Clinics and Research in Hepatology and Gastroenterology (2012) 36, 505—509

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CLINICAL CHALLENGE

Diffuse type gastric carcinoma presenting as giantgastric folds: Lessons learned from six missdiagnosed cases

Mei Meia, Ni Jingmeia, Chen Zongmingb, Jin Meic, Sun Leimina,∗

a Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University medical school, Hangzhou, 310016, PR Chinab Department of Pathology, Division of Surgical Pathology Northwestern University Feinberg School of Medicine 7-340, Chicago, IL60611,USAc Department of Pathology, Sir Run Run Shaw Hospital, Zhejiang University medical school, Hangzhou, 310016, PR China

Available online 29 May 2012

Summary Hyperplastic gastropathy is a rare condition characterized by giant gastric folds.There are numerous causes of giant gastric folds included benign diseases (Menetrier’s dis-ease, pseudolymphoma and lymphocytic gastritis) and malignant diseases (gastric carcinoma,lymphoma and Zollinger-Ellison syndrome). Six gastric carcinoma presenting as giant gastricfolds were described. Lessons learned from six miss diagnosed cases and how to improve theaccuracy of diagnosis were elucidated. Moreover, we propose a hypothesis that in diffuse type

gastric carcinoma gastric cancer, which manifested with thickness of gastric folds, there mustbe some media which is released by cancer cells to stimulate superficial mucosa layer benigncells proliferation, instead of malignant cells infiltrating directly.© 2012 Elsevier Masson SAS. All rights reserved.

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Introduction

Hyperplastic gastropathy characterized by giant gastric foldsis not commonly found in esophagogastroduodenoscopy(EGD). It is also called as giant hypertrophic gastritis, giantfold gastritis, giant rugal hypertrophy, chronic hypertrophicproliferative gastritis, or chronic hypertrophic glandular gas-

tritis. There are numerous causes of thickened gastric folds,ranging from primary epithelial hyperplasia of the mucosa(Menetrier’s disease) to secondary disorders (carcinoma and

∗ Corresponding author.E-mail address: sunleimin@yahoo.com (S. Leimin).

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2210-7401/$ – see front matter © 2012 Elsevier Masson SAS. All rights rehttp://dx.doi.org/10.1016/j.clinre.2012.04.009

ymphoma infiltration) and infections (Helicobacter pyloriastritis and cytomegalovirus infection especially those pro-ucing a granulomatous reaction) [1]. Giant gastric folds canresent a difficult diagnostic problem, especially when theres a clinical, endoscopic or endoscopic ultrasound suspicionf malignancy, but no proof can be obtained with routinendoscopic biopsies. To date, giant gastric folds remained

challenge for endoscopists even with the help of EUS ornare biopsy.

ase report

ix gastric carcinoma patients presenting as giant gastricolds were reported in the study, from 2004 to 2011 in Sir

served.

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et al.

Table 1 Patients’ characteristics and clinical symptoms.

Case 1 Case 2 Case 3 Case 4 Case 5 Case 6

Demographic informationAge (y) 74 33 43 54 65 66Gender F F F F M F

Clinical presentationa

Course (months) 5 3 2 20 3 6Abdominal discomfort N P P P P PNausea/Vomiting P N N P N PDiarrhea N P N N P NMelena N P N P N NWeight loss (kg) 10 3.5 5 6.5 NA 18Presence of ascites N P P N P N

LabsH. pyloria N N N P P NAnemiab − + + + NA +OB Testb + ++ − ++++ NA −Tumor markers Ft↑ CA125↑ Ft↓ Normal NA CA19-9↑

CA125↑Ft↑

Endoscopic features Rigid lackingperistalsis, erosion

Rigid, weakperistalsis

Rigid, weakperistalsis

Rigid lackingperistalsis, DU

Rigid, weakperistalsis

Rigid lackingperistalsis, GU

EUS FeaturesPosition of the thickness Body Body Body Body Body BodyWall thickness (mm) 9 NA 14 10 11 12Main thickened layerc 2 NA 2—3 2—3 2—3 3—4Stratification Preserved NA Absent Absent Absent AbsentPresence of lymph nodes (n)d 0 NA 1 0 1 0

Biopsye

Jumbo biopsy (n) 0 1 2 1 0 0EMR (n) 0 0 0 0 0 1Histologic finding Open peritoneal Sig Laparoscopy

SigLaparoscopyNA

BiopsySig

NA LaparoscopySig

F: female; M: male; NA: not available; OB test: occult blood test; Ft: Ferritin; CA-125: carbohydrate antigen-125; CA19-9: carbohydrate antigen19-9; DU: duodenal ulcer; GU: gastriculcer; EUS: endoscopic ultrasound; EMR: endoscopic mucosal resection; Sig: signet cell carcinoma.

a N: indicates negative symptom; P: indicates positive symptom.b −: negative; +: mild; ++: moderate; +++∼++++: severe.c 2: mucosa; 3: submucosa; 4: muscularis propria.d Data indicates the number of lymph nodes.e Data indicates the frequency of biopsy.

