Curative resection with endoscopic submucosal dissection of early gastric cancer in Helicobacter pylorinegative Ménétrier’s disease: A case report

Koh Fukushi, Kenichi Goda, Hitoshi Kino,Masayuki Kondo,Mimari Kanazawa, Ken Kashima, Akira Kanamori,Keiichiro Abe,Tsunehiro Suzuki, Keiichi Tominaga,Hidetsugu Yamagishi，Atsushi Irisawa

Abstract

Key Words: Ménétrier’s disease; Helicobacter pylori; Gastric cancer; Endoscopic resection; Endoscopic submucosal dissection; Case report

INTRODUCTION

Ménétrier’s disease (discovered in 1888 ) is a relatively rare gastric disease[1 ] characterized by giant rugae in the stomach accompanied by hypoproteinemia. Adult-onset Ménétrier’s disease is strongly associated withHelicobacter pylori(H. pylori) infection and an elevated risk of carcinogenesis[2 ]. Our literature review suggests thatH. pylorinegative cases of early-stage gastric cancer are extremely rare[3 ,4 ].

We report the first case ofH. pylori-negative Ménétrier’s disease with early gastric cancer in which complete curative resection was achieved through endoscopic submucosal dissection (ESD).

CASE PRESENTATION

Chief complaints

A 60 -year-old woman was referred to our hospital for examination and treatment of anemia.

History of present illness

After observing transient melena, the patient’s previous doctor conducted a medical examination and detected severe anemia (blood hemoglobin 6 .1 g/dL).

History of past illness

The patient had undergone successful treatment of chronic hepatitis C with interferon therapy performed by a previous doctor.

Personal and family history

The patient had no history of smoking or drinking alcohol. There was no relevant family history.

Physical examination

On admission, the patient’s temperature was 36 .7 °C, heart rate was 81 bpm, blood pressure was 128 /80 mmHg. There was conjunctival pallor and no spontaneous abdominal pain or no tenderness.

Laboratory examinations

The blood test revealed hypoproteinemia (serum albumin, 3 .4 g/dL), and the serumH.pyloriimmunoglobulin G antibody level was negative (＜ 3 ).

Imaging examinations

Computed tomography (CT) of the abdomen revealed marked mucosal thickening of the body of the stomach, with no enlarged lymph nodes around the stomach(Figure 1 A). Upper gastrointestinal (UGI) radiograph showed giant gastric rugae[5 ]and translucency of the nodule-aggregating surface in the greater curvature of the lower gastric body (Figure 1 B). The 99mTc-DTPA-human serum albumin (HSA-D)scintigraphy showed protein loss from the stomach after 24 h (Figure 1 C).

Endoscopic examination

UGI endoscopy revealed giant rugae in the gastric body, similar to contrast-enhanced radiographic findings (Figure 2 A). A 40 -mm broad-based, protruding erythematous lesion with lobular surface was observed on the giant rugae of the gastric body(Figure 2 B). UGI endoscopy showed no evidence of atrophic gastritis and intestinal metaplasia.

Endoscopic ultrasonography (EUS) demonstrated the five layers of the gastric wall.In the lesion area, hypertrophy was observed in the first two layers (equivalent to the mucosa and the muscularis mucosae); however, no noticeable structural changes were evident in the third layer (equivalent to the submucosal layer) or deeper (Figure 2 C).These findings were consistent with early tumor confined to the mucosal layer.

Low-magnification narrow-band imaging (NBI) showed granular surfaces with various sizes/forms and dilated vessels (Figure 2 D). High-magnification NBI demonstrated irregular microstructures of various forms and tortuous microvessels with changes in caliber (Figure 2 E).

Histopathological findings

Histological diagnosis based on endoscopic biopsy was Group 2 (non-tumorous changes suspected, though tumorous lesions cannot be ruled out)[6 ]. Considering the tumor size and high probability of a cancerous lesion based on the endoscopic images,en blocresection with ESD was performed for definitive diagnosis and treatment(Figure 3 A). Loupe image showed that the well-differentiated tubular adenocarcinoma was confined to the mucosal layer, with no lymphovascular invasion (ly0 /v0 ) or ulceration (UL0 ), and both the lateral and vertical margins were negative (Figure 3 B).

