Growth Patterns Of Liver Metastases Research Articles

Histopathological growth pattern of liver metastases as an independent marker of metastatic behavior in different primary cancers.

Surgical resection can lead to prolonged survival in patients with isolated liver metastases (LM) from various primary cancers. However, there are currently no validated predictive markers to discriminate between these oligo/argometastatic patients, who will benefit from surgery, and those with diffuse metastatic behavior in whom surgery will be futile. To evaluate whether the tumor microenvironment, or histopathological growth pattern (HGP), of LM reflects the type of metastatic progression independently of the origin of the primary cancer, we analyzed a combined series of patients who underwent surgery for colorectal LM (N=263) or non-colorectal LM (N=66). HGPs of LM were scored in each patient to distinguish between desmoplastic HGP (all LM showing a complete encapsulated pattern) and non-desmoplastic HGP (at least one LM with some infiltrating-replacement component). In the entire series, 5-year overall and progression-free survival were, 44.5% and 15.5%, respectively, with no significant differences between colorectal and non-colorectal LM. In patients with desmoplastic HGP, 5-year overall and progression-free survival were 57% and 32%, respectively, as compared to 41% and 12%, respectively, in patients with non-desmoplastic-HGP (p=0.03 and 0.005). Irrespective of cancer origin and compared to traditional risk factors, desmoplastic HGP was the most significant predictor for better post-operative overall survival (adjusted HR: 0.62; 95% CI: [0.49-0.97]; p=0.035) and progression-free survival (adjusted HR: 0.61; 95% CI: [0.42-0.87], p=0.006). This suggests that the HGP of LM may represent an accurate marker that reflects the mode of metastatic behavior, independently of primary cancer type.

Association between primary tumor characteristics and histopathological growth pattern of liver metastases in colorectal cancer.

The microarchitecture of liver metastases (LMs), or histopathological growth pattern (HGP), has been demonstrated to be a significant prognostic factor in patients undergoing resection of colorectal liver metastases (CRLMs). Currently, however, HGP can be only determined on the operative specimen. Therefore, the development of new tools to predict the HGP of CRLMs before surgery and to understand the mechanisms that drive these patterns is important for improving individualization of therapeutic management. In this study, we analyzed data from a retrospective series of patients who underwent surgery for CRLMs to compare primary tumor characteristics, including markers of local aggressiveness and migratory capacity, and HGP of liver metastases. Data from a retrospective series of 167 patients who underwent curative-intent resection of CRLMs and in whom pathological samples from both primary tumor and liver metastases were available were reviewed. At the primary tumor level, KRAS mutational status, grade of differentiation, and tumor budding were assessed. HGP was scored in each resected CRLM, according to consensus guidelines, and classified as desmoplastic (dHGP) or non-desmoplastic (non-dHGP). Associations between primary tumor characteristics and HGP of CRLMs were evaluated using a binary logistic regression model. Overall survival and disease-free survival were evaluated using Kaplan-Meier and multivariable Cox regression analyses. CRLMs were classified as dHGP in 36% of the patients and as non-dHGP in 64%. Higher rates of moderately or poorly differentiated primary tumors were observed in the non-dHGP CRLM group (80%), as compared with the dHGP group (60%) (OR = 3.6; 95%CI: 1.6-7.05; p = 0.001). Higher rates of tumor budding were observed in the non-dHGP CRLM group, with a median tumor budding value of 4 as compared with 2.5 in the dHGP group (p = 0.042). In the entire series, 5-year overall and disease-free survival were 43% and 32.5%, respectively. The non-dHGP CRLM group had worse post-hepatectomy survival, with 5-year overall and disease-free survival of 32.2% and 24.6%, respectively, as compared with 60.8% and 45.9%, respectively, for the dHGP group (p = 0.02). Colorectal tumors with moderate or poor differentiation and those with high tumor budding are more frequently associated with CRLMs with a non-dHGP. This suggests that primary tumor characteristics of local aggressiveness and migratory capacity could preferentially promote the development of CRLMs with an infiltrating pattern and that these parameters should be considered as part of new scores for predicting HGP before surgery. This finding may stimulate new lines of research for more individualized therapeutic decision in patients with CRLM candidate to surgery.

