CASE STUDY
Endoscopic resection of gastritis cystica profunda: preliminary experience with 34 patients from a single center in China Guifang Xu, MD, PhD, Chunyan Peng, MD, Xia Li, MD, Weijie Zhang, MD, Ying Lv, MD, Tingsheng Ling, MD, Zhihua Zhou, MD, Yuzheng Zhuge, MD, Lei Wang, PhD, Xiaoping Zou, MD, PhD, Xiaoqi Zhang, MD, PhD, Qin Huang, PhD Nanjing, China
Gastritis cystica profunda (GCP) is an uncommon lesion characterized by polypoid cystic ectasia of benign gastric glands involving the submucosa. This lesion has been described primarily in the previously operated stomach, leading to the notion of prior gastric wall injury as the predominant cause.1,2 Although the exact pathogenesis mechanism remains largely unknown, GCP has also been found to be associated with ischemia and chronic inflammation1 and has even been found in an un-operated stomach.3 Of note, several reports proposed GCP as a premalignant condition because hyperplastic changes in GCP can subsequently progress to carcinoma.1-4 However, strong evidence to clarify the relationship between cancer and GCP remains lacking. Because of insipid clinical presentations and unremarkable conventional endoscopic characteristics, GCP has been largely underdiagnosed. To date, a standardized management strategy for this lesion is far from being established. In this retrospective study, we investigated clinicopathologic, endoscopic, and ultrasonographic features of histopathology-proven GCP in un-operated stomachs. Our preliminary experience demonstrates that despite the deeply seated nature in the submucosal space, GCP can be safely and effectively resected endoscopically in a previously un-operated stomach.
METHODS Patients We retrospectively reviewed 34 consecutive cases of GCP diagnosed by histopathology in EMR (n Z 9) or endoscopic submucosal dissection (ESD, n Z 25) specimens. We reviewed each patients’ endoscopic and medical records and collected clinical information. Informed consent was obtained from all patients before the endoscopic procedure. The study protocol was approved by the Ethics Committee of the Nanjing Drum Tower Hospital.
EUS After conventional upper endoscopic examination of mucosal lesions according to the Paris classification,5 EUS with a high-frequency micro-probe (UM-DP20-25R; Olympus, Tokyo, Japan) was performed by experienced endoscopists before the resection procedure to assess the origin and extent of the lesion. The echo texture of GCP was classified as either homogeneous or heterogeneous. The echoic patterns were categorized as hypoechoic, hyperechoic, or mixed. The longest axis of GCP on EUS images was measured as the maximal dimension of the lesion.
EMR or ESD Abbreviations: ESD, endoscopic submucosal dissection; GCP, gastritis cystica profunda. DISCLOSURE: All authors received research support for this study from the National Natural Science Foundation of China (nos. 81000964 and 81201909). All authors disclosed no financial relationships relevant to this publication. Copyright ª 2014 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2014.11.017 Received March 9, 2014. Accepted November 10, 2014. Current affiliation: Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China. Reprint requests: Dr. Qin Huang, PhD, VA Boston Healthcare System and Harvard Medical School, West Roxbury, MA, USA.
www.giejournal.org
Endoscopic resection of GCP was carried out with either EMR or ESD, according to a standard EMR or ESD protocol with a video endoscope (GIFQ260J; Olympus). Hemostatic forceps (FD-410LR; Olympus) were used to coagulate visible active bleeding vessels in the resection area to prevent delayed bleeding.
Patient management after endoscopic resection A proton pump inhibitor, pantoprazole (40 mg) or esomeprazole (40 mg), was administered intravenously daily for 3 days and then given orally for 8 weeks. During the first year after the endoscopic resection, each patient was followed with EGD performed at 1, 6, and 12 months. Volume
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Endoscopic resection of gastritis cystica profunda
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Histopathology Endoscopically, resected fresh specimens were pinned on a dental wax plate, measured routinely, and then fixed in 10% neutral buffered formalin overnight. Fivemicrometer sections were cut and routinely stained with hematoxylin and eosin. Two experienced pathologists independently evaluated each case blindly without the knowledge of clinical and endoscopic information. The international diagnostic criteria on chronic gastritis and gastric epithelial dysplasia (low and high grade) and intramucosal carcinoma were followed.6,7
Statistical analysis Statistical analysis was performed with SPSS 11.5 software (SPSS Inc, Chicago, Ill). Clinical, endoscopic, and histopathologic characteristics of GCP and patient outcomes were analyzed. All values were presented as average SD. For categorical variables, data were also presented as value (%). The c2 test was used to evaluate differences in proportions, and the Mann-Whitney U test was used to evaluate continuous variables. P! .05 were considered statistically significant.
RESULTS Demographics The average age of GCP patients was 59.9 years (range, 24-77). The male-to-female ratio was 1.8. The reported symptoms included epigastric discomfort in 17, pain in 11, heartburn in 4, and hoarseness in 2. None had a history of gastric surgery. The average body mass index was 21.8 (range, 17-27). Laboratory tests for liver functions, peripheral blood cell counts, and tumor markers such as carcinoembryonic antigen (CA72-4, CA125, CA19-9), and afetoprotein were unremarkable.
