Immunohistochemical estimation of cell cycle entry and phase distribution in astrocytomas: applications in diagnostic neuropathology

Abstract

An immunohistochemical method for assessing cell cycle phase distribution in neurosurgical biopsies would enable such data to be incorporated into diagnostic algorithms for the estimation of prognosis and response to adjuvant chemotherapy in glial neoplasms, without the requirement for flow cytometric analysis. Paraffin-embedded sections of intracerebral gliomas (n = 48), consisting of diffuse astrocytoma (n = 9), anaplastic astrocytoma (n = 8) and glioblastoma (n = 31), were analysed by immunohistochemistry using markers of cell cycle entry, Mcm-2 and Ki67, and putative markers of cell cycle phase, cyclins D1 (G1-phase), cyclin A (S-phase), cyclin B1 (G2-phase) and phosphohistone H3 (Mitosis). Double labelling confocal microscopy confirmed that the phase markers were infrequently coexpressed. Cell cycle estimations by immunohistochemistry were corroborated by flow cytometric analysis. There was a significant increase in Mcm-2 (P < 0.0001), Ki67 (P < 0.0001), cyclin A (P < 0.0001) and cyclin B1 (P = 0.002) expression with increasing grade from diffuse astrocytoma through anaplastic astrocytoma to glioblastoma, suggesting that any of these four markers has potential as a marker of tumour grade. In a subset of glioblastomas (n = 16) for which accurate clinical follow-up data were available, there was a suggestion that the cyclin A:Mcm-2 labelling fraction might predict a relatively favourable response to radical radiotherapy. These provisional findings, however, require confirmation by a larger study. We conclude that it is feasible to obtain detailed cell cycle data by immunohistochemical analysis of tissue biopsies. Such information may facilitate tumour grading and may enable information of prognostic value to be obtained in the routine diagnostic laboratory.

Serum α2-HS Glycoprotein Predicts Survival in Patients with Glioblastoma

“…The prognostic value of serum AHSG was validated in a separate group of GBM patients treated in 2 different centers. The functional significance of these findings is supported by the observation that low serum AHSG concentration correlates with increased tumor proliferation (high Ki67 immunolabeling index) (24,25 ). The negative correlation of serum AHSG with tumor lipids and positive correlation with myoinositol suggests that serum AHSG inversely correlates with the fractional necrosis of GBM and hence its malignancy (12,26 ).…”

Minichromosome maintenance proteins 2, 3 and 7 in medulloblastoma: overexpression and involvement in regulation of cell migration and invasion

“…To date, most studies have focused on MCM2 expression alone. A high level of MCM2 proteins was linked to advanced stages of breast cancer, non-small-cell lung carcinoma, esophageal squamous cell carcinoma, colorectal cancer, gliomas and urothelial carcinoma (Ramnath et al, 2001;Wharton et al, 2001;Rodins et al, 2002;Gonzalez et al, 2003;Kato et al, 2003;Korkolopoulou et al, 2005;Scott et al, 2005;Hanna-Morris et al, 2009). The aberrant expression of MCM2 was also correlated with poor prognosis in patients (Meng et al, 2001;Ramnath et al, 2001;Wharton et al, 2001;Rodins et al, 2002;Korkolopoulou et al, 2005).…”

Clinical Significance of MCM-2 and MCM-5 Expression in Colon Cancer: Association with Clinicopathological Parameters and Tumor Proliferative Capacity

“…In this context, increased MCM protein expression has been reported in malignant tumors, including colon [14], cervix [15], breast [9], esophagus [16], kidney [8], brain [12,17], lung [18], thyroid [19], and prostate [20]. MCM protein expression was shown to be associated with important clinicopathological parameters, and patients' survival, presenting superior predictive value than the conventional index of proliferative capacity, Ki-67, in several of these tumors, and thus they could be considered as indicators of poor prognosis.…”