Association between primary tumor characteristics and histopathological growth pattern of liver metastases in colorectal cancer

Association between primary tumor characteristics and histopathological growth pattern of liver metastases in colorectal cancer

Histological growth patterns of colorectal cancer liver metastases: a strong prognostic marker associated with invasive patterns of the primary tumor and p53 alteration

The histological growth pattern of liver metastases (desmoplastic, pushing, and replacement patterns) at the tumor-liver parenchymal interface is a prognostic factor in patients with colorectal cancer. However, data regarding its association with the primary tumor characteristics and molecular alterations are limited. This study evaluated the histological growth pattern in 136 cases of colorectal cancer liver metastases without preoperative treatment, comparing it with the clinicopathological features of the primary tumor. Liver metastasis exhibiting predominantly non-desmoplastic pattern (<50%), observed in 74 cases (54%), was associated with hepatic vein invasion (P=0.025), worse recurrence-free survival (P<0.001) and overall survival (P=0.008). In multivariate analyses, multiple tumors (P<0.001) and non-desmoplastic patterns (P=0.009) were associated with worse recurrence-free survival, and tumor size (P=0.025) and non-desmoplastic pattern (P=0.025) were associated with worse overall survival. In 88 patients with available primary tumor tissue slides, non-desmoplastic pattern in the liver metastasis was associated with high-grade tumor budding (P=0.002), high-grade poorly differentiated cluster (P=0.021), absence of mucinous histology (P=0.016), and aberrant p53 expression (complete loss or overexpression; P0.001) of the primary colorectal cancer. In conclusion, the histological growth pattern in liver metastasis was a strong and independent prognostic factor for colorectal cancer. Our observations highlight the significant associations between histological growth patterns in liver metastases and histopathological features of the primary tumor, especially invasive front morphology and p53 aberration.

34P The interrelations between CLIC 1 expression and the histological growth pattern of liver metastases of digestive origin

Chloride intracellular channel 1 (CLIC1) is expressed by several malignancies, and it is involved in cell migration and metastasis. The histological growth pattern (HGP) such as desmoplastic (DGP), replacement (RGP), pushing (PGP) and mixed has been noticed in the liver metastases of colorectal, pancreatic, gastric, breast and uveal melanoma origin. The aim of this abstract is to determine the CLIC 1 immunoexpression variability amongst different liver metastasis HGP.

Association between the histopathological growth patterns of liver metastases and survival after hepatic surgery in breast cancer patients

Currently, there are no markers to identify patients with liver-only or liver-dominant metastases that would benefit from hepatic surgery. Here we characterized histopathological growth patterns (HGPs) of liver metastases in a consecutive series of 36 breast cancer patients who underwent hepatic surgery. Survival analyses showed that the presence of a desmoplastic HGP in the liver metastases (a rim of fibrous tissue separating cancer cells from the liver parenchyma, present in 20 (56%) patients) is independently associated with favorable progression-free and overall survival when compared with the replacement HGP (cancer cells growing into the liver parenchyma, present in 16 (44%) patients).

Can medical imaging identify the histopathological growth patterns of liver metastases?

The histopathological growth patterns (HGPs) of liver metastases of colorectal cancer and of several other tumor types predict outcome of patients in multiple studies. The HGPs of liver metastases have a prognostic but also a predictive value with one of the growth patterns, the replacement growth pattern, related to resistance to systemic treatment. Given that the HGP can only be assessed in a reliable manner when a surgical resection of the metastasis has been performed, this biomarker cannot be exploited to the full. For example, HGPs can at this moment, not be used to decide whether patients with liver metastatic breast or colorectal cancer will benefit or not from locoregional treatment, such as surgery or radiotherapy, and from peri-operative systemic treatment. In this review we highlight studies that suggest that the HGPs of liver metastases can be identified by medical imaging. Although still to be confirmed by a prospective multicenter approach, some studies indeed achieve a high accuracy in predicting the HGPs by applying radiomic algorithms on CT- or MR-images of liver metastases. This is an important step towards a treatment planning of patients with liver metastatic cancer that takes into account the biology and the progression kinetics of the metastases.