Endoscopic characteristics As shown in Table 1, GCP was identified most frequently, in descending order, in the gastric cardia (15/ 34, 41.1%), antrum (12/34, 35.3%), corpus (4/34, 11.8%), angularis incisura (2/34, 5.9%), and fundus (1/34, 2.9%). By conventional white-light endoscopy, mucosal alterations overlying GCP were primarily protruded (Paris classification 0-I, n Z 21, 61.8%, Fig. 1A)8 or, less frequently, flat with erosion (0-II, n Z 13, 38.2%, Fig. 1B). By EUS, GCP demonstrated characteristic echoic features, as shown in Table 1. The average maximal dimension was 2.9 cm (SD, 2.2; range, .5-8.5). All lesions originated from the basal mucosal layer and extended into the submucosal space. Twelve lesions (35.3%) were anechoic (Fig. 2A), and the hypoechoic pattern with microcysts was seen in only 5 cases. Half of the cases (17/34, 50%) exhibited mixed anechoic and hypoechoic patterns with thickened overlying mucosa (Fig. 2B). 2 GASTROINTESTINAL ENDOSCOPY Volume
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Surface mucosal erosion was noted in 15 of 17 mixed echoic lesions.
Histopathology All cases showed similar characteristics with ecstatically dilated tubular glands lined by bland foveolar epithelium without nuclear dysplasia or mitosis. The surrounding stroma was edematous with mild, mixed lymphoplasmacytic and, occasionally, neutrophilic and eosinophilic infiltration. Dilated glands were prominent in the basal mucosa, extending through the muscularis mucosa into the submucosal space with a rim of normal lamina propria (Fig. 3A). The overlying and adjacent gastric mucosa exhibited chronic active inflammation in 7 cases, intestinal metaplasia in 17, atrophy in 17, and inactive chronic gastritis in 11. Epithelial dysplasia was identified in 15 cases in the overlying mucosa without invasion through to the muscularis mucosa. Among these cases, low- and high-grade dysplasia and intramucosal carcinoma were found in 5 cases for each category (Fig. 3B).
Endoscopic resection outcomes Endoscopic resection of GCP was carried out in all cases with ESD in 25 patients and EMR in 9. As shown in Table 2, the en bloc resection rate was 100% in ESD and 78% in EMR. The complete resection rate was 92% in ESD and 78% in EMR. There was no difference in the complete resection rate between the 2 groups. The average operating time was 84 minutes (range, 20-180) in ESD and 13 minutes (range, 7-20) in EMR. The median operative time for the EMR group was significantly shorter than that for the ESD group (P ! .05). Intraoperative bleeding occurred in only 2 patients, both of which achieved endoscopic homeostasis by hot forceps. No perforation or delayed bleeding was found in any patient. Complete resection of the gastric mucosa with dysplasia and intramucosal carcinoma was accomplished in 11 cases, whereas a positive peripheral margin for low-grade dysplasia was seen in only 4. There were no recurrences of GCP during a median follow-up period of 23 months (range, 4-53).
DISCUSSION GCP has been proposed to be secondary to prior gastric trauma such as surgery, chronic inflammation, ischemia, or refluxed bile-induced gastric mucosal injury.2 In our series, GCP is associated with widespread chronic active/atrophic gastritis in the previously un-operated stomach, suggesting an important role of gastric chronic inflammation in the pathogenesis of GCP. Clinically, GCP could occur in young patients but occurs more commonly in the elderly. We found that all patients presented with nonspecific symptoms, and laboratory tests do not help make a diagnosis of GCP. www.giejournal.org
Xu et al
Endoscopic resection of gastritis cystica profunda
