2019 NPB-15

This case was originally published in 2019. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

A 7-year-old girl presented with new-onset seizures, nausea, and vomiting concerning for increased intracranial pressure. MRI demonstrated a left temporal-occipital mass with cystic and solid components (Image A and Image B). Biopsy was performed.

Tissue Site
Left temporal-occipital junction

The whole slide image provided is an H&E-stained image of the brain from a resection.

This hypercellular neoplasm is comprised of infiltrative, pleomorphic, atypical glial cells (Image C) with hyperchromatic nuclei and conspicuous mitotic activity (Image D) with up to 20 mitotic figures in a single high-magnification field. Perineuronal satellitosis is noted, and perivascular lymphocyte cuffing is prominent. Early microvascular proliferation is present. Some tumor cells demonstrate perinuclear cytoplasmic clearing (Image E) while others show moderate eosinophilic cytoplasm. GFAP IHC shows diffuse, strong positivity in tumor cells (Image F), as does p53 (Image G). Neurofilament IHC highlights entrapped axons (Image H), and ATRX staining is retained (Image I). MSH6 IHC shows loss of staining in tumor cells (Image J). Additionally, H3K27me3 immunoexpression is retained in the majority of tumor cells, and IHCs for H3 K27M, H3 G34R/V, IDH1 R132H, and BRAF V600E are negative for mutant proteins. Genetic sequencing in this patient identified a complex insertion/deletion germline mutation of one allele of MSH6 and a second somatic nonsense mutation in the tumor causing biallelic inactivation. The morphologic, genetic, and IHC features support a diagnosis of glioblastoma, IDH-wildtype and H3-wildtype, WHO grade IV, in the setting of Lynch syndrome with germline heterozygous MSH6 mutation.

Lynch syndrome, or hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal dominant cancer predisposition syndrome. It is defined genetically by germline mutation of any of the more than 20 known genes involved in DNA mismatch repair, including MLH1, MLH3, MSH2, MSH6, PMS2, and EXO1. Individuals inheriting a mutated mismatch repair gene are at significantly higher risk for development of colorectal carcinoma, endometrial carcinoma, and cancers of a variety of other organs including stomach, ovary, kidney, bladder, small intestine, and skin when compared to the general population. Patients with Lynch syndrome also have an increased risk for development of gliomas (approximately 50% to 60% of glioma cases are glioblastoma), and patients with mutations in MSH2 have a higher risk for development of central nervous system (CNS) tumors compared to patients with other mutations. Of interest, it has been reported that temozolomide, a standard chemotherapeutic agent for gliomas, induces somatic MSH6 mutations, and MSH6 mutations may confer temozolomide resistance, an important consideration for chemotherapy planning.

Defective mismatch repair (dMMR) may result from germline mutations, as in Lynch syndrome, or it may be sporadic, as in cases of somatic hypermethylation of the MLH1 gene promoter, the most common defect seen in sporadic cases of colorectal carcinoma associated with dMMR. dMMR leads to microsatellite instability (MSI) throughout the genome. For reasons that are, as of yet, poorly understood, CNS neoplasms with dMMR proteins typically do not show the same degree of MSI as other malignancies with underlying dMMR. The glioblastoma in this case showed instability of 14 of 918 microsatellites tested, consistent with a microsatellite stable tumor. Nevertheless, MSI is regarded as a positive prognostic and predictive biomarker for efficacy of immunotherapy in a variety of cancers as it can predict response rate and progression-free survival. MSI may be evaluated by next-generation sequencing to assess the genome or by IHC to show lost expression of mismatch repair components.

Cancer immunotherapy has emerged as a successful treatment modality that utilizes immune checkpoints as therapeutic targets in order to stimulate an immune system response to tumor cells. For example, the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint acts to suppress T-cell function when the PD-1 receptor on T cells encounters the PD-L1 ligand on target tumor cells. Treatment with anti-PD-1 antibody interferes with T-cell suppression and effectively promotes tumor cell death. Tumors with dMMR and MSI typically exhibit increased antigen presentation and are more responsive to immunotherapy.

Identification of patients with a cancer predisposition syndrome, as in this case of a pediatric glioblastoma arising in the setting of Lynch syndrome, allows for improved surveillance and ultimately decreased morbidity and mortality. Histopathologic clues in this case include giant cell features and prominent inflammatory infiltrates. Clinical clues may include young age and a positive family history for cancers.

• Lynch syndrome is a cancer predisposition syndrome with an increased risk for development of colorectal carcinoma, endometrial carcinoma, and cancers of a variety of other organs including stomach, ovary, kidney, bladder, small intestine, skin, and brain.
• The most common CNS malignancy associated with Lynch syndrome is glioblastoma.
• Lynch syndrome patients with mutations in the mismatch repair gene MSH2 have a higher risk for development of CNS tumors compared to patients with other mismatch repair mutations.
• Temozolomide, a standard chemotherapeutic agent for gliomas, induces somatic mutations in the mismatch repair gene MSH6, and MSH6 mutations may confer temozolomide resistance.

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