Very Well-differentiated Gastric Carcinoma of Intestinal Type

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

Disclosures

Mod Pathol. 2013;26(12):1620-1631. 

In This Article

Results

Clinicopathologic Features

The characteristics of the 21 cases are summarized in Table 1. The patients ranged in age from 53 to 84 years (mean, 67 years; median, 68 years) with a male to female ratio of 2:1 (14:7). Most cases were identified within the middle-third of the stomach (15 of 21, 71%), and the remaining six were equally distributed in the upper- and lower-third of the stomach. Tumor size ranged from 0.3 to 19 cm (mean, 3.2 cm; median, 1.5 cm). Endoscopically, all early cancers had the appearance of a predominantly superficial depressed lesion (n=17), except for one showing a superficial elevated lesion (Figure 2). The borders were ill-defined in 9 of 18 cases (50%), and 4 tumors (22%) were accompanied by submucosal fibrosis. Of the advanced cancers, two presented as Borrmann's type-4 lesions, demonstrating an irregular or flat surface with marked mural thickening, while one tumor formed a plateau-like elevated lesion (type 1). Endoscopic resections were performed in 12 cases, and 9 tumors were surgically resected. In addition, secondary surgical resection was performed in two cases (cases 11 and 12) when the resection margins returned positive after endoscopic resection.

Figure 2.

Endoscopic pictures of a very well-differentiated adenocarcinoma of intestinal type (case 5). Endoscopic examination demonstrates a superficial depressed erythematous lesion with an ill-defined margin using conventional endoscopic technique (a). Chromoendoscopy (b) and narrow-band imaging (c) better define the lesion.

Histologically, 86% of tumors (n=18) were early cancers, including 17 intramucosal cancers (pT1a) and 1 with superficial submucosal invasion (pT1b). The remaining three cases were advanced, all of which involved the serosal surface (pT4a). None of the 18 early cancers showed lymphovascular invasion, whereas it was present in all 3 advanced cancers. Nodal metastases were noted in only one of the advanced cancers (case 21).

Follow-up information was available in 17 cases (81%), ranging from 1 to 60 months (mean, 19 months). One patient (case 21), who had a pT4 tumor with nodal metastases, died of disease at 27 months postoperatively. The others were alive without disease at last contact (n=15) or alive without information about the disease status (n=1).

Assessment of a Series of Histologic Features

Intramucosal Very Well-differentiated Adenocarcinomas. Table 2 shows the histologic features observed in the 17 intramucosal cases. Tortuous, branching, and anastomosing glands were the predominant architectural patterns, and were observed to various degrees in all cases. Most cases also demonstrated distended glands (15 of 17, 88%), abortive glands (15 of 17, 88%), glandular outgrowth (13 of 17, 76%), and spiky glands (12 of 17, 71%). Discohesive neoplastic cells were focally present in four (24%) cases.

The distorted neoplastic glands were composed of absorptive cells with a mixture of scattered normal and dystrophic goblet cells, whereas some cases also had Paneth cells (9 of 17, 53%) and foveolar epithelium (4 of 17, 24%). Nuclear atypia was minimal. Nuclear enlargement was observed in all cases but was mild in degree. Nuclear hyperchromasia (10 of 17, 59%), prominent nucleoli (9 of 17, 53%), and clearing of chromatin (7 of 17, 41%) were also observed to various extents. Mitotic counts were 1–5 per 10 high-power fields (HPF) in eight (47%), 6–10 per 10 HPF in six (35%), and >10 (up to 12) per 10 HPF in three (18%) cases. Atypical mitoses were absent. Most cases (16 of 17, 94%) were accompanied by stromal lymphoplasmacytic inflammation in at least a portion of the lesion. The other stromal features included vascular ectasia (10 of 17, 59%), edema (4 of 17, 24%), and normal lamina propria (2 of 17, 12%). Only one case had a mild desmoplastic reaction focally.

In terms of growth pattern, 6 of 17 (35%) cases demonstrated a peripheral 'crawling' pattern, that is, lateral tumoral spread in the middle or lower half of the lamina propria extending beneath the non-neoplastic epithelial surface (Figure 3). Four of the 17 cases showed clusters of discohesive neoplastic cells indicative of focal transformation into poorly cohesive carcinoma.

Figure 3.

Low-power (a) and high-power (b, square frame in a) examples of a very well-differentiated adenocarcinoma with a 'crawling' pattern of intramucosal spread. The malignant glands infiltrate the lower half of the lamina propria (below the dotted line), extending laterally beneath the non-neoplastic surface epithelium (above the dotted line).

Submucosal or Deeply Invasive Very Well-differentiated Gastric Adenocarcinomas. The mucosal components of the four cases with submucosal or deeper involvement were relatively preserved in all cases, their features essentially similar to those cases limited to the mucosa. The degree of architectural atypia in two cases was in fact less severe than what was observed in the cases limited to the mucosa. Nuclear atypia was always mild, although nuclear enlargement, hyperchromasia, clearing of chromatin, and prominent nucleoli were observed to various degrees. Mitotic counts were 2–8 (mean, 4.8) per 10 HPFs without a significant difference compared with intramucosal cancers. A 'crawling' pattern of the mucosal components was absent in all cases. Discohesive neoplastic cells were focally present in one of these cases (case 21).