TABLE 1. Conventional endoscopic and ultrasonographic characteristics Patient number
Conventional endoscopy Gender
Age (y)
Location
Gross type
Surface
1
M
50
Cardia
0-I
Normal
4.2
Mixed echoic
2
M
71
Corpus
0-IIaþIIc
Abnormal
4.5
Mixed echoic
3
F
45
Cardia
0-I
Normal
1.6
Anechoic
4
F
64
Cardia
0-I
Abnormal
1.5
Anechoic
5
M
34
Corpus
0-I
Abnormal
1.5
Mixed echoic
6
M
67
Antrum
0-ⅡaþⅡc
Abnormal
2.3
Mixed echoic
7
M
56
Angularis
0-Ⅰ
Normal
1.5
Anechoic
8
F
77
Antrum
0-Ⅰ
Normal
0.5
Anechoic
9
F
59
Corpus
0-Ⅰ
Abnormal
1
Anechoic
10
M
69
Antrum
0-Ⅰ
Abnormal
4.5
Anechoic
11
F
58
Antrum
0-Ⅰ
Normal
1.3
Hypoechoic
12
F
64
Cardia
0-ⅡaþⅡc
Abnormal
1.2
Mixed echoic
13
M
73
Angularis
0-ⅡaþⅡc
Abnormal
8
Mixed echoic
14
M
59
Cardia
0-ⅡaþⅡc
Abnormal
8.5
Mixed echoic
15
F
60
Corus
0-Ⅰ
Abnormal
4
Anechoic
16
M
72
Cardia
0-ⅡaþⅡc
Abnormal
4
Mixed echoic
17
M
45
Cardia
Ⅱc
Abnormal
4
Mixed echoic
18
M
60
Cardia
0-ⅡaþⅡc
Abnormal
9
Mixed echoic
19
M
24
Cardia
0-Ⅰ
Abnormal
2
Anechoic
20
M
62
Antrum
0-Ⅰ
Normal
1.5
Anechoic
21
M
70
Cardia
0-ⅡaþⅡc
Abnormal
2.5
Hypoechoic
22
F
44
Antrum
0-Ⅰ
Normal
1.2
Hypoechoic
23
F
61
Antrum
0-Ⅰ
Normal
2
Anechoic
24
M
66
Cardia
0-ⅡaþⅡc
Abnormal
2.5
Mixed echoic
25
M
65
Antrum
Ⅱc
Abnormal
4.7
Mixed echoic
26
M
65
Antrum
0-Ⅰ
Abnormal
1.2
Mixed echoic
27
M
59
Cardia
0-Ⅰ
Normal
1.5
Anechoic
28
M
72
Fundus
0-Ⅰ
Normal
0.5
Hypoechoic
29
F
59
Cardia
0-Ⅰ
Normal
0.6
Hypoechoic
30
M
52
Antrum
0-Ⅰ
Normal
0.8
Anechoic
31
F
57
Cardia
0-Ⅰ
Abnormal
4
Mixed echoic
32
M
82
Antrum
0-Ⅰ
Abnormal
4
Mixed echoic
33
M
56
Cardia
Ⅱc
Abnormal
4
Mixed echoic
34
F
61
Antrum
Ⅱc
Abnormal
2
Mixed echoic
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Volume
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Size (cm)
EUS
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Endoscopic resection of gastritis cystica profunda
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Figure 1. Conventional gastroendoscopic characteristics of GCP (arrows) with a (A) submucosal protruded pattern and a (B) flat lesion with depressed mucosal pattern.
Figure 2. EUS characteristics of GCP (arrows) with a (A) dominant, homogenous cystic mass in the submucosal layer and a (B) multicystic, heterogeneous lesion in the submucosal space underneath thickened mucosa.
Figure 3. Microscopic features of GCP with a (A) large, dilated cyst in the submucosa (H&E, orig. mag. 40) and (B) multiple small ecstatic GCP glands with overlying intraepithelial neoplasia (H&E, orig. mag. 200).
Several previous reports propose GCP as a premalignant lesion on the basis of malignant progression from dysplasia to invasive carcinoma.2-4,8,9 Mitomi et al4 reported a case in which atypical or dysplastic epithelium in the deeper part of GCP was seen adjacent to carcinoma. According to a Korean report on 39 GCP cases,10 16 were associated 4 GASTROINTESTINAL ENDOSCOPY Volume
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with early gastric carcinoma, 9 with adenoma, and 3 with advanced adenocarcinoma. The Ki-67, p53, and p21 gene expression in epithelial cells of the deeper part of GCP were found to be higher than that for the superficial part or the surrounding mucosa. Ten-year follow-up of a case of GCP in an un-operated stomach revealed low-grade www.giejournal.org
Xu et al
Endoscopic resection of gastritis cystica profunda
TABLE 2. Comparison of endoscopic resection techniques for GCP ESD
EMR
25
9
En bloc resection rate (%)
25 (100)
7 (78)
Complete resection rate (%)
23 (92)
7 (78)
84 (20-180)
13 (7-20)
Perforation
0
0
Delayed bleeding
0
0
Total number
Median operation time, min (range) Adverse events
ESD, endoscopic submucosal dissection; GCP, gastritis cystica profunda.
