelasma. Chin. Med. J. 1989; 102: 639–43. Gencosmanoglu R, Sen-Oran E, Kurtkaya-Yapicier O, Tozun N. Xanthelasmas of the upper gastrointestinal tract. J. Gastroenterol. 2004; 39: 215–19. Yi SY. Dislipidmia and H Pylori in gastric xanthomatosis. World J. Gastroenterol. 2007; 13: 4598–601. Isomoto H, Mizuta Y, Inoue K et al. A close relationship between Helicobacter pylori infection and gastric xanthoma. Scand. J. Gastroenterol. 1999; 34: 346–52. Kimura K, Takemoto T. An endoscopic recognization of the atrophic border and its significance in chronic gastritis. Endoscopy 1969; 1: 87–97. Kitahara F, Kobayashi K, Sato T, Kojima Y, Araki T, Fujino MA. Accuracy of screening for gastric cancer using serum pepsinogen concentration. Gut 1999; 44: 693–7. Japanese Gastric Cancer Association. Japanese Classification of Gastric Carcinoma, 2nd English Edition. Gastric Cancer 1998; 1: 10–24.
956
19 Kikuchi S, Wada O, Nakajima T et al. Serum anti-Helicobacter pylori antibody and gastric carcinoma among young adults. Research Group on Prevention of Gastric Carcinoma among Young Adults. Cancer 1995; 75: 2789–93. 20 Lin JT, Wang LY, Wang JT, Wang TH, Yang CS, Chen CJ. A nested case-control study on the association between Helicobacter pylori infection and gastric cancer risk in a cohort of 9775 men in Taiwan. Anticancer Res. 1995; 15: 603–6. 21 Webb PM, Yu MC, Forman D et al. An apparent lack of association between Helicobacter pylori infection and risk of gastric cancer in China. Int. J. Cancer 1996; 67: 603–7. 22 Naylor GM, Gotoda T, Dixon M et al. Why does Japan have a high incidence of gastric cancer? Comparison of gastritis between UK and Japanese patients. Gut 2006; 55: 1545–52. 23 Roder DM. The epidemiology of gastric cancer. Gastric Cancer 2002; 5: 5–11. 24 Shipponen P, Kekki M, Siurala M. Increase risk of gastric cancer in males affects the intestinal type of cancer and is independent of age, location of the tumour and atrophic gastritis. Br. J. Cancer 1988; 57: 332–6. 25 You WC, Blot WJ, Li JY et al. Precancerous gastric lesions in a population at high risk of stomach cancer. Cancer Res. 1993; 53: 1317–21. 26 Tatsuta M, Iishi H, Nakaizumi A et al. Fundal atrophic gastritis as a risk factor for gastric cancer. Int. J. Cancer 1993; 53: 70–4. 27 Watabe H, Mitsushima T, Yamaji Y et al. Predicting the development of gastric cancer from combining Helicobacter pylori antibodies and serum pepsinogen status: a prospective endoscopic cohort study. Gut 2005; 54: 764–8. 28 Farinati F, Cardin R, Dagan P et al. Oxidative DNA damage accumulation in gastric carcinogenesis. Gut 1998; 42: 351–6. 29 Kountouras J, Chatzopoulos D, Zavos C. Reactive oxygen metabolites and upper gastrointestinal diseases. Hepatogastroenterology 2001; 48: 743–51. 30 The EUROGAST Study Group. An international association between Helicobacter pylori infection and gastric cancer. Lancet 1993; 341: 1359–62.
Supporting information Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Table S1 Comparison of clinical features between patients with and without gastric cancer Table S2 Multivariate analysis of factors related to gastric cancer Table S3 Comparison of clinicopathological features between gastric cancer patients with and without xanthelasma
Journal of Gastroenterology and Hepatology 29 (2014) 951–956 © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
doi:10.1111/jgh.12512
GASTROENTEROLOGY
Gastric xanthelasma may be a warning sign for the presence of early gastric cancer Akira Sekikawa,* Hirokazu Fukui,† Takanori Maruo,* Takehiko Tsumura,* Takashi Kanesaka,* Yoshihiro Okabe* and Yukio Osaki* *Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, and †Division of Upper Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
Key words age, atrophic gastritis, gastric cancer, gastric xanthelasma. Accepted for publication 7 December 2013. Correspondence Dr Akira Sekikawa, Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, 5-30, Fudegasaki, Tennoji-ku, Osaka 543-8555, Japan. Email: [email protected] Disclosure: The authors have declared no conflicts of interest.
