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Histological tumor response assessment in colorectal liver metastases after neoadjuvant chemotherapy: impact of the variation in tumor regression grading and peritumoral lymphocytic infiltration.

ABSTRACT: Background: The objective of this study was to evaluate the prognostic value of the variation in tumor regression grade (TRG) and peritumoral lymphocytic infiltration of colorectal liver metastases (CRLMs) after neoadjuvant chemotherapy (NACT). Methods: A retrospective review was performed in 98 patients with CRLMs who underwent NACT between 2010 and 2016. The TRG scores and counts of TILs at the tumor-normal interface were assessed in all 176 resected liver metastases to determine their association with prognosis. According to the variation in TRG scores, 40 patients with more than one liver metastasis were divided into a decreased TRG group and a stable TRG group. An additional independent cohort of 64 patients with 106 resected liver specimens was established to validate our main findings. Results: In the derivation cohort of 98 patients, 41.8% patients had a favourable pathological response to NACT (TRG 1-3), which were significantly associated with improved prognosis. Seventeen patients (42.5%) showed decreased TRG scores, and the remaining patients had stable scores. The multivariate analysis indicated that patients with decreased TRG scores had a better recurrence-free survival (RFS) compared with those with stable TRG scores (HR=0.42, P=0.034), and a similar trend was observed in the validation cohort (P=0.068). Dense TILs surrounding the metastases were present in 55.1% of the derivation cohort and associated with pathological response (P=0.008). Among patients with a pathological response to NACT, those with dense TILs had a superior RFS compared to those with weak TILs in both cohorts (derivation: HR=0.36, P=0.035; validation: HR=0.34, P=0.016). Conclusions: Variation in TRG scores and peritumoral lymphocytic infiltration may be proposed as secondary pathological parameters to evaluate the pathological response to NACT and predict the risk of recurrence after liver surgery.

SUBMITTER: Cai Y

PROVIDER: S-EPMC6843876 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Histological tumor response assessment in colorectal liver metastases after neoadjuvant chemotherapy: impact of the variation in tumor regression grading and peritumoral lymphocytic infiltration.

Cai Yibo Y Lu Xingang X Zhu Xiu X Ju Haixing H Sun Wenyong W Wu Wei W

Journal of Cancer 20191006 23

<b>Background:</b> The objective of this study was to evaluate the prognostic value of the variation in tumor regression grade (TRG) and peritumoral lymphocytic infiltration of colorectal liver metastases (CRLMs) after neoadjuvant chemotherapy (NACT). <b>Methods:</b> A retrospective review was performed in 98 patients with CRLMs who underwent NACT between 2010 and 2016. The TRG scores and counts of TILs at the tumor-normal interface were assessed in all 176 resected liver metastases to determine ...[more]

PMID: 31737121

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Project description:Neoadjuvant therapy is increasingly used to control local tumor spread and micrometastasis of pancreatic ductal adenocarcinoma (PDAC). Pathology assessments of treatment effects might predict patient outcomes after surgery. However, there are conflicting reports regarding the reproducibility and prognostic performance of commonly used tumor regression grading systems, namely College of American Pathologists (CAP) and Evans' grading system. Further, the M.D. Anderson Cancer Center group (MDA) and the Japan Pancreas Society (JPS) have introduced other grading systems, while we recently proposed a new, simple grading system based on the area of residual tumor (ART). Herein, we aimed to assess and compare the reproducibility and prognostic performance of the modified ART grading system with those of the four grading systems using a multicenter cohort. The study cohort consisted of 97 patients with PDAC who had undergone post-neoadjuvant pancreatectomy at four hospitals. All patients were treated with gemcitabine and S-1 (GS)-based chemotherapies with/without radiation. Two pathologists individually evaluated tumor regression in accordance with the CAP, Evans', JPS, MDA and ART grading systems, and interobserver concordance was compared between the five systems. The ART grading system was a 5-tiered system based on a number of 40× microscopic fields equivalent to the surface area of the largest ART. Furthermore, the final grades, which were either the concordant grades of the two observers or the majority grades, including those given by the third observer, were correlated with patient outcomes in each system. The interobserver concordance (kappa value) for Evans', CAP, MDA, JPS and ART grading systems were 0.34, 0.50, 0.65, 0.33, and 0.60, respectively. Univariate analysis showed that higher ART grades were significantly associated with shorter overall survival (p = 0.001) and recurrence-free survival (p = 0.005), while the other grading systems did not show significant association with patient outcomes. The present study revealed that the ART grading system that was designed to be simple and more objective has achieved high concordance and showed a prognostic value; thus it may be most practical for assessing tumor regression in post-neoadjuvant resections for PDAC.

Project description:Patients with microsatellite stable (MSS) colorectal cancer with liver metastases are resistant to immune checkpoint inhibitor (ICI) therapy, while about one-third of patients with colorectal cancer without liver metastases, particularly those with lung-only metastases, respond to ICI. We analyzed primary colorectal cancer tumors and major metastatic sites (liver, lung, peritoneal) using multiplex immunofluorescence and whole-slide spatial analyses to identify variations in immune contexture and regional localization within the tumor microenvironment. While levels of T and B cells within peritumoral regions were similar, their levels were significantly lower within the tumor core of liver and peritoneal metastases compared with lung metastases. In contrast, antigen-presenting cells (APC) and APC-T cell interactions were more abundant in all regions of lung metastases. We also identified an abundance of lymphoid aggregates throughout lung metastases, but these were present only within peritumoral regions of liver and peritoneal metastases. Larger lymphoid aggregates consistent with features of tertiary lymphoid structures were observed within or adjacent to primary tumors, but not metastatic lesions. Our findings were validated using NanoString GeoMx DSP, which further showed that liver metastases had higher expression of immune-suppressive markers, while lung metastases showed higher proinflammatory activity and T-cell activation markers. Peritoneal metastases demonstrated higher expression of cancer-associated fibroblast-related proteins and upregulated PD-1/PD-L1 signaling molecules. Our results demonstrate that functional status and spatial distribution of immune cells vary significantly across different metastatic sites. These findings suggest that metastatic site-dependent immune contexture may underlie discordant responses to ICI therapy in patients with MSS colorectal cancer.SignificanceOur results demonstrate that functional status and spatial distribution of immune cells vary significantly across different metastatic sites in MSS colorectal cancer. These findings suggest that metastatic site-dependent immune contexture may underlie discordant responses to ICI therapy in patients with MSS colorectal cancer.

Dataset Information

Histological tumor response assessment in colorectal liver metastases after neoadjuvant chemotherapy: impact of the variation in tumor regression grading and peritumoral lymphocytic infiltration.

Publications

Histological tumor response assessment in colorectal liver metastases after neoadjuvant chemotherapy: impact of the variation in tumor regression grading and peritumoral lymphocytic infiltration.

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