Very Well-differentiated Gastric Carcinoma of Intestinal Type

Tetsuo Ushiku; Thomas Arnason; Shinichi Ban; Tsunekazu Hishima; Michio Shimizu; Masashi Fukayama; Gregory Y Lauwers


Mod Pathol. 2013;26(12):1620-1631. 

In This Article

Abstract and Introduction


Very well-differentiated gastric adenocarcinoma of intestinal type is a rare variant of gastric cancer characterized by low-grade nuclear atypia, and for which the diagnostic criteria and clinical behavior are not fully established. This study presents a detailed histologic, immunohistochemical, and clinical analysis of 21 cases. Nuclear atypia was mild in all cases. Characteristic architectural features of this gastric adenocarcinoma variant were pit and glandular anastomosis, spiky glands, distended glands, discohesive cells, abortive glands, and glandular outgrowth. At least three of these features were present in all the cases. Retrospective review of preoperative biopsies in 18 patients revealed that half of the biopsies were originally reported as negative or indeterminate for malignancy. On the basis of immunohistochemical stains for intestinal (MUC2, CD10, and CDX-2) and gastric (MUC5AC and MUC6) markers, 11 (52%) cases had an intestinal immunophenotype and 10 (48%) cases had a mixed immunophenotype. Foci of discohesive neoplastic cells, indicating dedifferentiation toward a poorly cohesive carcinoma, were observed exclusively in neoplasms of mixed immunophenotype (n=5). All patients with follow-up but one were alive without disease at a mean of 19 months (range 1–60 months). One individual with a pT4 tumor with associated poorly cohesive carcinoma died of disease. In summary, very well-differentiated gastric adenocarcinomas are diagnostically challenging. Architectural features are critical to making the diagnosis. Cases with pure intestinal immunophenotype have not been associated with transformation into poorly cohesive carcinoma, and appear to behave as biologically low grade. Those with mixed immunophenotype appear more likely to dedifferentiate and behave more aggressively.


Very well-differentiated gastric adenocarcinoma of intestinal type is a distinct variant characterized by low-grade nuclear atypia and a morphology mimicking intestinal metaplasia.[1–3] The neoplastic glands show subtle architectural abnormalities such as branching and anastomosis, commonly reproducing the shapes of the letters W, H, Y, or X at low power.[4] Anecdotally, we have noted the challenge in diagnosing this variant of gastric adenocarcinoma, especially on biopsy specimens, which are often misinterpreted as reactive intestinal metaplasia. Endoscopically, this type of gastric cancer frequently presents as an ill-defined lesion with an indistinct border and a slightly depressed or flat appearance without marked mucosal tinctorial alteration.[5] Notoriously, the subtle endoscopic findings make the diagnosis of this lesion just as challenging for the endoscopist.[5] Although it has been suggested that very well-differentiated gastric adenocarcinomas have low malignant potential with slow growth, some cases have been reported with transformation into diffuse-type morphology resulting in more aggressive behavior.[1–3,6] As a matter of fact, the spectrum of this variant of gastric adenocarcinoma, including its clinicopathological features and biological behavior, has not been well characterized because this entity is rare, noted to comprise only 1.9% of early gastric cancer, and it has been described in only a few small series.[1–3,5]

Given the limited information available to date, we initiated this study to evaluate a series of very well-differentiated gastric adenocarcinomas of intestinal type in detail, with a notable focus on determining the key diagnostic features of this challenging lesion. We also investigated the biological behavior by reviewing the clinical course in this cohort of patients.