Molecular Advances in Glioblastoma Neuropathology

Glioblastoma is the most frequent and malignant brain tumor with a wide variety of morphological appearances. For a long time, the tumors were classified either as primary (“de novo”) glioblastomas that develop rapidly in elderly patients or as secondary glioblastomas with clinical or histological progression from low-grade diffuse astrocytoma or anaplastic astrocytoma. Recent data from the comprehensive genetic characterization of these tumors identified a number of common and diverging alterations and pathways that allow future stratification of glioblastomas into several age-dependent biological subgroups. While the histological classification of diffuse gliomas based on the WHO grading scheme is still necessary, the use of additional meaningful immunohistochemical (and mutation-specific) markers, such as IDH R132H, ATRX, and H3F3A K27M, has improved routine diagnosis. In recent years, the spectrum of clinically relevant molecular markers has expanded. The utility of MGMT, ATRX, TERT, H3F3A and LOH 1p/19q in predicting prognosis and response to therapy in routine diagnostic settings is discussed

Prognostic value of tumour volume in patients with a poor Karnofsky performance status scale – a bicentric retrospective study

Backround: Median overall survival (OS) after diagnosis of glioblastoma (GBM) remains 15 months amongst patients receiving aggressive surgical resection, chemotherapy and irradiation. Treatment of patients with a poor preoperative Karnofsky Performance Status Scale (KPSS) is still controversial. Therefore, we retrospectively assessed the outcome after surgical treatment in patients with a KPSS of ≤60%. Methods: We retrospectively included patients with a de-novo glioblastoma WHO °IV and preoperative KPSS ≤60%, who underwent surgery at two neurosurgical centres between September 2006 and March 2016. We recorded pre- and postoperative tumour volume, pre- and postoperative KPSS, OS, age and MGMT promoter status. Results: One hundred twenty-three patients (58 females/65 males, mean age 67.4 ± 13.4 years) met the inclusion criteria. Seventy-five of the 123 patients (61%) underwent surgical resection. 48/123 patients (39%) received a biopsy. The median preoperative and postoperative tumour volume of all patients was 33.0 ± 31.3 cm3 (IR 15.0–56.5cm3) and 3.1 ± 23.8 cm3 (IR 0.2–15.0 cm3), respectively. The median KPSS was 60% (range 20–60%) preoperatively and 50% (range 0–80%) postoperatively. Patients who received a biopsy showed a median OS for patients who received a biopsy only was 3.0 months (95% CI 2.0–4.0 months), compared to patients who had a resection and had a median OS of 8 months (95% CI 3.1–12.9 months). Age (p < 0.001, HR: 1.045 [95% CI 1.022–1.068]), postoperative tumour volume (p = 0.02, HR: 1.016 [95% CI 1.002–1.029]) and MGMT promotor status (p = 0.016, HR: 0.473 [95% CI 0.257–0.871]) were statistically significant in multivariate analysis. In subgroup analyses only age was shown as a significant prognostic factor in multivariate analyses for patients receiving surgery (p < 0.001, HR: 1.046 [95% CI 1.022–1.072]). In the biopsy group no significant prognostic factors were shown in multivariate analysis. Conclusion: GBM patients with a preoperative KPSS of ≤60% might profit from surgical reduction of tumour burden

Increased mRNA expression of CDKN2A is a transcriptomic marker of clinically aggressive meningiomas

Homozygous deletion of CDKN2A/B was recently incorporated into the World Health Organization classification for grade 3 meningiomas. While this marker is overall rare in meningiomas, its relationship to other CDKN2A alterations on a transcriptomic, epigenomic, and copy number level has not yet been determined. We therefore utilized multidimensional molecular data of 1577 meningioma samples from 6 independent cohorts enriched for clinically aggressive meningiomas to comprehensively interrogate the spectrum of CDKN2A alterations through DNA methylation, copy number variation, transcriptomics, and proteomics using an integrated molecular approach. Homozygous CDKN2A/B deletions were identified in only 7.1% of cases but were associated with significantly poorer outcomes compared to tumors without these deletions. Heterozygous CDKN2A/B deletions were identified in 2.6% of cases and had similarly poor outcomes as those with homozygous deletions. Among tumors with intact CDKN2A/B (without a homozygous or heterozygous deletion), we found a distinct difference in outcome based on mRNA expression of CDKN2A, with meningiomas that had elevated mRNA expression (CDKN2Ahigh) having a significantly shorter time to recurrence. The expression of CDKN2A was independently prognostic after accounting for copy number loss and consistently increased with WHO grade and more aggressive molecular and methylation groups irrespective of cohort. Despite the discordant and mutually exclusive status of the CDKN2A gene in these groups, both CDKN2Ahigh meningiomas and meningiomas with CDKN2A deletions were enriched for similar cell cycle pathways but at different checkpoints. High mRNA expression of CDKN2A was also associated with gene hypermethylation, Rb-deficiency, and lack of response to CDK inhibition. p16 immunohistochemistry could not reliably differentiate between meningiomas with and without CDKN2A deletions but appeared to correlate better with mRNA expression. These findings support the role of CDKN2A mRNA expression as a biomarker of clinically aggressive meningiomas with potential therapeutic implications