Preoperative systemic chemotherapy alters the histopathological growth patterns of colorectal liver metastases

Abstract

Histopathological growth patterns (HGPs) are a reliable, reproducible, and strong prognostic biomarker that can be assessed on haematoxylin and eosin-stained sections of resected colorectal liver metastases (CRLM). Assessment estimates the relative fraction of the tumour-liver interface for each of the three growth patterns; the desmoplastic HGP reflects good prognosis. Whether preoperative chemotherapy affects the HGP is currently unclear. The present international multicentre study evaluates this in an original cohort of 877 consecutive patients treated in the Netherlands, an external validation cohort of 1,203 consecutive patients treated in the USA, and a post hoc analysis from the phase III randomised controlled European Organization for Research and Treatment of Cancer (EORTC) 40983 trial (n = 70). All patients underwent resection of CRLM with or without preoperative systemic chemotherapy. Trial patients were randomised between perioperative chemotherapy and resection or resection alone. HGPs were determined according to consensus guidelines and compared for preoperative treatment status. Data from three separate tumour regression grading systems were available for the trial cohort. These were correlated with HGP stratified for treatment arm. In the original cohort, the average presence of desmoplastic HGP was 43% for chemo-naïve versus 67% for preoperatively treated patients (p < 0.001). A significant association between chemotherapy and desmoplastic HGP was found on multivariable analysis (β [95% confidence interval, CI]: 24.57 [18.28-30.87], p < 0.001). In the validation cohort, the average presence of desmoplastic HGP was 40% for chemo-naïve versus 63% for preoperatively treated patients (p < 0.001). This association remained on multivariable analysis (β [95% CI]: 24.18 [18.70-29.66], p < 0.001). In the EORTC 40983 trial, the average desmoplastic HGP presence was 33% in the resection arm versus 61% in the chemotherapy arm (p = 0.005). Chemotherapy was independently associated with an increase in desmoplastic HGP (β [95% CI]: 23.29 [1.78-44.79], p = 0.022). All three tumour regression gradings were significantly associated with the desmoplastic HGP in the chemotherapy arm (all p < 0.04). None were associated in the resection arm (all p > 0.11). Preoperative chemotherapy induces histopathological changes that alter the HGP of CRLM.

Histopathological growth patterns of liver metastasis: updated consensus guidelines for pattern scoring, perspectives, and recent mechanistic insights

“…There are, however, studies suggesting that chemotherapy induces the desmoplastic growth pattern in patients with replacement-type CRLM 18, 61 . Nierop and colleagues (2021) 61 have assessed the HGP of resected liver metastases in three cohorts of respectively 877, 1203 and 70 patients with CRC, respectively.…”

“…There are, however, studies suggesting that chemotherapy induces the desmoplastic growth pattern in patients with replacement-type CRLM 18, 61 . Nierop and colleagues (2021) 61 have assessed the HGP of resected liver metastases in three cohorts of respectively 877, 1203 and 70 patients with CRC, respectively. The latter cohort was derived from a phase III clinical trial in which patients were randomized between either peri-operative chemotherapy and resection or resection only.…”

“…We now propose the working hypothesis, based on immunohistochemical analyses, that the replacement HGP is the default growth pattern of liver metastases. Although there are data to support the view that pre-surgery chemotherapy can induce desmoplastic growth in some metastases 18, 61 and that a switch to replacement growth can occur upon resistance to systemic treatment 41 , the cellular and molecular mechanisms responsible for these transitions from one growth pattern to another remain to be elucidated. What these and other findings do seem to suggest is that epigenetic processes drive the growth patterns rather than mutational hardwiring.…”

“…Nierop P.M.H. J Pathol Clin Res 2021 61 In 3 cohorts of patients (n=877, 1203 and 70) the effect on pre-surgery chemotherapy on the HGP was assessed. The cohort of 70 patients belongs to a randomized clinical study.…”

“…Although these histological observations need further validation and quantification, they do support other observations consistent with growth pattern plasticity. Indeed, resistance to chemotherapy can coincide with a switch to the replacement HGP 41, 59 , while pre-operative chemotherapy converts metastases in some patients from replacement to desmoplastic HGP 61 . Also, during disease progression in patients with recurrent colorectal liver metastases, there is an evolution towards the more aggressive replacement HGP, as observed by analysing repeated resections 18 .…”