Medulloblastoma with extensive nodularity: a tumour exclusively of infancy?
A 39‐year‐old male patient developed ataxia. The MRI showed a 2.8 cm contrast‐enhancing cerebellar midline lesion (Figure 1a). After incomplete resection, the neuropathological examination revealed a tumour with a predominant (about 80% of the tumour tissue) grape‐like lobular architecture and presence of reticulin‐free islands with a neuropil‐like matrix (Figure 1b–c), positive for synaptophysin (Dako, Hamburg, Germany). These nodules contained small cells with neurocytic cytology (Figure 1d) strongly positive for NeuN (Millipore, Darmstadt, Germany) (Figure 1e). Focally, the tumour cells displayed a streaming pattern in the nodular areas. The internodular regions with increased cellularity displayed a dense reticulin meshwork. Here, the tumour cells showed hyperchromatic nuclei and scant cytoplasm. The tumour cells of these internodular areas expressed the low affinity neurotrophin receptor p75‐NTR (Thermo‐Scientific, Waltham, MA, USA) (Figure 1f), a known SHH target 5 and Yap‐1 (Cell Signaling, Danvers, MA, USA) indicative of SHH pathway activation. Neither nuclear positivity for ß‐catenin (Roche‐Ventana, Darmstadt, Germany) nor nuclear accumulation of p53 (Dako) was found. No expression of cytokeratins (Bachem, Weil am Rhein, Germany) and neurofilament protein (Dako) was observed. The proliferation marker MIB‐1 (Ki67) (Dako) stained more than 20% of tumour cells in the internodular areas but was almost negative within the nodular areas.
After the histological diagnosis, the patient received combined radio‐chemotherapy. Radiotherapy was administered to the entire neuraxis (single dose 1.6 Gy, 5 fractions/week, total dose 35.2 Gy) with a boost to the posterior fossa (single dose 1.8 Gy, 5 fractions/week, total dose 19.8 Gy). The total cumulative dose was 55.0 Gy. After irradiation, the residual tumour was no longer detectable in MRI.
After radiotherapy, the patient received chemotherapy (CCNU/cisplatin, since the 5th cycle CCNU/carboplatin). Actually, 11 months after diagnosis, the patient completed the six of the eight planned cycles of chemotherapy. Clinically, the patient showed a treatment‐related polyneuropathy and high‐frequency hearing loss in one ear.
For further molecular characterization, genomic DNA was extracted from FFPE tissue using standard methods (DNeasy Kit, Qiagen, Düsseldorf, Germany). A molecular inversion probe (MIP) analysis (Oncoscan v3, Affymetrix, Santa Clara, CA, USA) revealed, besides chr. 7q gain, no significant cytogenetic alterations or allelic imbalances (Figure 1g). In particular, there was no allelic loss of 9q (PTCH1) or 10q (SUFU). MYC, MYCN and GLI2 were not amplified.
The mutational probes included in the MIP assay revealed the presence of a PIK3CA E545K (c.1633 g‐>a) mutation, which was further confirmed by direct sequencing (Eurofins MWG Operon, Ebersberg, Germany) (not shown). Conversely, no TP53 allelic losses or mutations were evident in the MIP assay. The mutational analysis of exon 6 of Smoothened (SMOH) showed presence of an activating L412F mutation (Figure 1h).
Medulloblastoma is the most common malignant intracranial tumour in childhood but can also be observed, more rarely, in adults 1. Like MB in infants and small children, adult MBs show frequent activation of the SHH signaling pathway, usually caused by somatic mutations in PTCH1 or SMOH, 6.