dysplasia, and the sizes of both GCP and the overlying adenoma increased during the follow-up period.11 In our study, we failed to demonstrate unequivocal evidence of dysplastic changes in the epithelium of GCP. Instead, dysplastic glands and intramucosal carcinoma described in this report arose in the glands overlying GCP. Because up to 50% of GCP cases in our study were associated with dysplasia or intramucosal carcinoma, it is very important for endoscopists to perform multiple biopsy samplings to map the extent of dysplastic lesions and to investigate the depth of the lesion with EUS before endoscopic resection. In our opinion, the most important diagnostic modality is upper endoscopy with EUS. The most common endoscopic features of GCP by conventional white-light endoscopy are nonspecific. We agree with previous investigators that EUS is extremely valuable for an endoscopic diagnosis of GCP.12,13 We show that GCP on EUS exhibits primarily 3 major echoic patterns: anechoic (35.3%), mixed heterogeneous (50%) with thickened overlying mucosa, and hypoechoic (14.7%) with microcysts. We emphasize that although EUS is very useful in depicting the shape, extent, and echoic patterns of GCP, a definitive diagnosis should be determined by histologic examination. It is reported that EUS-guided FNA of the cystic fluid could distinguish GCP from a malignant tumor because tumor markers, such as CEA and CA19-9, could be tested in the cystic fluid.14 We did not perform EUS-guided FNA because most lesions in this study were relatively small and some were associated with intraepithelial neoplasia and needed to be resected endoscopically. There is no consensus on GCP treatment. Because of the paucity of the information on this disease, a variety of resection methods has been tried, ranging from EMR/ESD to total gastrectomy.15 In our patients at high risk for gastric cancer, we prefer a more proactive approach to remove GCP endoscopically, once diagnosed. Over the www.giejournal.org
years, we have developed an internal standard protocol to systemically investigate these lesions with EUS before EMR/ESD. Because the criterion standard for gastric cancer or GCP diagnosis relies on histopathology, endoscopic resection serves both diagnostic and therapeutic purposes. As we showed in this study, the combination of EUS and ESD appears to be very effective for the diagnosis of GCP and makes an open surgical procedure unnecessary. In fact, endoscopic resection with EMR or ESD is less invasive, more effective, safer, and more economical. More importantly, endoscopic resection of GCP better preserves gastric function with minimal injury. Despite being deeply seated in the submucosal space, GCP can be safely removed endoscopically with minimal hemorrhage, which was managed successfully by endoscopic techniques. Postoperatively, no delayed hemorrhage or perforation was observed in any patient in this series. There were no recurrences during a median follow-up period of 23 months. In this study, the complete resection rate was higher in the ESD group (92%) than in the EMR group (78%), despite the larger size of GCP in the ESD group. Our preliminary experience requires confirmation in larger studies. Because this retrospective study was performed in only 34 GCP cases from a single center, further studies are needed to establish a standard protocol of GCP diagnosis and management. Another limitation of this study is the short follow-up period. We need to carry out more longterm studies for therapeutic outcomes to fully determine the safety and long-term therapeutic effect of ESD in the treatment of GCP. In summary, we characterized diagnostic endoscopic and ultrasonic features of GCP and described our initial experience of successful endoscopic resection of this uncommon lesion in a previously un-operated stomach with a high en bloc resection rate and minimal adverse events. Compared with EMR, ESD appears to be a promising endoscopic technique for a more complete resection of GCP. Because of the small sample size, single institution experience, and retrospective nature, our results should be verified in larger scale studies, especially including the feasibility and clinical long-term outcomes of endoscopic resection of GCP in both previously un-operated and operated stomachs.
REFERENCES 1. Franzin G, Novelli P. Gastritis cystica profunda. Histopathology 1981;5: 535-47. 2. Franzin G, Musola R, Zamboni G, et al. Gastritis cystica polyposa: a possible precancerous lesion. Tumori 1985;71:13-8. 3. Béchade D, Desramé J, Algayres JP. Gastritis cystica profunda in a patient with no history of gastric surgery. Endoscopy 2007;39(Suppl 1): E80-1. 4. Mitomi H, Iwabuchi K, Amemiya A, et al. Immunohistochemical analysis of a case of gastritis cystica profunda associated with carcinoma development. Scand J Gastroenterol 1998;33:1226-9.
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5. Participants in the Paris Workshop. The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and colon: November 30 to December 1, 2002. Gastrointest Endosc 2003;58(6 Suppl):S3-43. 6. Schlemper RJ, Riddell RH, Kato Y, et al. The Vienna classification of gastrointestinal epithelial neoplasia. Gut 2000;47:251-5. 7. Rugge M, Meggio A, Pennelli G, et al. Gastritis staging in clinical practice: the OLGA staging system. Gut 2007;56:631-6. 8. Lee MJ, Lee SH, Kim BK, et al. A case of gastritis cystica profunda associated with tubular adenoma. Korean J Gastrointest Endosc 2006;32: 120-3. 9. Qizilbash AH. Gastritis cystica and carcinoma arising in old gastrojejunostomy stoma. Can Med Assoc J 1975;112:1432-3. 10. Kim YS, Heo WS, Chae KH, et al. Our experience of gastritis cystica profunda cases and its clinical study. Korean J Gastrointest Endosc 2006;33:135-9.
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11. Kim JH, Jang SY, Hwang JA, et al. A ten-year follow-up of a case with gastric adenoma accompanied with gastritis cystica profunda treated by endoscopic submucosal dissection. Korean J Gastroenterol 2012;59:366-71. 12. Deery S, Yates R, Hata J, et al. Gastric adenocarcinoma associated with gastritis cystica profunda in an unoperated stomach. Am Surg 2012;78: E379-80. 13. Matsumoto T, Wada M, Imai Y, et al. A rare cause of gastric outlet obstruction: gastritis cystica profunda accompanied by adenocarcinoma. Endoscopy 2012;44(Suppl 2 UCTN):E138-9. 14. Park CW, Park JM, Jung CK, et al. Early gastric cancer associated with gastritis cystica polyposa in the unoperated stomach treated by endoscopic submucosal dissection. Gastrointest Endosc 2009;69:e47-50. 15. Laratta JL, Buhtoiarova TN, Sparber LS, et al. Gastritis cystic profunda: a rare gastric tumor masquerading as a malignancy. Surg Sci 2012;3:158-64.
