2020 NPB-14

This case was originally published in 2020. 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.

The patient is a 30-year-old man with a history of depression and chronic headaches who presented with increasing frequency and severity of his headaches. Brain MRI revealed a 3.5-cm heterogeneously-enhancing, solid and cystic mass in the right cerebellar hemisphere (Image A). Diffusion-weighted imaging revealed restriction within the mass (not shown).

Tissue Site
Right cerebellum

The whole slide image provided is an H&E-stained section of the right cerebellar mass resection.

The morphologic and IHC features of this tumor are consistent with desmoplastic/nodular medulloblastoma, SHH-activated and TP53 wild-type.

Medulloblastoma is the most common malignant pediatric brain tumor, with a second age peak occurring in young adulthood, as in this case. Medulloblastomas are by definition located in the cerebellum or posterior fossa and are morphologically characterized as small round blue cell tumors with numerous mitotic figures and apoptotic bodies, with some also harboring Homer Wright rosettes. The 2016 revised World Health Organization (WHO) classification of CNS tumors describes four histologic subtypes: classic medulloblastoma, desmoplastic/nodular medulloblastoma, medulloblastoma with extensive nodularity, and large cell/anaplastic medulloblastoma.

In this case, H&E-stained sections show a small round blue cell tumor interrupted by pale, hypocellular islands or nodules (Image B and Image C). On higher power examination, the tumor cells within the nodules have small round uniform nuclei, lack mitotic activity, and are situated within ample neuropil. In contrast, the tumor cells in the internodular areas are characterized by hyperchromatic, irregular or angulated nuclei with scant cytoplasm and brisk mitotic activity (Image D). While not always obvious on H&E, a reticulin stain highlights reticulin deposition in the internodular areas (Image E), a requisite feature for the diagnosis of desmoplastic/nodular medulloblastoma, as occasional classic medulloblastomas may also display a nodular pattern but lack internodular reticulin. An immunostain for synaptophysin displays more intense staining within the nodules than in the internodular regions (Image F). The Ki-67 proliferative index is high in the internodular areas and very low within the nodules (Image G). These features are all characteristic of desmoplastic/nodular medulloblastoma.

Over the past decade, studies have revealed distinct molecular subgroups of medulloblastoma, which, in combination with the histologic subtype, are better able to predict prognosis than histology alone. There are four primary molecular subgroups: WNT-activated, SHH-activated, group 3, and group 4. For practical purposes, the 2016 revised WHO classification of CNS tumors combines groups 3 and 4 into one subgroup: non-WNT/non-SHH. A panel of immunostains consisting of ß-catenin, GAB1, and YAP1 has been proposed as a method for determining the molecular subgroup in clinical practice (Table 1). In this case, the tumor shows cytoplasmic staining for ß-catenin (Image H) and is extensively immunoreactive for GAB1 (Image I) and YAP1 (Image J); this staining pattern is consistent with SHH-activated molecular subgroup. Most desmoplastic/nodular medulloblastomas display activation of the SHH pathway, but not all SHH-activated medulloblastomas show this histologic pattern.

The SHH-activated subgroup can be further stratified on the basis of TP53 mutation status: those with TP53 mutations have a significantly worse prognosis than those without. IHC for p53 is a fairly sensitive marker for TP53 mutations and can therefore be used as a screening test. In this case, an immunostain for p53 shows only weak staining in a few scattered tumor cells (Image K), consistent with a TP53 wild-type staining pattern and therefore implying a better prognosis. TP53 mutations in SHH-activated medulloblastomas are primarily identified in children and adolescents (4 to 17 years) and portend a very poor prognosis. Approximately half of these tumors arise in the setting of Li-Fraumeni syndrome and Fanconi’s anemia. Detection of SHH-activated medulloblastomas is particularly important for identifying patients with clinically significant underlying germline mutations (eg, TP53/Li-Fraumeni syndrome, PTCH1 or SUFU/Gorlin syndrome), who should be referred for genetic counseling. Identification of SHH activation can also have therapeutic significance, since these patients may benefit from targeted therapy with agents such as smoothened inhibitors.

The WNT-activated subgroup is characterized by frequent CTNNB1 mutations, monosomy 6, and occasional germline APC mutations. TP53 mutations may also occur in WNT-activated medulloblastomas but do not have prognostic significance in this subgroup. Identifying the WNT-activated subgroup of medulloblastomas is also essential, as it is associated with an excellent prognosis and may be amenable to less aggressive treatment, thus resulting in fewer therapy-related neurocognitive sequelae. CTNNB1 mutations result in a translocation of the ß-catenin protein to the nucleus, which can be detected by IHC. In some cases, however, nuclear staining may be only focal or patchy, and some WNT medulloblastomas do not have CTNNB1 mutations. For these reasons, other surrogate IHC stains including LEF1 and ALK have more recently been proposed as additional WNT subgroup markers (Table 1).

The non-WNT/non-SHH subgroup is comprised of both groups 3 and 4 and is characterized by cytoplasmic ß-catenin staining and non-immunoreactivity for GAB1 and YAP1. More recent studies have highlighted the heterogeneity within groups 3 and 4, with an international meta-analysis demonstrating eight biologically and clinically significant subtypes within the non-WNT/non-SHH subgroup.

In addition to molecular subgrouping, testing for MYC and MYCN amplification also has important prognostic implications for the patient. MYC amplification is common in group 3 medulloblastomas and is associated with a poor prognosis. MYCN amplification may be seen in SHH-activated TP53-mutant medulloblastomas, as well as in group 4 medulloblastomas, but has only been shown to portend a worse prognosis in the SHH tumors.

Table 1: IHC staining patterns of molecular subgroups of medulloblastoma.

While the diagnosis is somewhat straightforward in this case, given the unique desmoplastic/nodular histology, other small round blue cell tumors should be considered in the differential of classic or large cell/anaplastic medulloblastoma. On intraoperative smear preparations in particular, care should be taken not to confuse granule cells of the normal cerebellar cortex with a small round blue cell tumor. In a child, the differential might include atypical teratoid/rhabdoid tumor (defined by INI1 or BRG1 loss), embryonal tumor with multilayered rosettes (characterized by C19MC alterations), and ependymoma. In an adult, metastatic small cell carcinoma, lymphoma, and small cell glioblastoma or glioblastoma with primitive neuronal component should be ruled out. Generally, histologic features along with IHC and/or targeted molecular testing allow the differentiation of medulloblastoma from these other small round blue cell tumors.

• The 2016 revised WHO classification of CNS tumors recommends that medulloblastoma be classified into both histologic (classic, desmoplastic/nodular, with extensive nodularity, and large cell/anaplastic) and molecular (WNT-activated, SHH-activated, and non-WNT/SHH) subgroups.
• A panel of IHC stains including ß-catenin, GAB1, YAP1, LEF1, and ALK, can be used to classify medulloblastomas into molecular subgroups.
• For SHH-activated medulloblastomas, TP53 mutation status should be determined, as those with a TP53 mutation have a significantly worse prognosis than those that are TP53 wild-type.
• MYC/MYCN amplification is also an important prognostic factor in medulloblastoma.
• Other small round blue cell neoplasms, including atypical teratoid/rhabdoid tumor, embryonal tumor with multilayered rosettes, ependymoma, glioblastoma, lymphoma and metastatic small cell carcinoma, among others, should be considered in the differential diagnosis.

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