Abstract Background and Aim: The significance of gastric xanthelasma in relation to gastric disease still remains unclear. We investigated the prevalence and significance of gastric xanthelasma in patients with atrophic gastritis and gastric cancer. Methods: A total of 3238 patients who underwent endoscopic examinations of the upper gastrointestinal tract were enrolled. We retrospectively investigated the presence of gastric xanthelasma, the severity of gastric atrophy, and the presence of gastric cancer, and examined the relationship between gastric xanthelasma and various clinicopathological features. Results: Gastric xanthelasma was detected in 249 (7.7%) of the 3238 patients and was significantly associated with age ≥ 65 years, male gender, open-type atrophy, and the presence of gastric cancer (P < 0.0001, P = 0.0002, P < 0.0001 and P < 0.0001, respectively). Multivariate analysis revealed that the presence of gastric cancer was independently related to the presence of gastric xanthelasma (odds ratio 6.19 [3.95–9.70], P < 0.0001). Age/sex/atrophy-matched control analysis demonstrated that the presence of gastric xanthelasma was significantly associated with the presence of gastric cancer (P < 0.0001). Moreover, the presence of xanthelasma in the upper region of the stomach was significantly associated with gastric cancer (P = 0.002). Gastric xanthelasma was observed in 50 (47.6%) of 105 patients with gastric cancer. Conclusion: Gastric xanthelasma may serve as a warning sign for the presence of gastric cancer.
Introduction Gastric cancer is one of the most common causes of cancer-related death worldwide.1,2 Because the outcome of patients with unresectable gastric cancer is very poor, adequate removal of the lesion at a curable stage by endoscopic or surgical resection remains the most likely curative treatment.3,4 In this context, detection of gastric cancer at an early stage improves the chances of survival. Gastric atrophy, which reflects the chronic gastritis induced by Helicobacter pylori (H. pylori) infection, is known to be a risk factor for gastric cancer.5–9 Although gastric atrophy is an important finding that should alert endoscopists to the possible presence of early gastric cancer, additional findings may be also helpful for this purpose. Gastric xanthelasma, also known as xanthoma or lipid island, is a small yellowish-white plaque or nodule characterized by accumulation of lipid, including oxidized low-density lipoprotein (LDL), in histiocytic foam cells.10 The reported incidence of gastric xanthelasma is 0.018–7%.11–14 Several investigators have suggested that xanthelasma may be the result of an inflammatory
response to mucosal damage or aging, although its developmental mechanism remains to be elucidated.13,15 Gastric xanthelasma has received little attention, as its benign nature has been considered to have little clinical significance. Accordingly, the prevalence and clinical significance of gastric xanthelasma in relation to gastric diseases, especially gastric cancer, still remain unclear. In the present study, we investigated the prevalence rate of gastric xanthelasma and its relationship to clinicopathological and endoscopic features. We then investigated whether gastric xanthelasma would be a useful marker for the presence of early gastric cancer.
Material and methods Patients. A total of 3238 patients who underwent endoscopic examinations of the upper gastrointestinal tract at Osaka Red Cross Hospital between 2007 and 2008 were enrolled. All the patients were recruited from this tertiary care center. This study was based on retrospective analysis conducted at this single
Journal of Gastroenterology and Hepatology 29 (2014) 951–956 © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
951
Gastric xanthelasma and gastric cancer
A Sekikawa et al.