Histology of ESD specimens also showed proliferation of atypical cells with an irregular glandular structure (Figure 4 A and B). Additionally, scattered p53 proteinpositive cells were observed (Figure 4 C). Based on these findings, the atypical glands were diagnosed with early gastric cancer of a well-differentiated tubular adenocarcinoma. Foveolar hyperplasia and atrophy of the proper gastric glands were observed in the non-tumor areas, a histological image corresponding to Ménétrier’s disease(Figure 4 D).

Immunohistochemical staining showed that the tumor cells were diffusely positive for MUC5 AC (Figure 5 A) and partially positive for MUC6 (Figure 5 B), and negative for MUC2 (Figure 5 C) and CD10 (Figure 5 D).H. pyloriwere not observed in any biopsy or ESD specimens.

FINAL DIAGNOSIS

The final diagnosis of the presented case was early-stage gastric cancer andH. pylorinegative Ménétrier’s disease.

TREATMENT

The patient underwent ESD.

Figure 1 Images of computed tomography scan, upper-gastrointestinal radiograph and scintigraphy. A: Computed tomography scan revealed marked mucosal thickening of the body of the stomach (yellow arrow); B: The double-contrast technique shows remarkably enlarged fold width ＞ 10 mm (black arrow)and translucency of nodule aggregating surface at the greater curvature in the lower gastric body (black arrowhead); C: 9 9 mTc-DTPA-human serum albumin (HSA-D)scintigraphy: The arrows indicate accumulation in the stomach (red arrow).

Figure 2 Upper gastrointestinal endoscopy. A: Upper gastrointestinal endoscopy shows marked fold enlargement from the ventricular angle to the fundus(black arrow); B: A 40 -mm broad-based protruding lesion is observed near the posterior wall of the greater curvature of the lower gastric body; C: Endoscopic ultrasonography shows the five layers of the gastric wall. In the lesion area, hypertrophy was observed in the first two layers. No noticeable structural changes were evident in the third layer or deeper; D: Low-magnification narrow-band imaging (NBI) shows granular surfaces with various sizes/forms and dilated vessels; E: Highmagnification NBI demonstrates irregular microstructures with various forms and tortuous microvessels with changes in caliber.

OUTCOME AND FOLLOW-UP

Histology of ESD specimens showed complete curative resection. Endoscopic followup was performed twice a year for 3 years after ESD, and no recurrence was detected(Figure 6 ). Even though no therapeutic agents were administered specifically for Méné trier’s disease, the giant rugae regressed spontaneously, hypoproteinemia and anemia improved gradually, and the remission was maintained until the last surveillance endoscopy.

Figure 3 Endoscopic submucosal dissection specimen. A: 45 mm × 38 mm resection specimen comprising a broad-based protruding lesion with nodular surface and uninvolved (non-tumor) tissue with giant rugae; B: Loupe image shows that the well-differentiated tubular adenocarcinoma was confined to the mucosal layer, with no lymphovascular invasion (ly0 /v0 ) or ulceration (UL0 ), and both the lateral and vertical margins were negative.

Figure 4 Histological findings. A: The protruding lesion exhibits proliferation of atypical glands with irregular tubular structures (HE; × 20 ); B: High magnification shows proliferation of atypical cells and enlarged nuclei (irregular or oval-shaped) in the irregular tubular structure (HE; × 20 ); C: Scattered positive image (in nuclei)in the region (p53 ; × 20 ); D: Foveolar hyperplasia and atrophy of the proper gastric glands in non-cancerous area, consistent with Ménétrier’s disease (HE; × 20 ).

DISCUSSION

We reported an extremely rare case of early gastric cancer as a complication ofH.pylori-negative Ménétrier’s disease. We succeeded in curative resection of the cancerous lesion with ESD. Three years after the ESD, there was no recurrence of gastric cancer and Ménétrier’s disease regressed spontaneously and had maintained regression for about 30 mo.

Figure 5 Immunohistochemical staining for mucin phenotypes. The tumor cells were diffusely positive for MUC5 AC and partially positive for MUC6 , and negative for MUC2 and CD10 . A: MUC5 AC; B: MUC6 ; C: MUC2 ; D: CD10 .