Liver Metastases and Histological Growth Patterns: Biological Behavior and Potential Clinical Implications-Another Path to Individualized Medicine?

Colorectal cancer is a major health burden and despite the recent advances in healthcare and screening programs, a great percentage of patients already present metastases once their disease is found. In those cases, liver surgery has an essential role, but even with neoadjuvant chemotherapy there is a high rate of intrahepatic recurrence. New prognostic factors are needed in order to decide the best surgical approach considering the biological behavior of the tumors in order to tailor the used therapies, moving towards individualized medicine/treatment. However, the majority of the factors described in literature are expensive, time consuming, and difficult to apply on a daily basis. Histological growth patterns have emerged over the past few years as a reproducible characteristic, an easy to apply one, and with very low costs since it only needs the standard Haematoxylin and Eosin stained slides of observation. In this article, we provide a review of the histological growth patterns of liver metastases and their prognostic significance, biological meaning, and therapeutic importance.

Inflammation and uPAR-Expression in Colorectal Liver Metastases in Relation to Growth Pattern and Neo-adjuvant Therapy.

Proteolytic activity and inflammation in the tumour microenvironment affects cancer progression. In colorectal cancer (CRC) liver metastases it has been observed that three different immune profiles are present, as well as proteolytic activity, determined by the expression of urokinase-type plasminogen activator (uPAR).The main objectives of this study were to investigate uPAR expression and the density of macrophages (CD68) and T cells (CD3) as markers of inflammation in resected CRC liver metastases, where patients were neo-adjuvantly treated with chemotherapy with or without the angiogenesis inhibitor bevacizumab. Chemonaive patients served as a control group. The markers were correlated to growth patterns (GP) of liver metastases, i.e. desmoplastic, pushing and replacement GP. It was hypothesised that differences in proteolysis and inflammation could reflect tumour specific growth and therapy related changes in the tumour microenvironment. In chemonaive patients, a significantly higher level of uPAR was observed in desmoplastic liver metastases in comparison to pushing GP (p = 0.01) or replacement GP (p = 0.03). A significantly higher density of CD68 was observed in liver metastases with replacement GP in comparison to those with pushing GP (p = 0.01). In liver metastases from chemo treated patients, CD68 density was significantly higher in desmoplastic GP in comparison to pushing GP (p = 0.03). In chemo and bevacizumab treated patients only a significant lower CD3 expression was observed in liver metastases with a mixed GP than in those with desmoplastic (p = 0.01) or pushing GP (p = 0.05). Expression of uPAR and the density of macrophages at the tumour margin of liver metastasis differ between GP in the untreated patients. A higher density of T cells was observed in the bevacizumab treated patients, when desmoplastic and pushing metastases were compared to liver metastases with a mix of the GP respectively, however no specific correlations between the immune markers of macrophages and T cells or GP of liver metastases could be demonstrated.

Tissue inhibitor of matrix metalloproteinase-1 expression in colorectal cancer liver metastases is associated with vascular structures.

Metastatic growth by colorectal cancer cells in the liver requires the ability of the cancer cells to interact with the new microenvironment. This interaction results in three histological growth patterns of liver metastases: desmoplastic, pushing, and replacement. In primary colorectal cancer several proteases, involved in the degradation of extracellular matrix components, are up‐regulated. In liver metastases, their expression is growth pattern dependent. Tissue inhibitor of matrix metalloproteinase‐1 (TIMP‐1) is a strong prognostic marker in plasma from colorectal cancer patients, with significant higher levels in patients with metastatic disease. We therefore wanted to determine the expression pattern of TIMP‐1 in primary colorectal cancers and their matching liver metastases. TIMP‐1 mRNA was primarily seen in α‐smooth‐muscle actin (α‐SMA)‐positive cells. In all primary tumors and liver metastases with desmoplastic growth pattern, TIMP‐1 mRNA was primarily found in α‐SMA‐positive myofibroblasts located at the invasive front. Some α‐SMA‐positive cells with TIMP‐1 mRNA were located adjacent to CD34‐positive endothelial cells, identifying them as pericytes. This indicates that TIMP‐1 in primary tumors and liver metastases with desmoplastic growth pattern has dual functions; being an MMP‐inhibitor at the cancer periphery and involved in tumor‐induced angiogenesis in the pericytes. In the liver metastases with pushing or replacement growth patterns, TIMP‐1 was primarily expressed by activated hepatic stellate cells at the metastasis/liver parenchyma interface. These cells were located adjacent to CD34‐positive endothelial cells, suggesting a function in tumor‐induced angiogenesis. We therefore conclude that TIMP‐1 expression is growth pattern dependent in colorectal cancer liver metastases. © 2015 The Authors. Molecular Carcinogenesis published by Wiley Periodicals, Inc.