Misdiagnosis of giant gastric folds 507

Figure 2 Endoscopic ultrasound view showing the wall ofgm

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Figure 1 Endoscopic view showing the body of plicae gastri-cae had become deep and thick, resembling gyrus.

Run Run Shaw hospital, China. Their characteristics and clin-ical symptoms were shown in Table 1. Among them, therewere five Asian women and only one Asian man, the meanage were 55.8 years. The courses of their illness were mostlyless than six months, with only one more than 1.5 years.Most of those patients (5/6) presented with abdominal dis-comfort with remarkable weight loss but without severestomachache. Some presented with ascites, nausea, vom-iting, diarrhea or melena.

For lab tests, only two were H. pylori positive on patho-logical exam. Almost all of the patients (5/6) presented withanemia. Three patients were fecal occult blood (OB) testpositive. Only two patients had elevated tumor markers onserum analysis (carbohydrate antigen [CA] 125).

For the endoscopic findings, those patients’ gastricmucosa were rigid either lacking peristalsis or with weakperistalsis (Fig. 1). Only the body of the gastric mucosawas thickened in all of our patients. EUS showed all of thepatients had thickness of gastric wall of 9 to 14 mm. Thethickness was localized at the deep mucosa layer togetherwith the submucosa layer (Fig. 2). Most of the patientsdid not present with stratification or enlargement of lymphnodes. Jumbo biopsies were performed for three patientsand endoscopic mucosal resection (EMR) was done for onlyone patient.

The diagnosis of gastric carcinoma was confirmed byendoscopic biopsy for only one patient, and four patientswere confirmed by operative pathology (either laparoscopyor open peritoneal surgery).

We did 18-F-Fluoro-2-deoxyglucose positron emissiontomography/computed tomography (PET-CT), which showeda thickened gastric wall with ascites, but no signs of gas-tric cancer for the second patient. A large cup pinch biopsyforceps and electrocautery snare biopsies of the folds with

saline injection technique were done for the third patient,but no positive pathologic findings. However, to review thiscase, three years later we rechecked the HE stained slideof the biopsy samples. At this time, three or five dysplasia

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astric body was thickened from 10 mm to 12 mm, and the sub-ucosa layer and muscle layer were 7.4 mm.

ells in the fundus of mucosa layer nearby lamina muscularisucosa were found by an experienced pathologist (Fig. 3).owever, it was only found in three of eight tissues of thene slide. Furthermore, we recut the paraffin block to try too immunohistochemistry (CKpan), but dysplasia cells wereot found even with rigorous observation.

iscussion

he main principle in the evaluation of giant gastric folds iso rule out neoplasia, either an infiltrating carcinoma or aymphoma. Among the six patients, the diagnosis of gastricarcinoma was confirmed by endoscopic biopsy for only oneatient (case 4). There were about 17,000 patients under-ent EGD examinations every year in our hospital, among

hem about 1.35% were gastric cancer patients. Althoughe were not short of experience of endoscopic diagnosingastric cancer, we still failed to make a definite diagno-is. During that period, there were another two patientsiagnosed as benign hypertrophic gastritis, which we didn’tresent in our case report. These two cases presented withiant gastric folds at the time of first EGD and turned outo be normal gastric mucosa after 5 yeas cautious follow-p. Although endoscopists in our hospital are experiencedt recognizing gastric cancers, but for those presenting asiant gastric folds, it was really difficult to make a definitiveiagnose. Therefore, giant gastric folds still was a challengeor endoscopists even with the help of EUS or snare biopsy.

Our series miss diagnosed cases indicated that giant gas-ric folds in Asian population are particularly suspicious forignet ring cell carcinoma and to maintain a high level oflertness is extremely important in China where the inci-

ence of gastric cancer is one of the highest in the world [2]o prevent miss diagnosis of gastric carcinoma. Signet ringell carcinoma is notoriously hard to diagnosis in small biopsypecimens. The cancer cells are usually blend looking, inter-

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Figure 3 A. Low power HE stain (arrow indicates dysplasiacell). B. High power HE stain showing several dysplasia cells inthe fundus of mucosa layer nearby lamina muscularis mucosa(

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cabdominal discomfort are particularly suspicious for signet

arrows).

