Definition of disease-risk stratification groups in childhood medulloblastoma using combined clinical, pathologic, and molecular variables

Abstract

Purpose: Medulloblastomas are heterogeneous and include relatively good-prognosis tumors characterized by Wnt pathway activation, as well as those that cannot be successfully treated with conventional therapy. Developing a practical therapeutic stratification that allows accurate identification of disease risk offers the potential to individualize adjuvant therapy and to minimize long-term adverse effects in a subgroup of survivors.

Methods: Using formalin-fixed paraffin-embedded (FFPE) tissue for immunohistochemistry, fluorescent in situ hybridization, and direct sequencing to identify tumors with a Wnt pathway signature and those harboring copy number abnormalities (CNAs) of potential prognostic significance (MYC/MYCN amplification, CNAs of chromosome 6 and 17), we evaluated clinical, pathologic, and molecular outcome indicators and stratification models in a cohort (n = 207) of patients with medulloblastoma 3 to 16 years of age from the International Society of Pediatric Oncology CNS9102 (PNET3) trial.

Results: Metastatic disease and large-cell/anaplastic (LC/A) phenotype were the clinicopathologic variables associated with poor progression-free survival (PFS). Nuclear immunoreactivity for β-catenin, CTNNB1 mutation, and monosomy 6 all identified a group of good-prognosis patients. MYC amplification was associated with poor outcome, but other CNAs were not. Low-risk medulloblastomas were defined as β-catenin nucleopositive tumors without metastasis at presentation, LC/A phenotype, or MYC amplification. High-risk medulloblastomas were defined as tumors with metastatic disease, LC/A phenotype, or MYC amplification. Low-risk, standard-risk, and high-risk categories of medulloblastoma had significantly (P < .0001) different outcomes.

Conclusion: Integrating assays of molecular biomarkers undertaken on routinely collected diagnostic FFPE tissue into stratification schemes for medulloblastoma alongside clinical and pathologic outcome indicators can refine current definition of disease risk and guide adjuvant therapy.

Fig 1.

(A) Widespread nuclear and cytoplasmic immunoreactivity for β-catenin is seen in this Wnt pathway medulloblastoma. (B) Patchy variable nuclear immunoreactivity for β-catenin characterizes this tumor, which contained a CTNNB1 mutation. (C through F) Interphase fluorescent in situ hybridization demonstrates (C) monosomy 6, (D) a 2 × 17p:6 × 17q profile, (E) gain of MYCN, and (F) amplification of MYC.

Fig 2.

Progression-free survival curves for patients split into (A) three or (B) four risk categories. Low risk = M0 classic tumors without MYC amplification showing β-catenin nucleopositivity; high risk = large-cell/anaplastic (LC/A) tumors or tumors with M+ disease or MYC amplification; worst risk = LC/A tumors plus M+ disease or MYC amplification; standard risk = the remainder. Numbers along x-axis represent patients at risk of event; log-rank tests, both data sets P < .0001.

Fig A1.

Progression-free survival and overall survival curves for the entire cohort (N = 207).

Fig A2.

(A) Progression-free survival (PFS) curves split by metastatic status: M0, M+; log-rank P = .0014. (B) PFS curves split by histopathologic variants: classic, desmoplastic/nodular (D/N), and large cell/anaplastic (LC/A); log-rank P = .0004.

Fig A3.

Progression-free survival curves for patients split by β-catenin nuclear immunoreactivity: nucleopositive, nucleonegative; log-rank P = .0095.

Fig A4.

Progression-free survival (PFS) plots for markers of good outcome; CTNNB1 status and chromosome (Chr) 6 copy number abnormalities alone or in combination with β-catenin immunohistochemical status do not identify a group of patients with a better outcome than children with β-catenin nucleopositive medulloblastomas. (A) PFS curves split by CTNNB1 status: mutation, wild type, log-rank P = .0325; (B) PFS curves split by chromosome 6 status, monosomy, not monosomy, log-rank P = .0327; (C) PFS curves split by a combination of β-catenin nuclear immunoreactivity and chromosome 6 status: β-catenin nucleopositive plus monosomy 6, other tumors, log-rank P = .0382; (D) PFS curves split by a combination of β-catenin nuclear immunoreactivity and CTNNB1 status: β-catenin nucleopositive plus CTNNB1 mutation, other tumors, log-rank P = .0340.

Fig A5.

Classification and regression tree analysis of outcome categories. Numbers are hazard ratios; P < .0001. M, metastasis; IR, immunoreactivity; D/N, desmoplastic or nodular; LC/A, large cell or anaplastic.