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Complement activation in astrocytomas: deposition of C4d and patient outcome

Katri Mäkelä14*, Pauli Helén2, Hannu Haapasalo13 and Timo Paavonen13

Author affiliations

1 Department of Pathology, University of Tampere Medical School, Tampere, Finland

2 Unit of Neurosurgery, Tampere University Hospital, Tampere, Finland

3 Department of Pathology, Fimlab laboratories, Tampere University Hospital, Tampere, Finland

4 University of Tampere, School of Medicine, Biokatu 6, Tampere 33520, Finland

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Citation and License

BMC Cancer 2012, 12:565  doi:10.1186/1471-2407-12-565

Published: 1 December 2012



C4d 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.


Tissue 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.


The 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).


The worsening of patient outcome and malignant progression of tumor cells seem to be connected to microenvironmental changes evoked by chronically activated complement.

Astrocytoma; Glioblastoma; C4d; Complement; Inflammation; Survival; Immunohistochemistry