institution. Gastric xanthelasma, gastric atrophy, and the presence of gastric cancer were evaluated endoscopically. We also examined the relationship between gastric xanthelasma and various clinicopathological features, including age, sex, presence of gastric atrophy, presence of gastric cancer, tumor location, tumor depth, Lauren’s histological classification, lymph node metastasis, and tumor size in the gastric cancer patients. Controls matched with the patients for age, sex, and atrophy severity were also examined. Patients who had undergone gastrectomy previously were excluded from this study. The gastric cancer specimens obtained by endoscopic or surgical resection were fixed in 10% formalin and embedded in paraffin. Multiple HE-stained sections of the lesions were examined. This study was carried out with the approval of the Osaka Red Cross Hospital Ethics Committee, and informed consent was obtained from all patients.
between two groups were analyzed using unpaired two-tailed t-test or by Mann–Whitney U-test when the data were not parametric. Chi-squared analyses were performed to investigate the relationships between groups and the various clinicopathological features. Multivariate stepwise logistic analysis was performed to identify variables that were related to the presence of gastric xanthelasma. Differences at P < 0.05 were considered to be statistically significant.
Results
Endoscopic procedure. Endoscopic examination was performed using panendoscopes (GIF-Q260 or GIF-H260; Olympus Medical Systems, Tokyo, Japan) equipped with an electronic endoscopy system (EVIS LUCERA system; Olympus Medical Systems). Briefly, 30 min before the endoscopic procedure, patients were given a mixture of 100 mL of water with 20 000 units of pronase (Pronase MS; Kaken Pharmaceutical Co., Ltd, Tokyo, Japan) and 10 mL of dimethylpolysiloxane (20 mg/dL; Horii Pharmaceutical Ind., Osaka, Japan). Basically, all patients were examined under conscious sedation using 1–3 mg of midazolam (Dormicum; Astellas Pharma, Inc., Tokyo, Japan). Ten experienced endoscopists performed each examination, carefully observing the esophagus, the entire stomach, and the bulbar portion of the duodenum. Endoscopic images were reviewed by two experienced endoscopists (A.S. and T.K.), respectively. The interobserver variability for detecting gastric xanthelasma was very small (kappa value = 0.937). Patients were diagnosed by endoscopic examinations as follows: gastric cancer (n = 105), esophageal cancer (n = 17), gastric malignant lymphoma (n = 4), gastric submucosal tumor (n = 26), gastric hyperplastic polyps (n = 74), gastric ulcer (n = 55), duodenal ulcer (n = 28), reflux esophagitis (n = 45), esophago-gastric varices (n = 49), atrophic gastritis (n = 1285), and no lesion (n = 1550). We classified the severity of gastric atrophy according to the criteria of Kimura and Takemoto, as reported previously.16,17 Briefly, by identifying the location of the borderline between the fundic and pyloric gland regions, the stage of atrophy was divided into three types: open type, closed type, and antral type. If the borderline between the fundic and pyloric regions was located in the angular part of the lesser curvature, it was defined as the antral type. If the borderline was located on the lesser curvature of the stomach, it was defined as the closed type. If the entire aspect of the lesser curvature was pyloric in nature, and the border was shifted orally, it was defined as the open type. Tumor location was classified according to the Japanese classification of gastric carcinoma.18
Relationship of gastric xanthelasma to age, gastric atrophy, and the presence of gastric cancer. The clinical features of the patients evaluated in the present study are summarized in Table 1. A total of 3238 patients underwent endoscopic examination. Gastric cancer was detected in 105 (3.2%) of the patients overall. The prevalence of gastric xanthelasma in these patients was then investigated. Gastric xanthelasma was detected in 249 (7.7%) of the 3238 patients. The patients were then divided into two groups based on the presence of gastric xanthelasma, and differences between these two groups were examined. Patients with gastric xanthelasma were significantly older than those without (P < 0.0001). The proportion of males was significantly higher in patients with than in those without xanthelasma (P = 0.0002). Moreover, a significantly higher proportion of patients with gastric xanthelasma had open-type atrophy than was the case for patients without (P < 0.0001, Table 1): gastric xanthelasma was observed in 244 (14.7%) of the 1660 patients with atrophic gastritis compared with only 5 (0.3%) of 1578 patients without gastric atrophy. Interestingly, the proportion of patients with gastric cancer was significantly higher among those with gastric xanthelasma than in those without (20.1% vs 1.8%, P < 0.0001, Table 1). Conversely, gastric xanthelasma was observed in 50 (47.6%) of the 105 patients with gastric cancer compared with 199 (6.4%) of the 3133 patients without gastric cancer (Fig. 1). Univariate analysis showed that the prevalence of gastric xanthelasma was significantly related to clinical features including, age, sex, gastric atrophy, and the presence of gastric cancer (Table 1). Therefore, these factors were evaluated by multivariate analysis in 3238 patients. This revealed that age ≥ 65 years, opentype atrophy, and the presence of gastric cancer were each factors independently related to the presence of gastric xanthelasma (Table 2). In addition, we examined the factors related to gastric cancer. Univariate analysis revealed that gastric cancer was significantly related to age ≥ 65 years, male gender, gastric atrophy, and the presence of gastric xanthelasma (Supporting Information Table S1). Furthermore, multivariate analysis indicated that age ≥ 65 years, male gender, open-type atrophy, and the presence of gastric xanthelasma were independently related to gastric cancer (Supporting Information Table S2).
