The Glasgow Microenvironment Score: an exemplar of contemporary biomarker evolution in colorectal cancer

Abstract

Colorectal cancer remains a leading cause of mortality worldwide. Significant variation in response to treatment and survival is evident among patients with similar stage disease. Molecular profiling has highlighted the heterogeneity of colorectal cancer but has had limited impact in daily clinical practice. Biomarkers with robust prognostic and therapeutic relevance are urgently required. Ideally, biomarkers would be derived from H&E sections used for routine pathological staging, have reliable sensitivity and specificity, and require minimal additional training. The biomarker targets would capture key pathological features with proven additive prognostic and clinical utility, such as the local inflammatory response and tumour microenvironment. The Glasgow Microenvironment Score (GMS), first described in 2014, combines assessment of peritumoural inflammation at the invasive margin with quantification of tumour stromal content. Using H&E sections, the Klintrup-Mäkinen (KM) grade is determined by qualitative morphological assessment of the peritumoural lymphocytic infiltrate at the invasive margin and tumour stroma percentage (TSP) calculated in a semi-quantitative manner as a percentage of stroma within the visible field. The resulting three prognostic categories have direct clinical relevance: GMS 0 denotes a tumour with a dense inflammatory infiltrate/high KM grade at the invasive margin and improved survival; GMS 1 represents weak inflammatory response and low TSP associated with intermediate survival; and GMS 2 tumours are typified by a weak inflammatory response, high TSP, and inferior survival. The prognostic capacity of the GMS has been widely validated while its potential to guide chemotherapy has been demonstrated in a large phase 3 trial cohort. Here, we detail its journey from conception through validation to clinical translation and outline the future for this promising and practical biomarker.

Keywords: biomarkers; colonic cancer; histopathology; inflammation; microenvironment score; prognosis; rectal cancer; stromal invasion; subtypes; tumour microenvironment.

Figure 1

H&E‐stained sections assessed for tumour inflammatory cell infiltrate and TSP. (A) High KM grade with florid cup‐like infiltrate at the invasive edge with destruction of cancer cell islands. (B) Low KM grade displaying no increase in inflammatory cells at the invasive margin. (C) Low TSP with less than 10% tumour stroma. (D) High TSP with approximately 80% tumour stroma.

Figure 2

Kaplan–Meier plot depicting the relationship between the GMS and cancer‐specific survival in patients undergoing elective, potentially curative resection of colorectal cancer. Reproduced from Figure 2, Park et al [36] with permission.

Figure 3

GMS‐stratified DFS among the TransSCOT cohort. The relationship between the GMS and DFS in (A) the TransSCOT cohort, (B) those treated with FOLFOX, and (C) those treated with CAPOX.

Figure 4

The biopsy‐derived Glasgow Microenvironment Score (bGMS). (A) Immunohistochemistry‐stained biopsy specimen showing high intra‐epithelial CD3⁺ density (122 cells/HPF), (B) immunohistochemistry‐stained biopsy specimen showing low intra‐epithelial CD3⁺ density (9 cells/HPF), (C) biopsy specimen showing high tumour stroma percentage. Adapted from Figure 1, Park et al [40] in accordance with the Creative Commons license (http://creativecommons.org/licenses/by/4.0/).

Figure 5

The relationship between combined Glasgow Microenvironment Score–tumour budding and cancer‐specific survival in patients with primary operable colorectal cancer (p < 0.001). Reproduced from Figure 4, van Wyk et al 2016 [44] in accordance with the Creative Commons license (https://creativecommons.org/licenses/by‐nc‐sa/4.0/).

Figure 6

(A) Colorectal cancer H&E whole slide image, (B) following tissue segmentation by U‐Net convolutional neural network.