An unusual case of synchronous gastric carcinomas occurred in a 28-year-old man with a family history of gastric disease. Two tumor foci were identified: a well-differentiated advanced carcinoma with the phenotypic properties of complete intestinal metaplasia and an early intestinal-type carcinoma. Histochemical and immunohistochemical stains to demonstrate complete intestinal metaplasia, ie, Alcian blue pH 2.5/periodic acid–Schiff, high iron diamine/Alcian blue pH 2.5, CD10, and MUC2, were all positive in the advanced adenocarcinoma. Of all markers used, only high iron diamine/Alcian blue pH 2.5 and Alcian blue pH 0.5 were positive in the early carcinoma. In these cases, mistakes frequently are made during examination of endoscopic biopsies. Fortunately, the advanced adenocarcinoma was low grade (the patient has shown no signs of disease at 6 years postsurgery). Histopathologic, histochemical, and immunohistochemical findings suggest that an extensive substrate of complete intestinal metaplasia (corpus) and of complete and incomplete intestinal metaplasia (antrum) can be associated with two independent tumors with different phenotypes.

When examining histologic sections from gastrectomy specimens from patients with either peptic ulcer disease or carcinoma using morphometric analysis of the distribution of complete and incomplete intestinal metaplasia (IM), we identified a gastric tumor displaying a growth pattern similar to that reported by Endoh et al.1 These authors described this type of cancer as a flat or depressed tumor located in the corpus and histologically characterized by neoplastic tubules showing branching, tortuous, or anastomosing structures. These structures displayed features of absorptive cells, with brush borders, sialomucin-rich goblet cells, and occasional Paneth cells. Endoh et al labeled this type of lesion a well-differentiated adenocarcinoma mimicking complete IM in the stomach (CIMC)1 and reported constant misdiagnosis at examination of endoscopic biopsies. Misdiagnosis was also a feature of the case reported here. This new case was associated with a family history of gastric disease, and we focus here on the histogenetic and histologic features and on patient progress.

Following endoscopy, a gastric ulcer was diagnosed in the incisura angularis of a 28-year-old carpenter/joiner. Examination of biopsies from the antrum and corpus led to the diagnosis of “chronic gastritis with H. pylori-associated neutrophil activity and focal IM.” Triple therapy (amoxicillin, clarythromycin, and omeprazol) failed to elicit clinical improvement or scarring of the ulcerated lesion. Endoscopy and biopsy were repeated 4 times over the course of 3 years; a total of 19 biopsies were taken from the antrum and corpus during 5 endoscopic examinations, always leading to the same histopathologic diagnosis. In view of the resistance encountered by various treatment strategies, surgical treatment was approached with the clinical suspicion of gastric carcinoma. The gastrectomy specimen included 2 lesions: an ulcer of maximum diameter 0.6 cm, which was difficult to visualize because it was covered by abundant sticky mucus and was located in the incisura angularis, and a raised, sessile lesion of maximum diameter 1 cm located in the antrum. This second polypoid lesion was observed in the gastrectomy specimen but it had not previously been referred to during endoscopic observation. The patient recently refused to undergo new endoscopic studies.

The patient's father, a carpenter, died 24 years previously of cancer of the gastroesophageal junction. A paternal uncle died 28 years previously in Brazil because of gastric carcinoma. The patient's paternal grandfather also died of unspecified gastric disease. An older brother, a car sprayer, had undergone surgery elsewhere for an adenomatous polyp in the antrum. Currently, both brothers are alive and show no sign of disease after a 6-year follow-up.

Our initial encounter with a case of pure CIMC of the stomach prompted us to retrospectively review 325 cases of advanced and 116 cases of early intestinal-type carcinoma of the stomach from the Surgical Pathology files of the Virgen Macarena University Hospital between 1980 and 1997 to identify cases with the CIMC histologic pattern.

In the case presented here, all available histologic material was reviewed and the following features were documented: percentage of CIMC pattern and percentage and type of non-CIMC pattern where present, presence of early carcinoma, and depth of invasion. IM was classified as extensive if it replaced more than 50% of the histologic section and as nonextensive otherwise. Histochemistry included (1) Alcian blue (AB) pH 2.5/periodic acid–Schiff; (2) AB pH 0.5; (3) high iron diamine/AB pH 2.5; and (4) paradoxical concanavalin A. Immunohistochemistry was performed on selected formalin-fixed, paraffin-embedded sections using a routine streptavidin-biotin peroxidase detection system and after microwave antigen retrieval in 10mM sodium citrate buffer, pH 6.0. The chromogen was 3,3′tetrachlorohidratediaminobenzidine. Stains were considered positive if the results obtained coincided with expected results. Antibodies used were (1) MUC5AC (CLH2) (45 M1, Novocastra, Newcastle upon Tyne, United Kingdom) to show gastric foveolar mucin; (2) MUC2 (Cer58, Novocastra) to demonstrate intestinal goblet-cell mucin; (3) CD10 (56C6, Novocastra) to demonstrate the brush border of absorptive cells; and (4) Ki-67 (MIB1, Novocastra) to show proliferative cells. Omission of primary antibodies was used as a negative control, and positive control sections were included in both histochemistry and immunohistochemistry studies.