Statistical analysis. Statview 5.0J statistical software (Abacus Concepts Inc., Berkeley, CA, USA) was used for all analyses. Data for age, number of gastric xanthlasmas, and the sizes of gastric xanthelasmas and tumors were expressed as the mean ± standard error of the mean. Differences in these values
Significant association of gastric xanthelasma with the presence of gastric cancer as demonstrated by age/sex/atrophy-matched control analysis. To clarify the value of gastric xanthelasma as an indicator of the presence of gastric cancer, an age/sex/atrophy-matched control
952
Journal of Gastroenterology and Hepatology 29 (2014) 951–956 © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
A Sekikawa et al.
Table 1
Gastric xanthelasma and gastric cancer
Comparison of clinical features between patients with and without gastric xanthelasma
Characteristics
Total patients (n = 3238)
Patients with GX (n = 249)
Patients without GX (n = 2989)
P value
Age (years) Age ≥ 65 < 65 Sex Male Female Atrophy Open type Closed type Antral type No atrophy Gastric cancer Present Absent
60.4 ± 0.3
69.2 ± 0.6
59.6 ± 0.3
< 0.0001†
1408 (43.5%) 1830 (56.5%)
180 (72.3%) 69 (27.7%)
1228 (41.1%) 1761 (58.9%)
< 0.0001‡ —
1660 (51.3%) 1578 (48.7%)
156 (62.7%) 93 (37.3%)
1504 (50.3%) 1485 (49.7%)
0.0002‡ —
1146 (35.4%) 341 (10.5%) 173 (5.3%) 1578 (48.8%)
222 (89.2%) 19 (7.6%) 3 (1.2%) 5 (2.0%)
924 (30.9%) 322 (10.8%) 170 (5.7%) 1573 (52.6%)
< 0.0001‡ — — —
105 (3.2%) 3133 (96.8%)
50 (20.1%) 199 (79.9%)
55 (1.8%) 2934 (98.2%)
< 0.0001‡ —
†
Mann–Whitney U-test. Chi-squared analysis. GX, gastric xanthelasma.
‡
a
b
Figure 1 Representative images showing gastric xanthelasmas occurred in patients with early gastric cancer. (a) Two gastric xanthelasmas are observed at the greater curvature of the lower body (arrows). Early gastric cancer is detected at the greater curvature of the antrum (arrow head). (b) Gastric xanthelasma is observed at the posterior wall of the upper body (arrow). Early gastric cancer is detected at the lesser curvature of the upper body (arrow head).
