Clinicopathologic Characteristics of Microsatellite Instable Gastric Carcinomas Revisited: Urgent Need for Standardization

Abstract

Microsatellite instable gastric cancer (MSI-GC) is a specific molecular subtype of GC. We studied the phenotypes, genotypes, and clinicopathologic characteristics of MSI-GC in a white GC cohort and compared our findings with an extended literature review. The study cohort consisted of 482 patients. Specimens were available from 452 cases and were used for immunostaining (MLH1, PMS2, MSH2, MSH6) and molecular biological analyses (BAT-25, BAT-26, NR-21, NR-24, NR-27; Epstein-Barr virus in situ hybridization). Thirty-four (7.5%) GCs were MSI. Loss of MLH1 and/or PMS2 was found in 30 (88%) MSI-GC, 3 (9%) showed loss of MSH2 and/or MSH6. One (3%) MSI-GC was identified only by molecular biological testing. A single case was heterogeneous and contained microsatellite-stable and instable tumor areas. Twenty-one (62%) MSI-GCs showed unusual histologic features. MSI-GC was not found in diffuse-type or Epstein-Barr virus-positive GC. MSI-GC was significantly more prevalent in elderly patients, distal stomach, and was associated with a significantly lower number of lymph node metastases and a significantly better overall and tumor-specific survival. MSI-GC constitutes a small but relevant subgroup of GC with distinct clinicopathologic characteristics. Our literature review illustrates the shortcomings of missing standardized testing algorithms with prevalences of MSI-GC ranging from 0% to 44.5%. Future studies should test the hypothesis that patients with MSI-GCs may not need adjuvant/perioperative chemotherapy. However, this will require a standardized, quality-controlled diagnostic algorithm of MSI for GC.

FIGURE 1

Immunohistochemistry for detection of mismatch repair (MMR) proteins in gastric cancer: MLH1 (A and C) and PMS2 (B and D). Typical staining pattern with combined loss of the complex forming MMR proteins. Lymphocytes and stromal cells serve as internal positive control. Especially in tumors with small tumor cells it is indispensable to differentiate these from the internal control to avoid misinterpretation (A, B, and D). Another potential source of error is the MLH1-deficient tumor that depicts a faint perinuclear staining pattern (C). In these, immunonegativity for PMS2 leads to the correct diagnosis. Original magnifications: (A and B) ×200; (C and D) ×400.

FIGURE 2

Heterogeneous expression of MSH2 with metastasizing microsatellite stable component. An adenocarcinoma of the proximal stomach—pT4a pN3a (10/19)—with mixed differentiation patterns: tubular, poorly cohesive, mucinous (A and B). No histologic evidence of a collision tumor. Focal expression of MSH2 [overall <15%, (C) after microdissection and molecular pathologic analysis: microsatellite stable] in otherwise complete loss of MSH2 [(D and E) after microdissection and molecular pathologic analysis: microsatellite instable]. All lymph node metastases were positive for MSH2 (F) and microsatellite stable. Original magnifications: (A–D) ×400; (E and F) ×200.

FIGURE 3

Tumor heterogeneity illustrated by virtual microscopy. The tumor of the proximal stomach showed a biphasic expression of MSH2, intermingling positive, microsatellite stable areas (red, positive nuclear staining) with larger areas that were MSH2 immunonegative and MSI (blue) (A and B). To illustrate the percent distribution, 2 large tissue sections were immunostained with MSH2, scanned, and using a viewer program with a polygon line drawing function, marked. The computed microsatellite stable tumor area was 23% (A) and 5% (B) in 2 separate tissue blocks from the same primary tumor.

FIGURE 4

Histomorphology in MSI gastric cancers. Diffuse and solid sheets of tumor cells (A and D) with large amounts of tumor-infiltrating or surrounding lymphocytes (A, C, and D). Solid, nested growth with comedo necrosis (C), pushing margins with lymphocytes aggregating peritumorally (C and D). Some tumors demonstrated a more conventional morphology but then combined >1 pattern in 1 tumor, such as glandular and mucinous (E and F). Hematoxylin and eosin stained. Original magnification: ×200.