Novel Internationally Verified Method Reports Desmoplastic Reaction as the Most Significant Prognostic Feature For Disease-specific Survival in Stage II Colorectal Cancer

Abstract

Multiple histopathologic features have been reported as candidates for predicting aggressive stage II colorectal cancer (CRC). These include tumor budding (TB), poorly differentiated clusters (PDC), Crohn-like lymphoid reaction and desmoplastic reaction (DR) categorization. Although their individual prognostic significance has been established, their association with disease-specific survival (DSS) has not been compared in stage II CRC. This study aimed to evaluate and compare the prognostic value of the above features in a Japanese (n=283) and a Scottish (n=163) cohort, as well as to compare 2 different reporting methodologies: analyzing each feature from across every tissue slide from the whole tumor and a more efficient methodology reporting each feature from a single slide containing the deepest tumor invasion. In the Japanese cohort, there was an excellent agreement between the multi-slide and single-slide methodologies for TB, PDC, and DR (κ=0.798 to 0.898) and a good agreement when assessing Crohn-like lymphoid reaction (κ=0.616). TB (hazard ratio [HR]=1.773; P=0.016), PDC (HR=1.706; P=0.028), and DR (HR=2.982; P<0.001) based on the single-slide method were all significantly associated with DSS. DR was the only candidate feature reported to be a significant independent prognostic factor (HR=2.982; P<0.001) with both multi-slide and single-slide methods. The single-slide result was verified in the Scottish cohort, where multivariate Cox regression analysis reported that DR was the only significant independent feature (HR=1.778; P=0.002) associated with DSS. DR was shown to be the most significant of all the analyzed histopathologic features to predict disease-specific death in stage II CRC. We further show that analyzing the features from a single-slide containing the tumor’s deepest invasion is an efficient and quicker method of evaluation.

Poorly differentiated clusters in colorectal cancer: a current review and implications for future practice

“…A subsequent study by the same group found that only DST but not PDC or TB was significantly associated with DSS on multivariate analysis. 9 In contrast, Konishi et al found PDC grade to have greater discriminatory power between low and high grade with respect to RFS than TB or stroma. 4 However, when the analysis was restricted to pT3/4 cases, DST had the most favourable AIC value.…”

“…2 More recently, they reported strong agreement for PDC grade between the current method evaluating all slides and a modified method in which only a single slide with the deepest invasion is assessed, with a kappa of 0.798. 9 If validated by other groups (and the association with clinical outcome holds), this modification may improve ease of assessment.…”

“…30 Six other studies have evaluated interobserver agreement for PDC grading using similar criteria, all reporting at least moderate agreement with median/average kappa values ranging from 0.51 to 0.81. 3,8,9,22,31,32 In three of these studies, interobserver agreement for WHO grade was concurrently evaluated and in all three studies agreement was lower than for PDC grade (Table 4). Finally, Barresi et al also evaluated interobserver agreement among two observers in 163 biopsy specimens, using cut-offs of 0, 1-2, and >2 for grades 1, 2 and 3 respectively, finding substantial agreement with a kappa value of 0.74.…”

“…Indeed, most studies evaluating both PDC and TB in the same cohort of patients have shown a strong association between these two prognostic factors. 1,4,5,[7][8][9][10][12][13][14]16,22,24,30 Some studies have shown TB 5,7,9,10,24 and others PDCs 1,4,14,16,17,23,24,30,31 to be of superior prognostic importance; the reason for such discrepancies is unclear. Possible explanations might include differences in methodology, varied skill sets of observers or differences in the case-mix across different cohorts.…”

“…[47][48][49][50][51][52] More recently, PDC grade has been significantly associated with another novel invasive front prognostic marker, desmoplastic stroma type (DST) (Figure 8). 4,9 Ueno et al postulated that both PDC and DST are morphological manifestations of EMT at the invasive front, and therefore sought to combine these features in a unified grading system, designated grade EMT . 53 This system defined G1 as the combination of G1 PDC and mature-type stroma and G3 as G3 PDC and immature-type stroma; any other combination of the two was classified as G2.…”