The Morphological Growth Patterns of Colorectal Liver Metastases are Prognostic for Overall Survival

Kåre Nielsen; Hans C Rolff; Rikke L Eefsen; Ben Vainer


Mod Pathol. 2014;27(12):1641-1648. 

In This Article

Abstract and Introduction


Colorectal metastases in the liver grow according to three histological patterns: a pushing pattern, a replacement pattern, and a desmoplastic pattern. The objective of the current study was to explore the prognostic significance of these three growth patterns for survival. The study included 217 consecutive patients, liver resected between 2007 and 2011 due to hepatic metastases from colorectal adenocarcinoma. The growth patterns were assessed on archival hematoxylin and eosin-stained tissue sections. In 150 metastases, the density of the immune cell infiltrate at the tumor periphery was judged by a semi-quantitative method. The prevalence of the pushing-type, the desmoplastic-type, and the replacement-type was 33%, 32%, and 11%, respectively; 24% of the metastases displayed a mixed pattern. Kaplan–Meier analysis and Cox regression demonstrated a prognostic significance of the growth patterns (P=0.0006, log-rank test), as the replacement pattern appeared as an independent predictor of poor overall survival. For patients with replacement growth, the hazard of death was 2–2.5 times higher than for patients with pushing growth (P=0.004, cox regression) or mixed growth (P=0.01), and nearly four times higher than for patients with desmoplastic growth (P<0.0001). The negative prognostic effect of the replacement growth pattern was even more pronounced after adjusting for tumor size. Desmoplastic growth corresponded with small tumor size, dense lymphocytic infiltration and a more favorable prognosis. Eventually, the growth patterns may contribute to a histology-based prognostic biomarker for patients with colorectal liver metastases.


During the last 5–10 years, major advances have been made in both the medical and surgical treatment of liver metastases from colorectal carcinoma. The number of patients who undergo liver resection with curative intent has therefore increased significantly. However, so far, little is known on the biological, clinical, and histopathological features that determine prognosis after hepatic resection. The revised and more active treatment strategy has thus fostered a demand for new and better prognostic and predictive markers that can be used for selecting the right treatment regimen for each patient. For primary colorectal cancer, the malignant transformation from adenoma to carcinoma is by now very well described; far less described are the events that govern the progression of metastases in the liver. A greater understanding of the diverse infiltration mechanisms of the metastases, including the intricate interaction with the hepatic microenvironment, might lead to new prognostic and therapeutic prospects.

Vermeulen et al[1] identified three histological growth patterns for colorectal liver metastases, suggesting biological differences: (i) a pushing growth pattern, in which the metastasis expands by compression of the surrounding liver parenchyma, pushing the liver cell plates aside; (ii) a desmoplastic growth pattern, in which a fibrous rim separates the metastasis from the liver parenchyma; and (iii) a replacement growth pattern, in which tumor cells infiltrate the liver cell plates, replacing the hepatocytes while co-opting hepatic stroma and sinusoids. Examples of the three types of expansion are included in Figure 1. The growth patterns differ with respect to angiogenesis, as replacement-type metastases exert virtually no angiogenic properties at the invasive front.[1–4] The desmoplastic growth pattern is consistent with high proteolytic activity.[4,5]

Figure 1.

Microphotographs of colorectal adenocarcinoma liver metastases (hematoxylin and eosin-stained sections; T, tumor; L, liver parenchyma; D, desmoplastic rim). (a and b) show a metastasis of the pushing-type. The metastasis grows by compression of the liver parenchyma. Along the edge of the tumor, liver cell plates are strongly narrowed and run in parallel with the tumor invasion front. In (c and d), a metastasis with replacement growth is depicted. (c) shows how the tumor tissue preserves the architecture of the hepatic tissue. The reticulin framework of the liver tissue is conserved in the peripheral 10–20 cell rows of the tumor. (d) shows the intimate cell–cell contacts between tumor cells and hepatocytes. In (e and f) a metastasis is depicted with a desmoplastic growth pattern. The metastasis is separated from the surrounding liver parenchyma by desmoplastic stroma. Typically, the desmoplastic rim presents as two compartments: a dense part toward the tumor and an edematous part toward the liver tissue harboring an intense immune cell infiltrate.

Although the morphological categorization described by Vermeulen et al[3] has been recognized in various studies, the prognostic significance remains controversial. Van den Eynden et al[3] identified pushing growth as an independent predictor of poor 2-year survival, whereas Nagashima et al[6] found a detrimental effect of an infiltrative tumor margin similar to the replacement pattern. Several studies comparing metastases with and without desmoplastic encapsulation have reported a positive impact on survival of desmoplasia per se.[7–13] In consequence, the aim of the present study was in a population treated according to modern guidelines and indications to examine the prognostic value of the histological growth patterns for survival.