The morphometric study, using Ki-67 as a marker, was performed on 300 tumoral cells counted in consecutive highly magnified histologic fields and in nonoverlapping nuclear areas with the sample well aligned.

We reviewed the medical records of patients and their families to obtain data on demographics, initial symptoms, occupations, type of therapy received, and available follow-up information.

At the time of histopathologic diagnosis, the patient was 28 years old. His father died at 45 years of age, his paternal uncle at 50, and his grandfather at 76. His brother is now 34 years old. All 4 of these men are/were white, and 3 of them had advanced gastric carcinomas. Pain was the most important symptom in our patient.

Pathology

Grossly, 2 lesions were apparent: a flat ulcerated lesion of maximum diameter 0.6 cm that was located in the incisura angularis (Figure 1, A and B) and a polypoid sessile lesion 1 cm in diameter located in the antrum (Figure 2). The 2 lesions were 2 cm apart. The mucosa of the ulcerated lesion contained neoplastic plexiform or anastomosing tubules morphologically consistent with complete IM. These structures retained the cell population common to this type of metaplasia (Figure 1, C and D). As the neoplasm invaded the various layers of the stomach wall (submucosa and muscularis propria), the tumor growth pattern gradually changed: the submucosa and the first bundles of the muscularis propria displayed extensive colloid areas, whereas deeper within the muscularis propria glandular structures were observed, with fewer goblet cells and Paneth cells than in the mucosa and submucosa. There was frequent invasion of perineural spaces. Glandular structures were bordered by cells displaying scarce atypia and few if any mitotic figures. Nuclei were generally basal, with fine chromatin and a prominent nucleolus. These histologic features were not observed in cases of ordinary intestinal-type carcinomas reviewed for this study.

Figure 1.

Advanced well-differentiated adenocarcinoma mimicking complete intestinal metaplasia in the stomach. A, Panoramic view (hematoxylin-eosin, original magnification ×10). B, Low magnification view (hematoxylin-eosin, original magnification ×100). C, Intramucosal pathognomonic foci with anastomosing glands (Alcian blue pH 2.5/periodic acid–Schiff, original magnification ×160). D, Same area as C (high iron diamine/Alcian blue pH 2.5, original magnification ×160). Figure 2. Early intestinal-type carcinoma. A, Panoramic view (hematoxylin-eosin, original magnification ×4). B, Detail of tumoral gland in submucosa (hematoxylin-eosin, original magnification ×400)

Figure 1.

Advanced well-differentiated adenocarcinoma mimicking complete intestinal metaplasia in the stomach. A, Panoramic view (hematoxylin-eosin, original magnification ×10). B, Low magnification view (hematoxylin-eosin, original magnification ×100). C, Intramucosal pathognomonic foci with anastomosing glands (Alcian blue pH 2.5/periodic acid–Schiff, original magnification ×160). D, Same area as C (high iron diamine/Alcian blue pH 2.5, original magnification ×160). Figure 2. Early intestinal-type carcinoma. A, Panoramic view (hematoxylin-eosin, original magnification ×4). B, Detail of tumoral gland in submucosa (hematoxylin-eosin, original magnification ×400)

Close modal

The neoplasm induced desmoplasia, and the intramucosal compartment contained a dense inflammatory infiltrate comprising lymphoplasmacytes and neutrophils, which prompted cryptitis. There was no evident permeation of lymph vessels and no metastasis in the 10 lymph nodes isolated from the greater and lesser curvature.

The surrounding mucosa from corpus contained extensive complete IM, which was not observed in ordinary intestinal-type gastric carcinomas (early and advanced) reviewed for this study.

The polypoid formation located in the antrum was an early intestinal-type carcinoma (type I). The surrounding mucosa showed both extensive and nonextensive complete and incomplete IM, respectively. These changes were similar to those observed in areas adjacent to the ordinary intestinal-type gastric carcinoma cases (early and advanced). The submucosa displayed extensive colloid areas containing fragments of glandular structures.

Histochemical and Immunohistochemical Analysis

Findings in tumor areas are shown in the Table. The CIMC retained the phenotype characteristic of complete IM: brush borders were CD10 positive, goblet cell mucus was consistently more reactive with AB pH 2.5 than with high iron diamine, and MUC2 expression was evident in perinuclear cytoplasm, apical areas, and the luminal border of more than 50% of intramucosal tubular structures and less than 40% of muscularis-invading structures. Expression of MUC5AC was intense in apparently normal nonneoplastic gastric mucosa (100% of gastric epithelium) and in a few glands with incomplete IM. Expression of MUC5AC in tumor tissue was consistently negative. Similarly, Ki-67–positive cells were observed in the distal third of intramucosal cancerous tubules, with a rate of expression the same as that observed in normal small intestine mucosa. However, the percentage of Ki-67–positive cells was lower in muscularis-invading areas (78 Ki-67–positive tumor cells/300 tumor cells counted).

