The microenvironment of liver metastases from Colorectal adenocarcinoma: -studies of histopathology and growth patterns

Colorectal adenocarcinoma (CRC) is the third most frequent cancer type worldwide and the third leading cause of cancer related death. During the course of the disease about 50% of patients are diagnosed with metastatic CRC (mCRC). The 5-year survival for patients who undergo a hepatic resection is about 40% and up to 58% in selected groups of patients, while the median overall survival for patients who receive palliative treatment has been reported to be from a few months and up to about 24 months, depending on dissemination of the cancer and response to treatment. The
initial neo-adjuvant treatment is crucial for patients with potential resectable liver metastases, allowing a subsequent hepatic resection if treatment have a downsizing effect on metastases.Antineoplastic agents include chemotherapy (e.g. 5-fluorouracil, oxaliplatin and irinotecan) or a
combination of chemotherapy and targeted drugs such as the vascular endothelial growth factor (VEGF) inhibitor bevacizumab or the epidermal growth factor receptor inhibitors (e.g. cetuximab or panitumumab). KRAS and NRAS mutational status predicts efficacy of EGFR-inhibitors, but a
predictive marker for bevacizumab is lacking. Three histological growth patterns (GP) have been observed in liver metastases: desmoplastic GP where a collagenous rim separates the metastatic tumour cells from the
surrounding liver parenchyma, pushing GP where tumour cells grow expansively, pushing and flattening the surrounding hepatocytes and replacement GP where infiltrative growth of tumour cells replace the hepatocytes, preserving the existing liver architecture. The desmoplastic GP correlates to a superior survival, but the prognostic impact of desmoplasia in relation to neoadjuvant therapy. It has been observed that the pushing GP correlates to a higher degree of angiogenesis in comparison to the remaining GPs. Furthermore, urokinase-type plasminogen activator receptor (uPAR) in plasma is correlates to a poor prognosis in CRC. Expression of uPAR in CRC liver metastases seem to depend on GP as a higher uPAR level is observed in desmoplastic
GP in comparison to pushing GP. Moreover, it has been observed that three different immune profiles appear in liver metastases from CRC, but the profiles have not been related to GPs.This study included a patient population (n=254), who underwent a hepatic resection of CRC liver metastases at Rigshospitalet in years 2007 to 2011. The patients were grouped according to neo-adjuvant therapy: untreated, chemo treated or treated with chemotherapy plus bevacizumab. GP of CRC liver metastasis was investigated and findings were correlated to recurrence free and overall survival as well as relation to neo-adjuvant therapy. GP of CRC liver
11 metastasis was also correlated to angiogenesis, proteolysis and inflammation by macrophage and T cell density. A longer recurrence free and overall survival was observed for patients resected for CRC liver metastases with a desmoplastic GP. The finding was independent of neo-adjuvant therapy. Liver metastases from patients with multiple lesions had the same GP within the individual liver in 38% of the cases. A reduced microvessel density was observed in liver metastases from patients who received chemotherapy and bevacizumab as neo-adjuvant therapy in comparison to chemo treated and untreated patients. In the total patient population as well as in the chemonaive patientss a significantly shorter recurrence free survival was observed in patients with highly proliferative metastases, measured by Ki67 expression, in comparison to metastases with no Ki67 expression. Furthermore, the uPAR expression was significantly higher in desmoplastic liver metastases in comparison to pushing and replacement GP. A significantly higher density of
macrophages was observed in replacement GP in comparison to pushing GP in the untreated patient population (p=0.013), while the T cell infiltration only differed between GPs in the bevacizumab treated patients, where T cell density was significantly higher in desmoplastic and pushing incomparison to the mixed liver metastases.