www.giejournal.org
Endoscopic resection of gastritis cystica profunda: preliminary experience with 34 patients from a single center in China Guifang Xu, MD, PhD, Chunyan Peng, MD, Xia Li, MD, Weijie Zhang, MD, Ying Lv, MD, Tingsheng Ling, MD, Zhihua Zhou, MD, Yuzheng Zhuge, MD, Lei Wang, PhD, Xiaoping Zou, MD, PhD, Xiaoqi Zhang, MD, PhD, Qin Huang, PhD Nanjing, China
Gastritis cystica profunda (GCP) is an uncommon lesion characterized by polypoid cystic ectasia of benign gastric glands involving the submucosa. This lesion has been described primarily in the previously operated stomach, leading to the notion of prior gastric wall injury as the predominant cause.1,2 Although the exact pathogenesis mechanism remains largely unknown, GCP has also been found to be associated with ischemia and chronic inflammation1 and has even been found in an un-operated stomach.3 Of note, several reports proposed GCP as a premalignant condition because hyperplastic changes in GCP can subsequently progress to carcinoma.1-4 However, strong evidence to clarify the relationship between cancer and GCP remains lacking. Because of insipid clinical presentations and unremarkable conventional endoscopic characteristics, GCP has been largely underdiagnosed. To date, a standardized management strategy for this lesion is far from being established. In this retrospective study, we investigated clinicopathologic, endoscopic, and ultrasonographic features of histopathology-proven GCP in un-operated stomachs. Our preliminary experience demonstrates that despite the deeply seated nature in the submucosal space, GCP can be safely and effectively resected endoscopically in a previously un-operated stomach.
METHODS Patients We retrospectively reviewed 34 consecutive cases of GCP diagnosed by histopathology in EMR (n Z 9) or endoscopic submucosal dissection (ESD, n Z 25) specimens. We reviewed each patients’ endoscopic and medical records and collected clinical information. Informed consent was obtained from all patients before the endoscopic procedure. The study protocol was approved by the Ethics Committee of the Nanjing Drum Tower Hospital.
EUS After conventional upper endoscopic examination of mucosal lesions according to the Paris classification,5 EUS with a high-frequency micro-probe (UM-DP20-25R; Olympus, Tokyo, Japan) was performed by experienced endoscopists before the resection procedure to assess the origin and extent of the lesion. The echo texture of GCP was classified as either homogeneous or heterogeneous. The echoic patterns were categorized as hypoechoic, hyperechoic, or mixed. The longest axis of GCP on EUS images was measured as the maximal dimension of the lesion.
EMR or ESD Abbreviations: ESD, endoscopic submucosal dissection; GCP, gastritis cystica profunda. DISCLOSURE: All authors received research support for this study from the National Natural Science Foundation of China (nos. 81000964 and 81201909). All authors disclosed no financial relationships relevant to this publication. Copyright ª 2014 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2014.11.017 Received March 9, 2014. Accepted November 10, 2014. Current affiliation: Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China. Reprint requests: Dr. Qin Huang, PhD, VA Boston Healthcare System and Harvard Medical School, West Roxbury, MA, USA.
www.giejournal.org
Endoscopic resection of GCP was carried out with either EMR or ESD, according to a standard EMR or ESD protocol with a video endoscope (GIFQ260J; Olympus). Hemostatic forceps (FD-410LR; Olympus) were used to coagulate visible active bleeding vessels in the resection area to prevent delayed bleeding.
Patient management after endoscopic resection A proton pump inhibitor, pantoprazole (40 mg) or esomeprazole (40 mg), was administered intravenously daily for 3 days and then given orally for 8 weeks. During the first year after the endoscopic resection, each patient was followed with EGD performed at 1, 6, and 12 months. Volume
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No.
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: 2014 GASTROINTESTINAL ENDOSCOPY 1
Endoscopic resection of gastritis cystica profunda
Xu et al
Histopathology Endoscopically, resected fresh specimens were pinned on a dental wax plate, measured routinely, and then fixed in 10% neutral buffered formalin overnight. Fivemicrometer sections were cut and routinely stained with hematoxylin and eosin. Two experienced pathologists independently evaluated each case blindly without the knowledge of clinical and endoscopic information. The international diagnostic criteria on chronic gastritis and gastric epithelial dysplasia (low and high grade) and intramucosal carcinoma were followed.6,7
Statistical analysis Statistical analysis was performed with SPSS 11.5 software (SPSS Inc, Chicago, Ill). Clinical, endoscopic, and histopathologic characteristics of GCP and patient outcomes were analyzed. All values were presented as average SD. For categorical variables, data were also presented as value (%). The c2 test was used to evaluate differences in proportions, and the Mann-Whitney U test was used to evaluate continuous variables. P! .05 were considered statistically significant.
RESULTS Demographics The average age of GCP patients was 59.9 years (range, 24-77). The male-to-female ratio was 1.8. The reported symptoms included epigastric discomfort in 17, pain in 11, heartburn in 4, and hoarseness in 2. None had a history of gastric surgery. The average body mass index was 21.8 (range, 17-27). Laboratory tests for liver functions, peripheral blood cell counts, and tumor markers such as carcinoembryonic antigen (CA72-4, CA125, CA19-9), and afetoprotein were unremarkable.