The morphology of the submucosal or deeper-invasive component differed from that of the mucosal component in the three pT4a neoplasms (cases 19, 20, and 21), while there was minimal variation in the case limited to submucosal invasion (case 18). Two of the pT4 tumors (cases 19 and 20) retained the very well-differentiated morphology, but most submucosal neoplastic glands were larger than those observed in mucosa and often displayed cystic dilatation and contained eosinophilic debris and neutrophilic inflammation (Figure 4). In addition, a desmoplastic reaction and dense inflammation were observed at least focally. One case (case 21), which demonstrated discohesive neoplastic cells focally in the mucosa, presented a similar diffuse-type infiltrating pattern (poorly cohesive carcinoma) with desmoplastic response involving the full thickness of the stomach including the serosal surface (Figure 5).

Figure 4.

Case 20: low-power view (a) and higher magnification of mucosal (b, upper dotted frame in a) and deeply invasive area (c, lower dotted frame in a). This case retains very well-differentiated morphology in the deeply invasive area, although the glandular structures are larger and more dilated compared with the intramucosal component.

Figure 5.

Case 21: low-power view (a) and higher magnification of mucosal (b, upper dotted frame in a) and deeply invasive area (c, lower dotted frame in a). In contrast to case 20 (Figure 4), this case demonstrates transformation from very well-differentiated adenocarcinoma (b) into poorly cohesive adenocarcinoma with desmoplastic reaction (c) involving the full thickness of the stomach.

Minimum Number of Architectural Features in Very Well-differentiated Adenocarcinoma. All 21 cases displayed a minimum of three of the following six architectural anomalies: anastomosing glands, spiky glands, distended glands, discohesive cells, abortive glands, and glandular outgrowth. Of these six features, three were present in 3 cases, four were present in 5 cases, five were present in 10 cases, and all six were present in 3 cases. In short, 86% of cases (18 of 21) had four or more of these architectural features.

Immunophenotype and Its Association With Clinicopathological Features

All 21 neoplasms were positive for intestinal markers, including MUC2 (21 of 21), CDX-2 (19 of 21, 90%), and CD10 (18 of 21, 86%). In addition, 10 of 21 (48%) cases were positive for gastric markers with MUC5AC expressed in all cases and MUC6 in 9 of the 10 cases. On this basis, 11 (52%) cases were classified as intestinal type (Figure 6) and 10 (48%) cases as mixed type (Figure 7). In cases with submucosal or deeper invasion, the immunophenotype was preserved at all levels of the tumors except for case 21, for which the deep-invasive component had a null phenotype.

Figure 6.

Very well-differentiated adenocarcinoma of intestinal immunophenotype (a, H&E). Tumor cell are positive for MUC2 (b) and CDX-2 (c), but negative for MUC5AC (d).

Figure 7.

Very well-differentiated adenocarcinoma of mixed immunophenotype (a, H&E). Tumor cells show positive staining for MUC2 (b), MUC5AC (c) and MUC6 (d).

No cases of intestinal phenotype had any discohesive neoplastic cells indicative of a poorly cohesive component, whereas 5 of 10 (50%) cases of mixed phenotype were accompanied by at least focal poorly cohesive carcinoma. There was no significant difference between the two immunophenotypes in the other histologic features, such as, patient age, gender, tumor location, macroscopic type, and nodal status.

Review of Pretreatment Endoscopic Biopsies

One to eight pre-therapeutic endoscopic examinations were performed in 18 patients (median, 2; mean, 2.5). A total of 196 tissue biopsies were available for review. Retrospective review revealed that 84 of these original biopsies were already diagnostic for very well-differentiated adenocarcinoma. Yet, the original diagnoses were 'adenocarcinoma' or 'suspicious for adenocarcinoma' in only 30 and 12 biopsies (36% and 14%), respectively, whereas the original diagnoses in the others were 'indeterminate for neoplasia' or 'reactive intestinal metaplasia' in 22 and 20 biopsies (26% and 24%), respectively. Of the cytoarchitectural features previously discussed, discohesive neoplastic cells and spiky glands were seen in 24% and 62% of the cases, respectively, and were significantly associated with a diagnosis of 'adenocarcinoma' or 'suspicious for adenocarcinoma' compared with the other diagnoses of 'indeterminate for neoplasia' or 'reactive intestinal metaplasia,' in which they were observed in only 4% for discohesive neoplastic cells and 33% for spiky glands, respectively. However, there was no significant difference in the other histologic characteristics between the two groups.

The delay in diagnosis was usually less than a few months: <1 month in 13 cases (72%), 1.5 months in 1 case (6%), and 3 months in 1 case (6%). However, in three cases (17%) more than a year elapsed: 23, 50, and 84 months. Endoscopically, these three lesions were ill defined and of small size, ranging from 1.2 to 1.5 cm in greatest dimension (Figure 8a and b). Notably, there were minimal changes in size between the first examination and resection in all the three cases. In addition, histologic evaluation of the resection specimen revealed that all three cases remained intramucosal cancers, and none had a poorly cohesive carcinoma component (Figure 8c and d). Table 3 summarizes the original pathologic diagnosis and endoscopic findings at resection of these three cases. On retrospective review, every set of biopsies from the three cases presented in Table 3 did contain tissue that was diagnostic for very well-differentiated adenocarcinoma.

Figure 8.

A case with a long-term follow-up before resection (case 4). An endoscopic picture just before resection demonstrates an ill-defined superficial depressed lesion (a). Narrow-band imaging highlights the lesion (b). The initial biopsy performed 23 months before resection (c). Although the original diagnosis was intestinal metaplasia with reactive change, retrospective review revealed that this biopsy was already diagnostic for very well-differentiated adenocarcinoma based on the aberrant branching, anastomosing, abortive glands, and glandular outgrowth (d).

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