Background:Liver metastases present with distinct histopathological growth patterns (HGPs), including the desmoplastic, pushing and replacement HGPs and two rarer HGPs. The HGPs are defined owing to the distinct interface between the cancer cells and the adjacent normal liver parenchyma that is present in each pattern and can be scored from standard haematoxylin-and-eosin-stained (H&E) tissue sections. The current study provides consensus guidelines for scoring these HGPs.Methods:Guidelines for defining the HGPs were established by a large international team. To assess the validity of these guidelines, 12 independent observers scored a set of 159 liver metastases and interobserver variability was measured. In an independent cohort of 374 patients with colorectal liver metastases (CRCLM), the impact of HGPs on overall survival after hepatectomy was determined.Results:Good-to-excellent correlations (intraclass correlation coefficient >0.5) with the gold standard were obtained for the assessment of the replacement HGP and desmoplastic HGP. Overall survival was significantly superior in the desmoplastic HGP subgroup compared with the replacement or pushing HGP subgroup (P=0.006).Conclusions:The current guidelines allow for reproducible determination of liver metastasis HGPs. As HGPs impact overall survival after surgery for CRCLM, they may serve as a novel biomarker for individualised therapies.

Background In patients with resectable colorectal liver metastases (CRLM), distinct histopathological growth patterns (HGPs) develop at the interface between the tumour and surrounding tissue. The desmoplastic (d) HGP is characterised by angiogenesis and a peripheral fibrotic rim, whereas non-angiogenic HGPs co-opt endogenous sinusoidal hepatic vasculature. Evidence from previous studies has suggested that patients with dHGP in their CRLM have improved prognosis as compared to patients with non-desmoplastic HGPs. However, these studies were relatively small and applied arbitrary cut-off values for the determination of the predominant HGP. We have now investigated the prognostic effect of dHGP in a large cohort of patients with CRLM resected either with or without neoadjuvant chemotherapy. Methods All consecutive patients undergoing a first partial hepatectomy for CRLM between 2000 and 2015 at a tertiary referral centre were considered for inclusion. HGPs were assessed in archival H&E stained slides according to recently published international consensus guidelines. The dHGP was defined as desmoplastic growth being present in 100% of the interface between the tumour and surrounding liver. Results In total, HGPs in CRLMs from 732 patients were assessed. In the chemo-naive patient cohort ( n = 367), the dHGP was present in 19% ( n = 68) and the non-dHGP was present in 81% ( n = 299) of patients. This dHGP subgroup was independently associated with good overall survival (OS) (HR: 0.39, p < 0.001) and progression-free survival (PFS) (HR: 0.54, p = 0.001). All patients with any CRLM with a non-dHGP had significantly reduced OS compared to those patients with 100% dHGP, regardless of the proportion of non-dHGP (all p values ≤ 0.001). In the neoadjuvantly treated patient cohort ( n = 365), more patients were found to express dHGP ( n = 109, 30%) (adjusted odds ratio: 2.71, p < 0.001). On univariable analysis, dHGP was associated with better OS (HR 0.66, p = 0.009) and PFS (HR 0.67, p = 0.002). However, after correction for confounding by means of multivariable analysis no significant association of dHGP with OS (HR 0.92, p = 0.623) or PFS (HR 0.76, p = 0.065) was seen. Conclusions The current study demonstrates that the angiogenic dHGP in CRLM resected from chemo-naive patients acts as a strong, positive prognostic marker, unmatched by any other prognosticator. This observation warrants the evaluation of the clinical utility of HGPs in prospective clinical trials. Electronic supplementary material The online version of this article (10.1007/s1045...

Background After resection of colorectal cancer liver metastases (CRLM) two main histopathological growth patterns can be observed; a desmoplastic and a non-desmoplastic subtype. The desmoplastic subtype has been associated with superior survival. These findings require external validation. Methods An international multicenter retrospective cohort study was conducted in patients treated surgically for CRLM at three tertiary hospitals in the US and the Netherlands. Determination of histopathological growth patterns was performed on hematoxylin & eosin stained sections of resected CRLM according to international guidelines. Patients displaying a desmoplastic histopathological phenotype (only desmoplastic growth observed) were compared to patients with a non-desmoplastic phenotype (any non-desmoplastic growth observed). Cut-off analyses on the extent of non-desmoplastic growth were performed. Overall (OS) and disease-free (DFS) survival were estimated using Kaplan-Meier and multivariable Cox analysis. All statistical tests were 2-sided. Results In total 780 patients were eligible. A desmoplastic phenotype was observed in 19.1% and was associated with microsatellite instability (14.6% versus 3.6%, p = .01). Desmoplastic patients had superior 5-year OS (73.4% [95% CI = 64.1–84.0] versus 44.2% [95% CI = 38.9–50.2], p &lt; .001) and DFS (32.0% [95% CI = 22.9–44.7] versus 14.7% [95% CI = 11.7–18.6], p &lt; .001) compared to their non-desmoplastic counterparts. A desmoplastic phenotype was associated with an adjusted hazard ratio for death of 0.36 (95% CI = 0.23–0.58), and 0.50 (95% CI = 0.37–0.66) for cancer recurrence. Prognosis was independent of KRAS and BRAF status. The cut-off analyses found no prognostic relationship between either OS or DFS and the extent of non-desmoplastic growth observed (all p &gt; .1). Conclusions This external validation study confirms the remarkably good prognosis after surgery for CRLM in patients with a desmoplastic phenotype. The extent of non-desmoplastic growth does not impact prognosis.

