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


Very well-differentiated adenocarcinoma 'mimicking intestinal metaplasia' was described first by Endoh et al,[1] and later by Yao et al,[3] who reported nine additional examples of 'extremely well-differentiated adenocarcinoma,' including gastric type (n=5) and intestinal type (n=4). Recently, Okamoto et al[2] reported a large series of such cases (n=25), emphasizing the characteristic lateral (crawling) spread pattern of these neoplasms. These previous studies reported some of the features that we assess here, including tortuous, branching, anastomosing, and distended glands, as well as the presence of discohesive cells.[1–3] A limited set of stromal features including desmoplasia and inflammation have also been noted previously.[3] The finding of 'spiky' glands, glandular outgrowth, and abortive glands as architectural features and the assessment of the remaining stromal features have not previously been described. Similarly, no prior study has systematically assessed the combined set of cytomorphologic features that we present in Table 2.

Although very well-differentiated gastric adenocarcinoma of intestinal type is well established in the Japanese literature, there is a possibility that western pathologists may view this diagnosis with skepticism because of the bland nuclear features and limited exposure owing to its extreme rarity. Consequently, the particular importance of this study is that it demonstrates that very well-differentiated adenocarcinoma, despite having minimal nuclear atypia, is an irrefutably malignant lesion, as evidenced by a number of cases with associated submucosal or transmural invasion and discohesive (signet-ring) cell transformation.

Although very well-differentiated gastric adenocarcinoma is currently regarded a rare entity, it is likely that advances in endoscopic imaging, such as chromoendoscopy, magnifying endoscopy, and narrow-band imaging, and increased screening will increase the frequency of detection of this entity.[9–11] Consequently, it is important for pathologists and endoscopists to be aware of this variant of gastric cancer. Our evaluation resulted in the recognition of a set of morphologic features that may serve as a useful diagnostic reference for pathologists faced with a possible case of very well-differentiated adenocarcinoma of intestinal type. We found architectural features to be most informative, and we determined that no less than three of the six architectural features (anastomosing glands, spiky glands, distended glands, discohesive cells, abortive glands, and glandular outgrowth) were present in all the cases. Adherence to these architectural criteria should prevent the overdiagnosis of very well-differentiated adenocarcinoma. In difficult cases, re-biopsy or consultation with an expert gastrointestinal pathologist who has experience with this entity should be considered. Fortunately, failure to make the diagnosis of very well-differentiated adenocarcinoma on the first biopsy will generally have little consequence because the lesions are slow growing.

Endoscopically, intramucosal very well-differentiated adenocarcinomas are frequently ill defined with indistinct borders, a characteristic associated with higher rates of incomplete resection along the lateral margins when compared with other histologic types of gastric cancer.[5] This seems to be partly due to the 'crawling' pattern of growth at the periphery that was indeed recognized in our series. We also showed that the endoscopic challenges are matched by histologic difficulties in establishing malignancy, with 50% of the original diagnostic biopsies incorrectly interpreted as either 'indeterminate for neoplasia' or 'reactive intestinal metaplasia.' Yet it is also important to stress that despite the delay in diagnosis, extending over 1 year in a non-negligible 17% of our cases, only limited progression was noted.

Immunophenotypically, 48% of the tumors had a mixed phenotype and 52% presented an intestinal immunophenotype. Very well-differentiated adenocarcinomas with mixed immunophenotype appear to preserve a low-grade malignancy profile as long as discohesive neoplastic cells are absent. In our series, the five intramucosal cancers falling into that category remained without nodal metastasis. However, it is noteworthy that all of the cases in which discohesive neoplastic cells were detected presented a mixed phenotype, suggesting a heightened risk of transformation specific to this subgroup which then acquires a more aggressive behavior.

Interestingly, comparing this observation with the three previous series that included immunophenotypic analysis (n=58 in total, including our cases)[1–3] (Table 4), it appears that a poorly cohesive carcinoma component was present in 69% of the cases with mixed phenotype, but was absent in all cases of intestinal phenotype (P<0.0001). This observation confirms our inference. Finally, nodal metastases were present in 5 of these 58 cases, all of which showed mixed phenotype tumors with poorly cohesive carcinoma components.

On the contrary, those cases of intestinal immunophenotype had less aggressive biological behavior, were not accompanied by a focal component of poorly cohesive carcinoma, and retained their well-differentiated morphology in submucosal and deeper-invasive areas.[1–3] Furthermore, nodal metastases were absent and no fatal cases have been reported in this subgroup, even in pT4 tumors. As further evidence of its indolent behavior, two cases of pure intestinal phenotype in our series remained intramucosal without significant increase in size during a long-term preoperative follow-up (50 and 84 months). This observation is indirectly supported by the previous reports of a low Ki67 labeling index and a lack of p53 or c-erbB2 protein overexpression in this subtype.[1,3]

In summary, very well-differentiated gastric adenocarcinoma of intestinal type represents a diagnostic challenge, particularly on biopsy specimens. On the basis of our series, the histologic diagnosis is best established using a combination of at least three of the six architectural features, including anastomosing glands, spiky glands, distended glands, discohesive cells, abortive glands, and glandular outgrowth. However, a blinded sensitivity/specificity analysis of these criteria is an important focus for future research. This variant can be divided into two groups based on the immunophenotype. Those with an intestinal immunophenotype do not appear to be associated with a risk of development of poorly cohesive carcinoma, and appear to be indolent. Alternatively, those with mixed immunophenotype are not infrequently associated with a focus of discohesive neoplastic cells, and are more likely to present an aggressive behavior.