Endoscopic characteristics As shown in Table 1, GCP was identified most frequently, in descending order, in the gastric cardia (15/ 34, 41.1%), antrum (12/34, 35.3%), corpus (4/34, 11.8%), angularis incisura (2/34, 5.9%), and fundus (1/34, 2.9%). By conventional white-light endoscopy, mucosal alterations overlying GCP were primarily protruded (Paris classification 0-I, n Z 21, 61.8%, Fig. 1A)8 or, less frequently, flat with erosion (0-II, n Z 13, 38.2%, Fig. 1B). By EUS, GCP demonstrated characteristic echoic features, as shown in Table 1. The average maximal dimension was 2.9 cm (SD, 2.2; range, .5-8.5). All lesions originated from the basal mucosal layer and extended into the submucosal space. Twelve lesions (35.3%) were anechoic (Fig. 2A), and the hypoechoic pattern with microcysts was seen in only 5 cases. Half of the cases (17/34, 50%) exhibited mixed anechoic and hypoechoic patterns with thickened overlying mucosa (Fig. 2B). 2 GASTROINTESTINAL ENDOSCOPY Volume
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Surface mucosal erosion was noted in 15 of 17 mixed echoic lesions.
Histopathology All cases showed similar characteristics with ecstatically dilated tubular glands lined by bland foveolar epithelium without nuclear dysplasia or mitosis. The surrounding stroma was edematous with mild, mixed lymphoplasmacytic and, occasionally, neutrophilic and eosinophilic infiltration. Dilated glands were prominent in the basal mucosa, extending through the muscularis mucosa into the submucosal space with a rim of normal lamina propria (Fig. 3A). The overlying and adjacent gastric mucosa exhibited chronic active inflammation in 7 cases, intestinal metaplasia in 17, atrophy in 17, and inactive chronic gastritis in 11. Epithelial dysplasia was identified in 15 cases in the overlying mucosa without invasion through to the muscularis mucosa. Among these cases, low- and high-grade dysplasia and intramucosal carcinoma were found in 5 cases for each category (Fig. 3B).
Endoscopic resection outcomes Endoscopic resection of GCP was carried out in all cases with ESD in 25 patients and EMR in 9. As shown in Table 2, the en bloc resection rate was 100% in ESD and 78% in EMR. The complete resection rate was 92% in ESD and 78% in EMR. There was no difference in the complete resection rate between the 2 groups. The average operating time was 84 minutes (range, 20-180) in ESD and 13 minutes (range, 7-20) in EMR. The median operative time for the EMR group was significantly shorter than that for the ESD group (P ! .05). Intraoperative bleeding occurred in only 2 patients, both of which achieved endoscopic homeostasis by hot forceps. No perforation or delayed bleeding was found in any patient. Complete resection of the gastric mucosa with dysplasia and intramucosal carcinoma was accomplished in 11 cases, whereas a positive peripheral margin for low-grade dysplasia was seen in only 4. There were no recurrences of GCP during a median follow-up period of 23 months (range, 4-53).
DISCUSSION GCP has been proposed to be secondary to prior gastric trauma such as surgery, chronic inflammation, ischemia, or refluxed bile-induced gastric mucosal injury.2 In our series, GCP is associated with widespread chronic active/atrophic gastritis in the previously un-operated stomach, suggesting an important role of gastric chronic inflammation in the pathogenesis of GCP. Clinically, GCP could occur in young patients but occurs more commonly in the elderly. We found that all patients presented with nonspecific symptoms, and laboratory tests do not help make a diagnosis of GCP. www.giejournal.org