ixed with inflammatory cells, and without desmoplasticeaction. So for signet ring cell carcinoma presenting giantastric folds, accurate diagnosis requires close communi-ation between the referring physicians, endoscopist andathologist, since giant gastric folds seen in a large numberf benign and malignant conditions is a complicated diagno-is that requires careful correlation of clinical, laboratory,GD, EUS and pathological findings. Our series cases wereore likely to be advanced age and female, which differed

rom the previously reported [3]. It could not exclude theossibility that the limitation of case number. In addition tolinical presentation, we found that the course of patientsas short (presented by median value 4 months), all patientsresented abdominal discomfort, weight loss and/or nau-ea/vomiting, and one third of patients presented diarrheand/or melena. While clinical presentation may favor oneiagnosis, laboratory tests are also helpful in establishinghe diagnosis of gastric cancer. We found that more than half

f patients had anemia, positive OB test and abnormal tumorarkers such as CA-125, CA19-9 and Ferritin. So we con-

idered that for referring physicians, short course, severe

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M. Mei et al.

eight loss, anemia and positive OB test were particularlyuspicious presents for malignant disease.

Another clue to the proper diagnosis of gastric carci-oma presenting as giant gastric folds is the endoscopists’xperience and subtle findings. EGD must be used for directisualization and biopsy sampling, and with the help of EUSo define the depth and extent of the lesions. It was con-idered that the enlargement of deep layers is the onlyndependent predictor of malignancy in patients with largeastric folds at endoscopy and endoscopic biopsies negativeor malignancy [4]. In present study, the thickened gastricall involved the deeper layers (submucosa and/or muscu-

aris propria) indicated that the thickening of deep layersay be related with gastric carcinoma. Besides the thicken-

ng of deep layers, the other endosonographic parametersredicting malignancy included a non-preserved wall layertructure, the presence of ascites, and the presence ofymph nodes with endosonographic features.

Sampling issue is a major factor to diagnose gastric car-inoma presenting as giant gastric folds. We believed thatultiple biopsies which included many pieces in one pro-

edure and follow-up EGD with biopsy in suspicious patientsre necessary and many times of deep biopsy (jumbo forcep)ay be helpful. In highly suspicious cases, EMR, EUS guidedne-needle aspiration and the guillotine-needle biopsy maye suggested to obtain diagnostic tissue. Pathologists shoulde properly alert by endoscopists with severity of clinicaluspicion. For highly suspicious cases, multiple levels of theame block need to be examined and proper immunostain-ngs should be applied. Seeking second opinion from seniorathologists is also recommended. Laparoscopy was the lasttep, doctors can do to make a definite diagnose to differ-ntiate benign from malignant.

Moreover, we suspected that the cancer cells releaseome media to stimulate superficial mucosa layer cells pro-iferation, but the mucosa cancer cells infiltrated down toubmucosa layer even muscular layer, which was not ableo be obtained by standard biopsy. The proliferation waso thick that even deep snare biopsy couldn’t get cancerells. So sometimes it was difficult to diagnose gastric can-er according to the clinical manifestations, repeated EGD,US and even PET-CT. We proposed E-cadherin may play anmportant role in the process. E-cadherin is a cell adhesionrotein, which plays an important role in tumor infiltration,etastasis and dissemination [5]. It has led to a concept

f E-cadherin acting as a suppressor of tumor invasion andetastasis, and the significance of the loss of E-cadherin for

nvasiveness and metastasis had been demonstrated in gas-ric carcinoma via distinct pathways that do not require anyrowth advantages [6—9]. The etiology of proliferate super-cial mucosa layer benign cells in gastric cancer might beome media or factors such as E-cadherin released by cancerells. All of these factors, instead of stimulating cancer cellsnfiltration into superficial mucosa layer, promote superfi-ial mucosa cells proliferation. To confirm this hypothesis,urther basic research will be required.

In conclusion, giant gastric folds in Asian population espe-ially elderly women with less than half year history of

ing cell carcinoma even if EGD, EUS, endoscope biopsy andlectrocautery snare biopsies did not find any malignantigns at beginning. Sometimes a group of manifestations

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[9] Shimada S, Mimata A, Sekine M, Mogushi K, Akiyama Y, Fuka-machi H, et al. Synergistic tumour suppressor activity of

Misdiagnosis of giant gastric folds

involved abdominal discomfort, nausea/vomiting, anemia,melena and weight loss, careful EGD exam characterized byrigid gastric wall, lacking peristalsis accompanying erosionor ulcer, EUS manifested by a thickening of deeper layers, anon-preserved wall layer structure, the presence of ascites,and the presence of lymph nodes, multiple biopsies, snarebiopsy or laparoscopy, multiple levels of the same block andproper immunostainings might be helpful. There must besome factors, which can promote superficial gastric mucosacells proliferation instead of dysplasia.

Disclosure of interest

The authors declare that they have no conflicts of interestconcerning this article.

Declaration of funding source: No funding sources todeclare.

Acknowledgements

The authors acknowledge to Dr. Charles Carter from Univer-sity of Michigan for his revising of English writing.

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