Pathology, diagnostics, and classification of medulloblastoma

Abstract

Medulloblastoma (MB) is the most common CNS embryonal tumor. While the overall cure rate is around 70%, patients with high-risk disease continue to have poor outcome and experience long-term morbidity. MB is among the tumors for which diagnosis, risk stratification, and clinical management has shown the most rapid advancement. These advances are largely due to technological improvements in diagnosis and risk stratification which now integrate histomorphologic classification and molecular classification. MB stands as a prototype for other solid tumors in how to effectively integrate morphology and genomic data to stratify clinicopathologic risk and aid design of innovative clinical trials for precision medicine. This review explores the current diagnostic and classification of MB in modern neuropathology laboratories.

Keywords: Group 3; Group 4; SHH; WNT; classification; diagnosis; histology; medulloblastoma; neuropathology; non-WNT/non-SHH.

Figure 1

Medulloblastoma, histologically defined groups consist of four histologic variants including the classic variant (A‐D) characterized by small cells with round to ovoid nuclei (A), frequent Homer Wright rosettes (B), and no significant cytologic pleomorphism or cell molding (C). A slight increase in cell size and cytologic pleomorphism (D) are still within the spectrum of histologies in the classic variant. The desmoplastic/nodular variant (E‐H) is characterized by nodules of neurocytic differentiation surrounded by more primitive internodular areas (E and G). The differentiated nodules show desmoplasia surrounding the nodules which can be detected by pericellular reticulin deposition (H). Medulloblastoma with extensive nodularity (MBEN) (I‐L) is characterized by a high proportion of differentiated elements compared to primitive internodular elements (F‐J). The nodules in the MBEN variant often coalesce together forming irregular patterns accompanied by a pattern of linear “streaming” between nodules. Similar to other desmoplastic nodular tumors, MBENs show reticulin deposition in the internodular regions (L). The large cell/anaplastic variant (LCA) is a combination of two variant the anaplastic variant and the large cell variant (M‐P). The anaplastic variant is characterized by increased cell size, cytologic pleomorphism, cell molding and wrapping, frequent mitotic activity, and apoptotic bodies (M and N). The large cell variant is characterized by large discohesive cells with prominent nucleoli (O and P).

Figure 2

Medulloblastomas with divergent differentiation most often are characterized by myogenic. Here, a case of medulloblastoma with myogenic differentiation is presented (A‐H). These tumors typically show histology in regions that are typical of other medulloblastomas with primitive elements, often with some anaplastic features (A). In some, overt myogenic differentiation can be observed and can be detected by the presence of “strap” cells (B). Myogenic elements in medulloblastoma with myogenic differentiation can be detected by immunohistochemistry to myogenin (C) or desmin (D). The neuronal elements of medulloblastoma with myogenic differentiation is immunoreactive for synaptophysin (E). The panel of stains used for molecular subgrouping yield a discordant phenotype, showing immunoreactivity for YAP1 (F), no staining for GAB1 (G), and cytoplasmic only staining for beta‐catenin (H). Divergent differentiation can also take the form of melanotic differentiation (I‐P). This case demonstrates the more typical primitive elements of medulloblastoma (I) and neurocytic differentiation (J). A mixed population of the neuronal and melanotic elements can be seen in (K). The neuronal element is immunopositive for synaptophysin (L), whereas the melanotic element is detectable with antibodies to HMB45 (M). Medulloblastomas with divergent melanotic differentiation also yield a discordant pattern on the molecular subgrouping stains, demonstrating immunoreactivity for YAP1 in the melanotic element (N), no significant immunoreactivity for GAB1 (O), and cytoplasmic only staining for beta‐catenin (P).

Figure 3

Histologic variants outside of those in the medulloblastoma, include the classic biphasic variant (A‐D) and the ganglioneuroblastoma variant (E‐L). Classic biphasic tumors are characterized by nodules of differentiation with primitive internodular areas (A). These tumors can be differentiated from desmoplastic/nodular tumors by reticlulin stain (B) which fails to outline the nodules. On the molecular subgrouping stains, classic biphasic tumors fall into the non‐WNT/non‐SHH molecular group based on negativity for YAP1 (C) and GAB1 (D), and staining for beta‐catenin that is restricted to the cytoplasm (not shown). The ganglioneuroblastoma variant is characterized by a mixture of primitive elements mixed with areas ganglion cell differentiation (E‐G). The ganglion cell differentiation is marked by especially high intensity staining for synaptophysin (H) and immunoreactivity for NeuN (I). Tumors showing ganglioneuroblastoma histology typically fall in the non‐WNT/non‐SHH molecular subgroup, showing negative staining for YAP1 (J), negative staining for GAB1 (K), and cytoplasmic only staining for beta‐catenin (L).

Figure 4

Example staining patterns for molecular subgrouping medulloblastoma using the panel of YAP1, GAB1, and beta‐catenin. WNT‐activated medulloblastomas typically demonstrate immunoreactivity for YAP1, but are immunonegative for GAB1. Immunoreactivity for beta‐catenin is positive in both the cytoplasm and nucleus of WNT‐activated tumors (top panels). SHH‐activated medulloblastomas are immunoreactive for YAP1 and GAB1, but show reactivity for beta‐catenin that is restricted to the cytoplasm (middle panels). Non‐WNT/non‐SHH medulloblastomas show no immunoreactivity for YAP1 or GAB1, and immunoreactivity for beta‐catenin that is restricted to the cytoplasm only (bottom panels).

Figure 5

The presence of a TP53‐mutation is an important prognostic feature in SHH‐activated medulloblastomas. A typical wild‐type tumor is depicted in panels A‐D. The tumor demonstrates the typical pattern of immunoreactivity for YAP1 and GAB1 (B and C, respectively). Immunoreactivity for p53 restricted to weak expression in the minority of tumor cells in TP53‐wild‐type tumors (D). A tumor from a patient with Li‐Fraumeni syndrome is shown in panels E‐H. SHH‐activated, TP53‐mutant tumors often show large cell/anaplastic histology (E). This case demonstrates the typical immunophenotype of a SHH‐activated tumor with immunoreactivity for YAP1 and GAB1 (F and G). Strong, diffuse immunoreactivity for p53 is present (H) indicative of a dominant‐negative TP53‐mutation. Because many SHH‐activated tumors with TP53 mutations are associated with germline TP53 mutations, genetic testing is recommended for all cases showing a mutant pattern.