Results of Special Stains in Tumoral Cells (CIMC) and Early Intestinal-Type Gastric Carcinoma (Type I)*

Results of Special Stains in Tumoral Cells (CIMC) and Early Intestinal-Type Gastric Carcinoma (Type I)*
Results of Special Stains in Tumoral Cells (CIMC) and Early Intestinal-Type Gastric Carcinoma (Type I)*

The early intestinal-type carcinoma was negative for CD10, MUC2, and MUC5AC but intensely positive for high iron diamine/AB pH 2.5 and for AB pH 0.5. The distribution of Ki-67–positive cells was more extensive and irregular than in the CIMC. A total of 188 positive tumor cells were found per 300 tumor cells counted.

In both tumors and with both histochemical and immunohistochemical stains, negative results were obtained for Paneth cells.

This case comprised 2 histologic varieties of stomach cancer. The first was a well-differentiated adenocarcinoma phenotypically resembling complete IM and thus similar to the cases published by Endoh et al.1 Our interest in this histologic type of gastric carcinoma was prompted by initially encountering 1 such neoplasm that was misdiagnosed at biopsy examination. These samples represent a very small portion of the stomach mucosa, and therefore the sensitivity of the gastric mucosal biopsy in the detection of patchy processes, such as gastritis or IM, is often limited. To overcome this problem, we followed a mapping protocol.2 In the present case, endoscopic information was precise and suggested gastric carcinoma; however, histopathologic examination, repeated twice, wrongly indicated Helicobacter pylori–associated gastritis with IM and epithelial regenerative changes. Endoh et al1 reported similar diagnostic difficulty. This type of adenocarcinoma is so well differentiated that it becomes unrecognizable on examination of an endoscopic biopsy. This material is practically impossible to distinguish from low-grade, hyperplastic-type dysplasia.3 This type of dysplasia often arises on a background of chronic atrophic gastritis with IM.4 This type of carcinoma also displays a neutrophilic inflammatory infiltrate, leading to cryptitis. In the present case, this feature was not of great diagnostic value because of the presence of a neighboring ulcer, but in the cases reported by Endoh et al1 this feature was of diagnostic value. Inflammation tends to subside as the spread of IM increases in the lesser curvature of the stomach; however, this is not the case in the greater curvature,5 which complicates differential diagnosis when the lesion is located in the greater curvature. The cases reported by several Japanese authors1 and that reported here underline the importance of evaluating glandular architecture when diagnosing or at least suggesting the possibility of a malignant lesion on the basis of a stomach biopsy. The diagnosis of virtually all neoplastic epithelial processes in surgical pathology relies on both cytologic and architectural criteria. Changes in glandular architecture in the form of tortuous or plexiform anastomosing structures have been identified as abnormal with respect to underlying complete IM6 and may thus be considered pathognomonic in the study of these tumors.1 

A further noteworthy aspect of this case is the evaluation and significance of the extension and subtype of IM in the area where the tumor originated. This tumor clearly developed from a complete IM, which appears to contradict the findings of previous studies7–9 but supports the hypothesis that the extent of IM10 is more closely linked than the histochemical IM subtype (type III)11 to intestinal-type gastric carcinoma. However, in our case incomplete IM (type III) was more extensively represented in the antrum than in the corpus; therefore, this IM subtype is associated more with early carcinoma than with advanced carcinoma, where incomplete IM is minimally represented or absent (Table).

In the muscularis-invading form, all histochemical and immunohistochemical test results (Table) suggested a phenotype resembling complete IM. However, although the early intestinal-type carcinoma did not share these staining characteristics, it did display histochemical and immunohistochemical properties corresponding to an intestinal-type gastric carcinoma (Table). The two tumors clearly followed differing carcinogenic pathways: the sequence followed by the early intestinal-type carcinoma is well documented,12 but that followed by the advanced form, where tumor development was characterized by a direct progression from intramucosal growth to the submucosa and muscularis propria, is less well known. This tumor appears to represent incomplete carcinogenesis although it was derived from complete IM, possibly linked to mutagenic factors associated with the patient's occupation, to inflammation, or to hereditary factors. The patient was 28 years old at the time of diagnosis, and the presence of extensive areas of antrum and corpus IM is not common at that age and in that environment. Nevertheless, this case of gastric carcinoma, like those reported by Endoh et al,1 is a good example of an extensive substrate of IM (independent of the subtype) playing a necessary but not sufficient role in the genesis of this type of carcinoma.

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Author notes

Reprints: Francisco Rivera-Hueto, MD, Dpto Anatomía Patológica, Hospital Universitario Virgen Macarena, Avda Dr Fedriani, s/n, 41009 Sevilla, Spain ([email protected])