While the Wang nomogram had the best discriminatory ability relative to OS and DFS, no ICC staging system or nomogram demonstrated excellent prognostic discrimination. The AJCC staging for ICC performed reasonably, although its overall discrimination was only modest-to-good.

Background and ObjectivesPatients with isolated colorectal‐cancer‐liver‐metastases (CRCLM) frequently undergo metastatectomy. Tumor‐infiltrating‐lymphocytes (TILs) have prognostic potential in the setting of primary colorectal cancer, however, their role in CRCLM is less studied. We aimed to study the spatial distribution and prognostic role of tumor‐infiltrating CD8+ cytotoxic T‐cells and FoxP3+ regulatory T‐cells at the metastatic site of CRCLM patients.MethodsTILs were isolated from fresh metastatic tissues of 47 patients with CRCLM. Archived paraffin‐embedded tissue, from the same patients, was retrieved. CD8+ and FoxP3+ cells, both in the intra‐tumoral and the peri‐tumoral compartments, were measured by immunohistochemistry on full tissue sections. Proportions of cytotoxic T‐cells (CD8+) and regulatory T‐cells (CD4+CD25+FoxP3+), within CD45+TILs, were measured by flow‐cytometry.ResultsBy immunohistochemistry, individual densities of intra‐tumoral or peri‐tumoral CD8+ and FoxP3+ cells were not prognostic of survival. However, the intra‐tumoral, but not the peri‐tumoral, CD8+/FoxP3+ ratio was an independent predictor of survival (HR 0.43, 95%CI 0.19‐0.95, P = 0.032). By flow cytometry, the intra‐tumoral CD8+/regulatory T‐cell ratio was also an independent predictor of survival (HR 0.45, 95%CI 0.20‐0.99, P = 0.044).ConclusionsThe ratio of cytotoxic (CD8+) to regulatory (FoxP3+) T‐cells, in the intra‐tumoral compartment, but not in the peri‐tumoral compartment, can predict survival after resection of CRCLM.

Purpose: Liver metastasis develops in >50% of patients with colorectal cancer (CRC), and is a leading cause of CRC-related mortality. We aimed to identify which inhibitory immune checkpoint pathways can be targeted to enhance functionality of intra-tumoral T-cells in mismatch repair-proficient liver metastases of colorectal cancer (LM-CRC). Methodology: Intra-tumoral expression of multiple inhibitory molecules was compared among mismatch repair-proficient LM-CRC, peritoneal metastases of colorectal cancer (PM-CRC) and primary CRC. Expression of inhibitory molecules was also analyzed on leukocytes isolated from paired resected metastatic liver tumors, tumor-free liver tissues, and blood of patients with mismatch repair-proficient LM-CRC. The effects of blocking inhibitory pathways on tumor-infiltrating T-cell responses were studied in ex vivo functional assays. Results: Mismatch repair-proficient LM-CRC showed higher expression of inhibitory receptors on intra-tumoral T-cells and contained higher proportions of CD8+ T-cells, dendritic cells and monocytes than mismatch repair-proficient primary CRC and/or PM-CRC. Inhibitory receptors LAG3, PD-1, TIM3 and CTLA4 were higher expressed on CD8+ T-cells, CD4+ T-helper and/or regulatory T-cells in LM-CRC tumors compared with tumor-free liver and blood. Antibody blockade of LAG3 or PD-L1 increased proliferation and effector cytokine production of intra-tumoral T-cells isolated from LM-CRC in response to both polyclonal and autologous tumor-specific stimulations. Higher LAG3 expression on intra-tumoral CD8+ T-cells associated with longer progression-free survival of LM-CRC patients. Conclusion: Mismatch repair-proficient LM-CRC may be more sensitive to immune checkpoint inhibitors than mismatch repair-proficient primary CRC. Blocking LAG3 enhances tumor-infiltrating T-cell responses of mismatch repair-proficient LM-CRC, and therefore may be a new promising immunotherapeutic target for LM-CRC.

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Purpose This population-based study determined the cumulative incidence (CI) of local, regional, and distant recurrences, examined metastatic patterns, and identified risk factors for recurrence after curative treatment for CRC. Methods All patients undergoing resection for pathological stage I–III CRC between January 2015 and July 2015 and registered in the Netherlands Cancer Registry were selected (N = 5412). Additional patient record review and data collection on recurrences was conducted by trained administrators in 2019. Three-year CI of recurrence was calculated according to sublocation (right-sided: RCC, left-sided: LCC and rectal cancer: RC) and stage. Cox competing risk regression analyses were used to identify risk factors for recurrence. Results The 3-year CI of recurrence for stage I, II, and III RCC and LCC was 0.03 vs. 0.03, 0.12 vs. 0.16, and 0.31 vs. 0.24, respectively. The 3-year CI of recurrence for stage I, II, and III RC was 0.08, 0.24, and 0.38. Distant metastases were found in 14, 12, and 16% of patients with RCC, LCC, and RC. Multiple site metastases were found often in patients with RCC, LCC, and RC (42 vs. 32 vs. 28%). Risk factors for recurrence in stage I–II CRC were age 65–74 years, pT4 tumor size, and poor tumor differentiation whereas in stage III CRC, these were ASA III, pT4 tumor size, N2, and poor tumor differentiation. Conclusions Recurrence rates in recently treated patients with CRC were lower than reported in the literature and the metastatic pattern and recurrence risks varied between anatomical sublocations.