study was performed. A total of 240 patients with gastric xanthelasma and 240 age/sex/atrophy-matched controls without gastric xanthelasma were examined. The clinical features of these two groups are shown in Table 3. Interestingly, gastric cancer was detected in 50 (20.8%) of the 240 patients with gastric xanthelasma, whereas it was detected in 8 (3.3%) of the 240 age/sex/atrophy-matched controls without gastric xanthelasma (P < 0.0001, Table 3). Thus, the presence of gastric xanthelasma was significantly associated with the presence of gastric cancer independently of age and gastric atrophy, suggesting that gastric xanthelasma may serve as a biomarker for the presence of gastric cancer. Presence of xanthelasma in the upper region of the stomach is associated with gastric cancer. A total of 249 patients with gastric xanthelasma were then divided
into two groups based on the presence of gastric cancer, and differences between these two groups were examined. Patients with xanthelasma who had gastric cancer were significantly older than those without. Among the xanthelasma patients, a significantly higher proportion of those with cancer were males compared with those without cancer. Interestingly, a significantly higher proportion of patients with cancer had xanthelasma in the upper region of the stomach compared with patients who did not have cancer (50.0% vs 23.1%, P = 0.002, Table 4). None of the other parameters, including gastric atrophy, presence of xanthelasma in the middle region, presence of xanthelasma in the lower region, and the number and size of xanthelasma lesions, was significantly related to the presence of gastric cancer (Table 4). Moreover, we classified the xanthelasma into three grades: grade 1 (one xanthelasma), grade 2 (two xanthelasmas), and grade 3 (more than three xanthelasmas). Thereafter, we examined the relationship between the grade of xanthelasma and the presence of gastric cancer. Gastric cancer was present in 25 (18.4%) of 136 grade 1 patients, 11 (17.2%) of 64 grade 2 patients, and 14 (28.6%) of 49 grade 3 patients (P = 0.249). These findings showed that no correlation was present between the grade of xanthelasma and the presence of gastric cancer.
Comparison of clinicopathological features between gastric cancer patients with and without xanthelasma. We next investigated the clinicopathological features of the 105 patients with gastric cancer in relation to the presence or absence of gastric xanthelasma; the data are summarized in the Supporting Information Table S3. Gastric xanthelasma was present in 50 (47.6%) of the gastric cancer patients. We then examined the relationship between gastric xanthelasma and clinicopathological features in these patients. Gastric cancer patients with gastric xanthelasma included a significantly higher proportion of individuals older than 65 years than those without (86.0%
Journal of Gastroenterology and Hepatology 29 (2014) 951–956 © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
953
Gastric xanthelasma and gastric cancer
Table 2
A Sekikawa et al.
Multivariate analysis of factors related to gastric xanthelasma
Age Sex Atrophy GC
≥ 65 years Male Open type Present
Crude odds ratio
P value
Adjusted odds ratio
P value
3.74 (2.81–4.98) 1.66 (1.27–2.16) 18.38 (12.23–27.61) 13.40 (8.90–20.18)
< 0.0001 0.0002 < 0.0001 < 0.0001
1.78 (1.30–2.44) 1.32 (0.99–1.77) 13.22 (8.70–20.12) 6.19 (3.95–9.70)
0.0003 0.0616 < 0.0001 < 0.0001
GC, gastric cancer.
Table 3 Comparison of the presence of gastric cancer between patients with gastric xanthelasma and age/sex/atrophy-matched controls without gastric xanthelasma Characteristics
Patients with GX (n = 240)
Controls without GX (n = 240)
P value
Age (years) Age ≥ 65 < 65 Sex Male Female Atrophy Open type Closed type Antral type No atrophy Gastric cancer Present Absent
69.5 ± 0.4
69.5 ± 0.4
175 (72.9%) 65 (27.1%)
175 (72.9%) 65 (27.1%)
1.0‡ —
151 (62.9%) 89 (37.1%)
151 (62.9%) 89 (37.1%)
1.0‡ —
215 (89.5%) 17 (7.1%) 3 (1.3%) 5 (2.1%)
215 (89.5%) 17 (7.1%) 3 (1.3%) 5 (2.1%)
1.0‡ — — —
50 (20.8%) 190 (79.2%)
8 (3.3%) 232 (96.7%)
1.0†
< 0.0001‡ —
†
Mann–Whitney U-test. Chi-squared analysis. GX, gastric xanthelasma.
‡
vs 65.5%, P = 0.015). None of the other parameters, including sex, the proportion of patients with open-type atrophy, tumor location, tumor depth, Lauren’s classification, lymph node metastasis, and tumor size, was significantly correlated with the presence of gastric xanthelasma in gastric cancer patients (Supporting Information Table S3).