Growth patterns of liver metastases as compared to resected tumors of the same colorectal cancer patients.

519 Background: Colorectal cancer (CRC) affects one million people a year. 25% of the patients have metastatic disease at the time of diagnosis. Metastatic disease is one of the major challenges in the treatment of cancer. Even though the TNM staging system is a good prognostic marker, tumours have a biological diversity that cannot be evaluated by the TNM system. Recently three different growth patterns of CRC liver metastases were identified. The aim of this study was to determine the growth patterns of CRC liver metastases from patients with more than one metastasis. Methods: A pilot study was conducted including 34 patients resected for CRC liver metastases, 28 patients selected from a database of 200 patients, operated in Copenhagen between 2007-2010 and 6 patients, operated in Montreal. From these 34 patients, 15 patients were resected for two or more liver metastases. All paraffin embedded tissue sections were stained for reticulin and haematoxylin and eosin at the Finsen Laboratory. Evaluation of the growth pattern was done by three different observers from Antwerp and Copenhagen. Reproducibility was &gt;90%. Results: In the fifteen patients, 9 from Copenhagen and 6 from Montreal, that had multiple hepatic metastases, there was uniformity in the growth pattern of the individual metastases. 40% had a desmoplastic, 33% a pushing and 20% a replacement growth pattern and 7% had a mix pattern. Of the 9 patients from Copenhagen 33% were synchronous and 67% metachronous metastases. Within patients, all patterns were identical. Conclusions: The uniformity of growth patterns seen in each patient suggests that these patterns are not random. The identical growth pattern may be determined by specific interactions between the tumor and the host microenvironment, as postulated by Paget’s seed and soil theory. This could represent three different stromal and cytokine responses or oncogenic pathway responses and could represent metastatic tumour growth in different microenvironments.

Histopathological Growth Pattern, Proteolysis and Angiogenesis in Chemonaive Patients Resected for Multiple Colorectal Liver Metastases

The purpose of this study was to characterise growth patterns, proteolysis, and angiogenesis in colorectal liver metastases from chemonaive patients with multiple liver metastases. Twenty-four patients were included in the study, resected for a median of 2.6 metastases. The growth pattern distribution was 25.8% desmoplastic, 33.9% pushing, and 21% replacement. In 20 patients, identical growth patterns were detected in all metastases, but in 8 of these patients, a second growth pattern was also present in one or two of the metastases. In the remaining 4 patients, no general growth pattern was observed, although none of the liver metastases included more than two growth patterns. Overall, a mixed growth pattern was demonstrated in 19.3% of the liver metastases. Compared to metastases with pushing, those with desmoplastic growth pattern had a significantly up-regulated expression of urokinase-type plasminogen activator receptor (P = 0.0008). Angiogenesis was most pronounced in metastases with a pushing growth pattern in comparison to those with desmoplastic (P = 0.0007) and replacement growth pattern (P = 0.021). Although a minor fraction of the patients harboured metastases with different growth patterns, we observed a tendency toward growth pattern uniformity in the liver metastases arising in the same patient. The result suggests that the growth pattern of liver metastases is not a random phenomenon.