Xu et al
Endoscopic resection of gastritis cystica profunda
TABLE 1. Conventional endoscopic and ultrasonographic characteristics Patient number
Conventional endoscopy Gender
Age (y)
Location
Gross type
Surface
1
M
50
Cardia
0-I
Normal
4.2
Mixed echoic
2
M
71
Corpus
0-IIaþIIc
Abnormal
4.5
Mixed echoic
3
F
45
Cardia
0-I
Normal
1.6
Anechoic
4
F
64
Cardia
0-I
Abnormal
1.5
Anechoic
5
M
34
Corpus
0-I
Abnormal
1.5
Mixed echoic
6
M
67
Antrum
0-ⅡaþⅡc
Abnormal
2.3
Mixed echoic
7
M
56
Angularis
0-Ⅰ
Normal
1.5
Anechoic
8
F
77
Antrum
0-Ⅰ
Normal
0.5
Anechoic
9
F
59
Corpus
0-Ⅰ
Abnormal
1
Anechoic
10
M
69
Antrum
0-Ⅰ
Abnormal
4.5
Anechoic
11
F
58
Antrum
0-Ⅰ
Normal
1.3
Hypoechoic
12
F
64
Cardia
0-ⅡaþⅡc
Abnormal
1.2
Mixed echoic
13
M
73
Angularis
0-ⅡaþⅡc
Abnormal
8
Mixed echoic
14
M
59
Cardia
0-ⅡaþⅡc
Abnormal
8.5
Mixed echoic
15
F
60
Corus
0-Ⅰ
Abnormal
4
Anechoic
16
M
72
Cardia
0-ⅡaþⅡc
Abnormal
4
Mixed echoic
17
M
45
Cardia
Ⅱc
Abnormal
4
Mixed echoic
18
M
60
Cardia
0-ⅡaþⅡc
Abnormal
9
Mixed echoic
19
M
24
Cardia
0-Ⅰ
Abnormal
2
Anechoic
20
M
62
Antrum
0-Ⅰ
Normal
1.5
Anechoic
21
M
70
Cardia
0-ⅡaþⅡc
Abnormal
2.5
Hypoechoic
22
F
44
Antrum
0-Ⅰ
Normal
1.2
Hypoechoic
23
F
61
Antrum
0-Ⅰ
Normal
2
Anechoic
24
M
66
Cardia
0-ⅡaþⅡc
Abnormal
2.5
Mixed echoic
25
M
65
Antrum
Ⅱc
Abnormal
4.7
Mixed echoic
26
M
65
Antrum
0-Ⅰ
Abnormal
1.2
Mixed echoic
27
M
59
Cardia
0-Ⅰ
Normal
1.5
Anechoic
28
M
72
Fundus
0-Ⅰ
Normal
0.5
Hypoechoic
29
F
59
Cardia
0-Ⅰ
Normal
0.6
Hypoechoic
30
M
52
Antrum
0-Ⅰ
Normal
0.8
Anechoic
31
F
57
Cardia
0-Ⅰ
Abnormal
4
Mixed echoic
32
M
82
Antrum
0-Ⅰ
Abnormal
4
Mixed echoic
33
M
56
Cardia
Ⅱc
Abnormal
4
Mixed echoic
34
F
61
Antrum
Ⅱc
Abnormal
2
Mixed echoic
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: 2014 GASTROINTESTINAL ENDOSCOPY 3
Endoscopic resection of gastritis cystica profunda
Xu et al
Figure 1. Conventional gastroendoscopic characteristics of GCP (arrows) with a (A) submucosal protruded pattern and a (B) flat lesion with depressed mucosal pattern.
Figure 2. EUS characteristics of GCP (arrows) with a (A) dominant, homogenous cystic mass in the submucosal layer and a (B) multicystic, heterogeneous lesion in the submucosal space underneath thickened mucosa.
Figure 3. Microscopic features of GCP with a (A) large, dilated cyst in the submucosa (H&E, orig. mag. 40) and (B) multiple small ecstatic GCP glands with overlying intraepithelial neoplasia (H&E, orig. mag. 200).
Several previous reports propose GCP as a premalignant lesion on the basis of malignant progression from dysplasia to invasive carcinoma.2-4,8,9 Mitomi et al4 reported a case in which atypical or dysplastic epithelium in the deeper part of GCP was seen adjacent to carcinoma. According to a Korean report on 39 GCP cases,10 16 were associated 4 GASTROINTESTINAL ENDOSCOPY Volume
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with early gastric carcinoma, 9 with adenoma, and 3 with advanced adenocarcinoma. The Ki-67, p53, and p21 gene expression in epithelial cells of the deeper part of GCP were found to be higher than that for the superficial part or the surrounding mucosa. Ten-year follow-up of a case of GCP in an un-operated stomach revealed low-grade www.giejournal.org
Xu et al
Endoscopic resection of gastritis cystica profunda
TABLE 2. Comparison of endoscopic resection techniques for GCP ESD
EMR
25
9
En bloc resection rate (%)
25 (100)
7 (78)
Complete resection rate (%)
23 (92)
7 (78)
84 (20-180)
13 (7-20)
Perforation
0
0
Delayed bleeding
0
0
Total number
Median operation time, min (range) Adverse events
ESD, endoscopic submucosal dissection; GCP, gastritis cystica profunda.