Discussion The incidence of gastric xanthelasma has been reported to be 0.018% in the European population and 0.2% in Turkey compared with 7% in Korea.11,13,14 In the present series, the prevalence of gastric xanthelasma was 7.7%, consistent with the report by Yi.14 In addition, we found that gastric xanthelasma was associated with not only age but also the severity of gastric atrophy. These data suggest that differences in the reported incidence of xanthelasma may be due mainly to differences in the prevalence of atrophic gastritis, the prevalence of H. pylori infection, and its associated atrophic gastritis being higher in the Asian adult population.19–21 On the other hand, we found that 3.2% of total patients had gastric cancer in the endoscopic examinations. This rate is relatively high when compared with that in western countries.22,23 However, we consider it reasonable because in Japan, 954
the prevalence of H. pylori infection is higher, the H. pylori virulence is stronger, and high salt intake is possible to promote gastric cancer development. The most interesting finding of this study was that the incidence of gastric cancer was significantly higher in patients with gastric xanthelasma than in those without. Multivariate analysis showed that gastric cancer was an independent factor related to the presence of gastric xanthelasma. Moreover, it is noteworthy that gastric xanthelasma was significantly associated with the presence of gastric cancer in controls matched for age, sex, and gastric atrophy. Previous reports have indicated that both age and severe gastric atrophy are risk factors for gastric cancer.24–27 We found that the presence of gastric xanthelasma, in addition to age and severe gastric atrophy, was a risk factor for gastric cancer. Although it is still unclear whether gastric xanthelasma would be a useful feature for indicating the possible presence of gastric cancer, our data suggest that this might be the case in patients with atrophic gastritis. Why is gastric cancer present more frequently in patients with gastric xanthelasma than in those without? We found in the present study that the presence of gastric xanthelasma was associated with patient age and/or the presence of severe atrophy; however, it was independently associated with gastric cancer. Thus, gastric xanthelasma may reflect not only gastric atrophy and aging but also
Journal of Gastroenterology and Hepatology 29 (2014) 951–956 © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
A Sekikawa et al.
Table 4
Gastric xanthelasma and gastric cancer
Comparison of the features of gastric xanthelasma between patients with and without gastric cancer
Characteristics
Total GX patients (n = 249)
GX patients with GC (n = 50)
GX patients without GC (n = 199)
Age (years) Age ≥ 65 < 65 Sex Male Female Atrophy Open type Closed type Antral type No atrophy GX in upper region Present Absent GX in middle region Present Absent GX in lower region Present Absent Number of GXs Size of GXs (mm)
69.2 ± 0.6
72.5 ± 1.0
68.4 ± 0.7
P value
0.002†
180 (72.3%) 69 (27.7%)
43 (86.0%) 7 (14.0%)
137 (68.8%) 62 (31.2%)
0.015‡ —
156 (62.7%) 93 (37.3%)
38 (76.0%) 12 (24.0%)
118 (59.3%) 81 (40.7%)
0.029‡ —
221 (88.7%) 20 (8.1%) 3 (1.2%) 5 (2.0%)
44 (88.0%) 6 (12.0%) 0 0
177 (88.9%) 14 (7.0%) 3 (1.5%) 5 (2.6%)
0.356‡ — — —
71 (28.5%) 178 (72.5%)
25 (50.0%) 25 (50.0%)
46 (23.1%) 153 (76.9%)
0.002‡ —
120 (48.2%) 129 (51.2%)
29 (58.0%) 21 (42.0%)
91 (45.7%) 108 (54.3%)
0.121‡ —
139 (56.4%) 110 (43.6%) 1.9 ± 0.1 4.8 ± 0.1
23 (46.0%) 27 (53.0%) 2.2 ± 0.2 4.6 ± 0.1
116 (58.3%) 83 (41.7%) 1.8 ± 0.1 4.9 ± 0.1
0.118‡ — 0.259† 0.154†
†
Mann–Whitney U-test. Chi-squared analysis. GC, gastric cancer; GX, gastric xanthelasma.