Two distinct expression patterns of urokinase, urokinase receptor and plasminogen activator inhibitor-1 in colon cancer liver metastases

With great interest we read the article Two distinct expression patterns of urokinase, urokinase receptor and plasminogen activator inhibitor-1 (PAI1) in colon cancer liver metastases’ by Martin Illemann et al. The authors describe 2 distinct patterns of the expression of urokinase-type plasminogen activator (uPA), urokinase-type plasminogen activator receptor (uPAR), and PAI1 in 14 colon cancer liver metastases that correlate closely with 2 morphological growth patterns. In the liver metastases with a predominantly desmoplastic reaction at the periphery, the expression of uPAR, uPA and PAI1 is very similar to that found in the primary colon tumours. These molecules were primarily expressed in stromal cells at the metastases’ periphery. Furthermore, uPAR and uPA were also expressed in a subset of budding cancer cells at the tumour interface. In the liver metastases of which the growth is characterised by direct contact between the cancer cells and the hepatocytes on the contrary, uPAR and uPA-mRNA expression were only seen associated with the presence of necrosis within the liver metastases. In addition, PAI1-immunoreactivity was in all liver metastases seen in hepatocytes at the metastases periphery. We have been studying growth patterns of human colorectal cancer metastases for many years now. As mentioned by Illeman et al., we described 3 different growth patterns with differences in angiogenesis and desmoplasia. In the desmoplastic growth pattern, the metastases are separated from the surrounding liver parenchyma by a rim of desmoplastic stroma in which a dense inflammatory infiltrate and numerous capillaries are present. In the pushing pattern, liver cell plates are pushed aside and run in parallel with the circumference of the metastases at the tumour–liver parenchyma interface. There is no desmoplastic stroma formation. In the nonangiogenic replacement growth pattern, tumour cells replace hepatocytes in the liver plates, at the interface or throughout the metastasis, conserving tissue architecture of the liver, without inflammation or fibrosis. The growth pattern of liver metastases seems not only to vary between tumours of the same histological subtype, but also between tumours of a different subtype. Although liver metastases of patients with colorectal cancer grow according to the desmoplastic , pushing and replacement growth pattern in, respectively, 42, 46 and 12%, liver metastases of patients with breast cancer on the contrary grow according to the replacement growth pattern in virtually all cases. Although we have published data that show important differences in hypoxia and angiogenesis between the different growth patterns, the biology and underlying molecular mechanisms of the different growth pattern of liver metastases remain largely unknown. Therefore, the findings of Illeman et al. regarding different expression of 3 key components of the uPA extracellular protease system in metastases with a desmoplastic and pushing growth pattern are important. In this letter, we would like to add extra data suggesting a role not only in liver metastases of patients with colorectal cancer, but also of patients with breast cancer. In a study of differential expression of hypoxia and (lymph)angiogenesis-related genes at different metastatic sites in breast cancer, uPA (in that paper called PLAU) was among the 49 genes that were differentially expressed between primary tumours and/or lymph node metastases and/or liver metastases. The expression of uPA was higher in liver metastases compared with primary breast tumours and to lymph node metastases. There was no significant difference between the expression of uPA between primary breast tumours and lymph node metastases. uPAR and PAI1 were not investigated in that study. To further explore possible differences in expression of the uPA system between breast cancer localisations in different organs, we now analysed the expression of uPA, uPAR and PAI1 using the data described in that paper. The localisations were grouped in primary tumours (n 5 11), lymph node metastases (n 5 15), liver metastases (n 5 4), lung metastases (n 5 8) and other metastases (n 5 24). For a detailed description of materials and methods, we refer to the previous publication. Figure 1 represents the results. The median mRNA expression for uPA was significantly lower in liver metastases compared with primary tumours (p 5 0.04) and lymph node metastases (p 5 0.04). There was a borderline significant difference in uPA mRNA expression between liver metastases and other metastases (p 5 0.09), and there was no difference between liver metastases and lung metastases. There was a significantly higher mRNA expression of PAI1 in liver metastases than in lymph node metastases (p 5 0.04) and a borderline significant higher expression in liver metastases than in primary tumours (p 5 0.08). There were no significant differences in the expression of uPAR between liver metastases and other tumour sites. Furthermore, there was a significantly higher PAI1 expression in lung metastases, than in primary tumours (p 5 0.009), lymph node metastases (p 5 0.002) and other metastases (p 5 0.03) and there was a