Abstract
BackgroundC4d is a cleavage product of complement component C4 and is considered to serve as a marker for the site of complement activation. In this study C4d staining of grade I-IV astrocytic tumors was studied to explore if there is an association between complement activation and the grade of tumor, or patient survival.MethodsTissue micro-array samples of 102 astrocytomas were stained immunohistochemically. The material consisted of 9 pilocytic astrocytomas and 93 grade II-IV astrocytomas, of which 67 were primary resections and 26 recurrent tumors. The intensity of C4d staining as well as extent of C4d and CD34 staining were evaluated. The intensity of C4d staining was scored semiquantitatively. The extent of the staining was counted morphometrically with a point counting grid yielding a percent of C4d and CD34 positive area of the sample.ResultsThe intensity and extent of C4d staining increased in grade II-IV diffusely infiltrating astrocytoma tumors in line with the malignancy grade (p = 0.034 and p = 0.016, respectively, Kruskal-Wallis test). However, C4d positive tumor area percentages were higher in grade I pilocytic astrocytomas than in grade II-IV diffusely infiltrating astrocytomas (p = 0.041, Mann–Whitney test). There was a significant correlation between CD34 positive and C4d positive endothelial area fraction in diffusely infiltrating astrocytomas (p < 0.001, Pearson correlation). In these tumors, the increasing intensity of C4d staining was also associated with worsened patient outcome (p = 0.014, log-rank test).ConclusionThe worsening of patient outcome and malignant progression of tumor cells seem to be connected to microenvironmental changes evoked by chronically activated complement.
Highlights
C4d is a cleavage product of complement component C4 and is considered to serve as a marker for the site of complement activation
The C4d positive tumor area fractions of astrocytomas were between 0–84.7%, the mean value being 6.7%
We found a correlation between the CD34 positive area fraction and C4d positive endothelial area fraction in diffusely infiltrating astrocytoma samples
Summary
C4d is a cleavage product of complement component C4 and is considered to serve as a marker for the site of complement activation. Grade I astrocytomas are called pilocytic astrocytomas They are considered benign as they have a clear borderline and are generally slow growing. Grade IIIV astrocytomas have a diffuse growing manner and lack a clear borderline. They are referred to as Complement is an innate component of the immune system. It can be initiated by three different pathways, including the classical pathway, lectin pathway and the alternative pathway [2]. There is no apparent biological function associated with C4d alone [4], but due to its covalent binding and relatively long half-life, it can be considered as an activation marker of the classical and lectin pathways of complement. The classical and lectin pathways are known to involve C4d, whilst in the alternative pathway there is no cleavage of the C4 component [5]
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