‡
other biological factors. Interestingly, Kaiserling et al. reported that increased release of oxygen-free radicals may be involved in accumulation of oxidized LDL cholesterol and development of gastric xanthelasma.10 On the other hand, oxygen-free radicals are known to cause DNA damage and associated oncogenic changes.28,29 Overall, it is tempting to speculate that excessive production of free radicals may be involved in the development of not only gastric xanthelasma but also gastric cancer, although further studies will be needed to clarify the significance of gastric xanthelasma in relation to gastric cancer. Atrophic gastritis is widely accepted as an important risk factor for gastric cancer.6,7 In Asia, endoscopic examination for detection of early gastric cancer reveals many patients with atrophic gastritis, in view of the high prevalence of H. pylori infection.30 Moreover, although open-type atrophy is associated with a higher risk of cancer development than closed-type atrophy, it may be difficult to distinguish these two types precisely by endoscopic examination. Therefore, in addition to gastric atrophy, it may be necessary to look for other features in order to detect early gastric cancer more effectively. In the present study of patients with atrophic gastritis, we found that gastric cancer was detected more frequently in those with gastric xanthelasma than in those without. Therefore, awareness of gastric xanthelasma in patients with atrophic gastritis may be an effective approach for surveillance of early gastric cancer. Moreover, the presence of xanthelasma in the upper region of the stomach was significantly associated with gastric cancer. Thus, not only the presence of gastric xanthelasma but also its location may be important.
However, our study was limited in the fact that it was based on retrospective analysis conducted at a single institution. Therefore, multicenter prospective studies will be needed to clarify the diagnostic performance of this feature. In summary, we have examined the prevalence of gastric xanthelasma and shown that it is associated with patient age, gastric atrophy, and the presence of gastric cancer. Gastric xanthelasma was significantly associated with the presence of gastric cancer in age/sex/atrophy-matched control analysis. In the context of clinical application, our present data suggest that the presence of gastric xanthelasmas in patients with atrophic gastritis may be an effective approach for surveillance of early gastric cancer and may serve as a marker for alerting clinicians to its possible presence. Therefore, closer attention to gastric xanthelasma seems warranted.
References 1 Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J. Clin. Oncol. 2006; 24: 2137–50. 2 Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer 2010; 127: 2893–917. 3 Chau I, Norman AR, Cunningham D, Waters JS, Oates J, Ross PJ. Multivariate prognostic factor analysis in locally advanced and metastatic esophago-gastric cancer-pooled analysis from three
Journal of Gastroenterology and Hepatology 29 (2014) 951–956 © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
955
Gastric xanthelasma and gastric cancer
4
5
6
7
8
9
10
11
12 13
14 15
16
17
18
A Sekikawa et al.
multicenter, randomized, controlled trials using individual patient data. J. Clin. Oncol. 2004; 22: 2395–403. Sekikawa A, Fukui H, Zhang X et al. REG Iα is a biomarker for predicting response to chemotherapy with S-1 plus cisplatin in patients with unresectable stage IV gastric cancer. Br. J. Cancer 2013; 108: 395–401. Parsonnet J, Friedman GD, Vandersteen DP et al. Helicobacter pylori infection and risk of gastric carcinoma. N. Engl. J. Med. 1991; 325: 1127–31. Nomura A, Stemmmermann GN, Chyou PH, Kato I, Perez-Perez GI, Blaser MJ. Helicobacter pylori infection and risk of gastric carcinoma among Japanese Americans in Hawaii. N. Engl. J. Med. 1991; 325: 1132–6. Uemura N, Okamoto S, Yamamoto S et al. Helicobacter pylori infection and the development of gastric cancer. N. Engl. J. Med. 2001; 345: 784–9. De Vries AC, van Grieken NC, Looman CW et al. Gastric