Histotype-based prognostic classification of gastric cancer

Abstract

Aim: To test the efficiency of a recently proposed histotype-based grading system in a consecutive series of gastric cancers.

Methods: Two hundred advanced gastric cancers operated upon in 1980-1987 and followed for a median 159 mo were investigated on hematoxylin-eosin-stained sections to identify low-grade [muconodular, well differentiated tubular, diffuse desmoplastic and high lymphoid response (HLR)], high-grade (anaplastic and mucinous invasive) and intermediate-grade (ordinary cohesive, diffuse and mucinous) cancers, in parallel with a previously investigated series of 292 cases. In addition, immunohistochemical analyses for CD8, CD11 and HLA-DR antigens, pancytokeratin and podoplanin, as well as immunohistochemical and molecular tests for microsatellite DNA instability and in situ hybridization for the Epstein-Barr virus (EBV) EBER1 gene were performed. Patient survival was assessed with death rates per 100 person-years and with Kaplan-Meier or Cox model estimates.

Results: Collectively, the four low-grade histotypes accounted for 22% and the two high-grade histotypes for 7% of the consecutive cancers investigated, while the remaining 71% of cases were intermediate-grade cancers, with highly significant, stage-independent, survival differences among the three tumor grades (P = 0.004 for grade 1 vs 2 and P = 0.0019 for grade 2 vs grade 3), thus confirming the results in the original series. A combined analysis of 492 cases showed an improved prognostic value of histotype-based grading compared with the Lauren classification. In addition, it allowed better characterization of rare histotypes, particularly the three subsets of prognostically different mucinous neoplasms, of which 10 ordinary mucinous cancers showed stage-inclusive survival worse than that of 20 muconodular (P = 0.037) and better than that of 21 high-grade (P < 0.001) cases. Tumors with high-level microsatellite DNA instability (MSI-H) or EBV infection, together with a third subset negative for both conditions, formed the T8 cell-rich HLR group, the largest group among low-grade histotypes. Coexisting HLR proved to be a factor in improved prognosis in tumors with microsatellite instability (P = 0.0015 vs HLR-/MSI-H tumors) or DR type human leukocyte antigen expression (P = 0.033 vs HLR⁻/HLA-DR⁺ tumors).

Conclusion: Identification of low- and high-grade histotypes can improve the prognostic assessment of a substantial proportion of gastric cancers in routine diagnostic practice.

Keywords: Epstein-Barr virus; Gastric cancer; High-grade histotype; Low-grade histotype; Lymphoid response; Microsatellite instability.

Figure 1

Histological and histochemical aspects of high lymphoid response cancers. A: Lymphoepithelioid pattern of an HLR EBV⁺ tumor (hematoxylin-eosin, × 200); B: High intratumor T8 cells infiltration in an HLR EBV^-/MSI^- case (CD8 immunoperoxidase-hematoxylin, × 200); C: Peritumor dendritic cell rich demarcating band in an HLR MSI-H tumor (CD11c immunoperoxidase-hematoxylin, × 100); in the inset, focal enlargement of image C to show interaction of CD11c-reactive dendritic cells with unreactive neoplastic cells (× 400); D: HLA-DR reactivity of an HLR MSI-H case (immunoperoxidase-hematoxylin, × 400); E: Low-grade very-well-differentiated tubular carcinoma (hematoxylin-eosin, × 200); F: Low-grade desmoplastic tumor with spindle neoplastic cells interspersed among fibroblast rich stroma (CAR5, immunoperoxidase-hematoxylin, × 200).

Figure 2

Muconodular, well-differentiated tubular, diffuse desmoplastic and high lymphoid response. A: Low-grade muconodular cancer with expansile growth (hematoxylin-eosin, × 20); in the inset, note tumor cells floating inside mucin, free of contact with stroma (× 400); B: intermediate-grade, locally infiltrative mucinous cancer (hematoxylin-eosin, × 200); C: massive lymphoinvasion of a high-grade mucinous cancer (podoplanin immunoperoxidase-hematoxylin, × 200); D: Diffuse anaplastic cancer invading the muscularis propria (hematoxylin-eosin, × 200), in the inset the enlargement shows cellular pleomorphism (× 400) .

Figure 3

Kaplan-Meier survival estimate of 200 gastric cancers according to histotype-based grade.