dysplasia, and the sizes of both GCP and the overlying adenoma increased during the follow-up period.11 In our study, we failed to demonstrate unequivocal evidence of dysplastic changes in the epithelium of GCP. Instead, dysplastic glands and intramucosal carcinoma described in this report arose in the glands overlying GCP. Because up to 50% of GCP cases in our study were associated with dysplasia or intramucosal carcinoma, it is very important for endoscopists to perform multiple biopsy samplings to map the extent of dysplastic lesions and to investigate the depth of the lesion with EUS before endoscopic resection. In our opinion, the most important diagnostic modality is upper endoscopy with EUS. The most common endoscopic features of GCP by conventional white-light endoscopy are nonspecific. We agree with previous investigators that EUS is extremely valuable for an endoscopic diagnosis of GCP.12,13 We show that GCP on EUS exhibits primarily 3 major echoic patterns: anechoic (35.3%), mixed heterogeneous (50%) with thickened overlying mucosa, and hypoechoic (14.7%) with microcysts. We emphasize that although EUS is very useful in depicting the shape, extent, and echoic patterns of GCP, a definitive diagnosis should be determined by histologic examination. It is reported that EUS-guided FNA of the cystic fluid could distinguish GCP from a malignant tumor because tumor markers, such as CEA and CA19-9, could be tested in the cystic fluid.14 We did not perform EUS-guided FNA because most lesions in this study were relatively small and some were associated with intraepithelial neoplasia and needed to be resected endoscopically. There is no consensus on GCP treatment. Because of the paucity of the information on this disease, a variety of resection methods has been tried, ranging from EMR/ESD to total gastrectomy.15 In our patients at high risk for gastric cancer, we prefer a more proactive approach to remove GCP endoscopically, once diagnosed. Over the www.giejournal.org
years, we have developed an internal standard protocol to systemically investigate these lesions with EUS before EMR/ESD. Because the criterion standard for gastric cancer or GCP diagnosis relies on histopathology, endoscopic resection serves both diagnostic and therapeutic purposes. As we showed in this study, the combination of EUS and ESD appears to be very effective for the diagnosis of GCP and makes an open surgical procedure unnecessary. In fact, endoscopic resection with EMR or ESD is less invasive, more effective, safer, and more economical. More importantly, endoscopic resection of GCP better preserves gastric function with minimal injury. Despite being deeply seated in the submucosal space, GCP can be safely removed endoscopically with minimal hemorrhage, which was managed successfully by endoscopic techniques. Postoperatively, no delayed hemorrhage or perforation was observed in any patient in this series. There were no recurrences during a median follow-up period of 23 months. In this study, the complete resection rate was higher in the ESD group (92%) than in the EMR group (78%), despite the larger size of GCP in the ESD group. Our preliminary experience requires confirmation in larger studies. Because this retrospective study was performed in only 34 GCP cases from a single center, further studies are needed to establish a standard protocol of GCP diagnosis and management. Another limitation of this study is the short follow-up period. We need to carry out more longterm studies for therapeutic outcomes to fully determine the safety and long-term therapeutic effect of ESD in the treatment of GCP. In summary, we characterized diagnostic endoscopic and ultrasonic features of GCP and described our initial experience of successful endoscopic resection of this uncommon lesion in a previously un-operated stomach with a high en bloc resection rate and minimal adverse events. Compared with EMR, ESD appears to be a promising endoscopic technique for a more complete resection of GCP. Because of the small sample size, single institution experience, and retrospective nature, our results should be verified in larger scale studies, especially including the feasibility and clinical long-term outcomes of endoscopic resection of GCP in both previously un-operated and operated stomachs.
REFERENCES 1. Franzin G, Novelli P. Gastritis cystica profunda. Histopathology 1981;5: 535-47. 2. Franzin G, Musola R, Zamboni G, et al. Gastritis cystica polyposa: a possible precancerous lesion. Tumori 1985;71:13-8. 3. Béchade D, Desramé J, Algayres JP. Gastritis cystica profunda in a patient with no history of gastric surgery. Endoscopy 2007;39(Suppl 1): E80-1. 4. Mitomi H, Iwabuchi K, Amemiya A, et al. Immunohistochemical analysis of a case of gastritis cystica profunda associated with carcinoma development. Scand J Gastroenterol 1998;33:1226-9.
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5. Participants in the Paris Workshop. The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and colon: November 30 to December 1, 2002. Gastrointest Endosc 2003;58(6 Suppl):S3-43. 6. Schlemper RJ, Riddell RH, Kato Y, et al. The Vienna classification of gastrointestinal epithelial neoplasia. Gut 2000;47:251-5. 7. Rugge M, Meggio A, Pennelli G, et al. Gastritis staging in clinical practice: the OLGA staging system. Gut 2007;56:631-6. 8. Lee MJ, Lee SH, Kim BK, et al. A case of gastritis cystica profunda associated with tubular adenoma. Korean J Gastrointest Endosc 2006;32: 120-3. 9. Qizilbash AH. Gastritis cystica and carcinoma arising in old gastrojejunostomy stoma. Can Med Assoc J 1975;112:1432-3. 10. Kim YS, Heo WS, Chae KH, et al. Our experience of gastritis cystica profunda cases and its clinical study. Korean J Gastrointest Endosc 2006;33:135-9.
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11. Kim JH, Jang SY, Hwang JA, et al. A ten-year follow-up of a case with gastric adenoma accompanied with gastritis cystica profunda treated by endoscopic submucosal dissection. Korean J Gastroenterol 2012;59:366-71. 12. Deery S, Yates R, Hata J, et al. Gastric adenocarcinoma associated with gastritis cystica profunda in an unoperated stomach. Am Surg 2012;78: E379-80. 13. Matsumoto T, Wada M, Imai Y, et al. A rare cause of gastric outlet obstruction: gastritis cystica profunda accompanied by adenocarcinoma. Endoscopy 2012;44(Suppl 2 UCTN):E138-9. 14. Park CW, Park JM, Jung CK, et al. Early gastric cancer associated with gastritis cystica polyposa in the unoperated stomach treated by endoscopic submucosal dissection. Gastrointest Endosc 2009;69:e47-50. 15. Laratta JL, Buhtoiarova TN, Sparber LS, et al. Gastritis cystic profunda: a rare gastric tumor masquerading as a malignancy. Surg Sci 2012;3:158-64.
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