cancer risk in patients with premalignancy lesions: a nationwide cohort study in the Netherlands. Gastroenterology 2008; 134: 945–52. Yamaji Y, Mitsushima T, Ikuma H et al. Inverse background of Helicobacter pylori antibody and pepsinogen in reflux oesophagitis compared with gastric cancer: analysis 5732 Japanese subjects. Gut 2001; 49: 335–40. Kaiserling E, Heine H, Itabe H, Takano T, Remmele W. Lipid islands in human gastric mucosa: morphological and immunohistochemical findings. Gastroenterology 1996; 110: 369–74. Petov S, Churtchev J, Mitova R, Boyanova L, Tarassov M. Xanthoma of the stomach-some morphometrical peculiarities and scanning electron microscopy. Hepatogastroenterology 1999; 46: 1220–2. Chen YS, Lin JB, Dai KS et al. Gastric xanthelasma. Chin. Med. J. 1989; 102: 639–43. Gencosmanoglu R, Sen-Oran E, Kurtkaya-Yapicier O, Tozun N. Xanthelasmas of the upper gastrointestinal tract. J. Gastroenterol. 2004; 39: 215–19. Yi SY. Dislipidmia and H Pylori in gastric xanthomatosis. World J. Gastroenterol. 2007; 13: 4598–601. Isomoto H, Mizuta Y, Inoue K et al. A close relationship between Helicobacter pylori infection and gastric xanthoma. Scand. J. Gastroenterol. 1999; 34: 346–52. Kimura K, Takemoto T. An endoscopic recognization of the atrophic border and its significance in chronic gastritis. Endoscopy 1969; 1: 87–97. Kitahara F, Kobayashi K, Sato T, Kojima Y, Araki T, Fujino MA. Accuracy of screening for gastric cancer using serum pepsinogen concentration. Gut 1999; 44: 693–7. Japanese Gastric Cancer Association. Japanese Classification of Gastric Carcinoma, 2nd English Edition. Gastric Cancer 1998; 1: 10–24.
956
19 Kikuchi S, Wada O, Nakajima T et al. Serum anti-Helicobacter pylori antibody and gastric carcinoma among young adults. Research Group on Prevention of Gastric Carcinoma among Young Adults. Cancer 1995; 75: 2789–93. 20 Lin JT, Wang LY, Wang JT, Wang TH, Yang CS, Chen CJ. A nested case-control study on the association between Helicobacter pylori infection and gastric cancer risk in a cohort of 9775 men in Taiwan. Anticancer Res. 1995; 15: 603–6. 21 Webb PM, Yu MC, Forman D et al. An apparent lack of association between Helicobacter pylori infection and risk of gastric cancer in China. Int. J. Cancer 1996; 67: 603–7. 22 Naylor GM, Gotoda T, Dixon M et al. Why does Japan have a high incidence of gastric cancer? Comparison of gastritis between UK and Japanese patients. Gut 2006; 55: 1545–52. 23 Roder DM. The epidemiology of gastric cancer. Gastric Cancer 2002; 5: 5–11. 24 Shipponen P, Kekki M, Siurala M. Increase risk of gastric cancer in males affects the intestinal type of cancer and is independent of age, location of the tumour and atrophic gastritis. Br. J. Cancer 1988; 57: 332–6. 25 You WC, Blot WJ, Li JY et al. Precancerous gastric lesions in a population at high risk of stomach cancer. Cancer Res. 1993; 53: 1317–21. 26 Tatsuta M, Iishi H, Nakaizumi A et al. Fundal atrophic gastritis as a risk factor for gastric cancer. Int. J. Cancer 1993; 53: 70–4. 27 Watabe H, Mitsushima T, Yamaji Y et al. Predicting the development of gastric cancer from combining Helicobacter pylori antibodies and serum pepsinogen status: a prospective endoscopic cohort study. Gut 2005; 54: 764–8. 28 Farinati F, Cardin R, Dagan P et al. Oxidative DNA damage accumulation in gastric carcinogenesis. Gut 1998; 42: 351–6. 29 Kountouras J, Chatzopoulos D, Zavos C. Reactive oxygen metabolites and upper gastrointestinal diseases. Hepatogastroenterology 2001; 48: 743–51. 30 The EUROGAST Study Group. An international association between Helicobacter pylori infection and gastric cancer. Lancet 1993; 341: 1359–62.
Supporting information Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Table S1 Comparison of clinical features between patients with and without gastric cancer Table S2 Multivariate analysis of factors related to gastric cancer Table S3 Comparison of clinicopathological features between gastric cancer patients with and without xanthelasma
Journal of Gastroenterology and Hepatology 29 (2014) 951–956 © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