Figure 6 Uppeer-gastrointestinal endoscopy 3 yr after endoscopic submucosal dissection. A: Endoscopic submucosal dissection scar but no recurrence of tumor; B: The giant rugae with erythematous and edema has regressed spontaneously. Ménétrier’s disease has remained in remission for the past 3 yr.

Although the present case wasH. pylori-negative, there have been two reports of close associations between adult-onset Ménétrier’s disease andH. pyloriinfection[7 ,8 ].It has been reported that Ménétrier’s disease with hypertrophic gastropathy increases the risk of gastric carcinogenesis[9 ]; however, the association between gastric carcinogenesis andH. pyloriinfection in Ménétrier’s disease remains unclear.

There have been about 80 case reports on gastric cancer (including advanced cancer)in adult-onset Ménétrier’s disease, though few have reported early-stage cancers. Our literature search found four case reports of Ménétrier’s disease with early gastric cancer and recorded endoscopic findings andH. pyloriinfection status (Table 1 ); two of these cases wereH. pylori-positive[10 ,11 ], and three cases, including the present one,wereH. pylori-negative[3 ,4 ]. Our case was the second early gastric cancer to undergo endoscopic resection and the first resection with ESD instead of conventional endoscopic mucosal resection. Macroscopically, all the lesions of early gastric cancer were of protruding-type[12 ] and located on the oral side of the ventricular angle(corpus/fundus region)[13 ]. Hypoalbuminemia was observed in three cases and wasunclear in one case.

Table 1 Case reports on early-stage gastric cancer in patients with Ménétrier’s disease

These findings (protruding lesions located in the corpus or fundus region and hypoalbuminemia) may depict the clinicopathological features of Ménétrier’s diseaseassociated early gastric cancer.

Ménétrier’s disease generally presents with hypertrophic gastropathy, primarily in the fundic gland region, which may explain the tendency for Ménétrier’s diseaseassociated early-stage gastric cancer to occur in this region[14 ]. Endoscopic gastric cancer screening of patients with Ménétrier’s disease should focus on two characteristics: The location (corpus or fundus) and the macroscopic type.

In the present case, cancer could not be confirmed by preoperative biopsy; therefore,a definitive diagnosis of cancer was made using the specimen from the endoscopic resection specimen. Based on histopathological findings, Ménétrier’s disease is considered a chronic inflammatory disease[15 ], making it difficult to differentiate between inflammatory atypia and neoplastic atypiaviasmall tissue biopsy alone, as in the present case. When endoscopic biopsy tissue from a superficial tumor-like lesion exhibits atypical glands in patients with Ménétrier’s disease, total biopsy withen blocESD can be useful for definitive diagnosis as well as treatment including complete curative resection, such as in this case.

Severe Ménétrier’s disease cases with clinical symptoms such as abdominal pain and vomiting require total gastrectomy to control severe hypoalbuminemia[16 ,17 ]. Besides the present patient, the two other patients withH. pylori-negative early-stage cancer underwent total gastrectomy. There was one case of surgery-related death. Therefore,if Ménétrier’s disease is not severe and the stomach can be preserved, ESD seems a beneficial therapy for early-stage gastric cancer, especially for mucosal cancer, because of its low invasiveness and high complete curative resection rate.

The mucin phenotype of the early gastric cancer in this case was gastric type with strongly positive for MUC5 AC and low expression of MUC6 . These suggest the gastric-type mucin of foveolar-dominant type. In the non-tumor area involved by Mén étrier’s disease, although p53 staining was negative and Ki-67 index was low,significant hyperplasia of foveolar epithelium was shown in the fundic gland region.We deduced that early cancer in the present case could be developed from a polypoid lesion with foveolar hyperplasia along hyperplasia-dysplasia-carcinoma sequence[18 ], even though the mechanism of gastric cancer development in Ménétrier’s disease is unknown.

CONCLUSION

To our knowledge, this is the first report of an extremely rare case of early-stage gastric cancer detected in a patient withH. pylori-negative Ménétrier’s disease in which complete curative resection was achieved with ESD.

ACKNOWLEDGEMENTS

We express our sincere thanks to Prof. Takashi Yao (the Department of Human Pathology, Juntendo Graduate University School of Medicine) for the helpful advice on histopathology of this case.