Acta Neuropathologica

, Volume 121, Issue 3, pp 381–396 | Cite as

Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups

  • David W. Ellison
  • James Dalton
  • Mehmet Kocak
  • Sarah Leigh Nicholson
  • Charles Fraga
  • Geoff Neale
  • Anna M. Kenney
  • Dan J. Brat
  • Arie Perry
  • William H. Yong
  • Roger E. Taylor
  • Simon Bailey
  • Steven C. Clifford
  • Richard J. Gilbertson
Original Paper

Abstract

Medulloblastoma is heterogeneous, being characterized by molecular subgroups that demonstrate distinct gene expression profiles. Activation of the WNT or SHH signaling pathway characterizes two of these molecular subgroups, the former associated with low-risk disease and the latter potentially targeted by novel SHH pathway inhibitors. This manuscript reports the validation of a novel diagnostic immunohistochemical method to distinguish SHH, WNT, and non-SHH/WNT tumors and details their associations with clinical, pathological and cytogenetic variables. A cohort (n = 235) of medulloblastomas from patients aged 0.4–52 years was studied for expression of four immunohistochemical markers: GAB1, β-catenin, filamin A, and YAP1. Immunoreactivity (IR) for GAB1 characterizes only SHH tumors and nuclear IR for β-catenin only WNT tumors. IRs for filamin A and YAP1 identify SHH and WNT tumors. SHH, WNT, and non-SHH/WNT tumors contributed 31, 14, and 55% to the series. All desmoplastic/nodular (D/N) medulloblastomas were SHH tumors, while most WNT tumors (94%) had a classic phenotype. Monosomy 6 was strongly associated with WNT tumors, while PTCH1 loss occurred almost exclusively among SHH tumors. MYC or MYCN amplification and chromosome 17 imbalance occurred predominantly among non-SHH/WNT tumors. Among patients aged 3–16 years and entered onto the SIOP PNET3 trial, outcome was significantly better for children with WNT tumors, when compared to SHH or non-SHH/WNT tumors, which showed similar survival curves. However, high-risk factors (M+ disease, LC/A pathology, MYC amplification) significantly influenced survival in both SHH and non-SHH/WNT groups. We describe a robust method for detecting SHH, WNT, and non-SHH/WNT molecular subgroups in formalin-fixed medulloblastoma samples. In corroborating other studies that indicate the value of combining clinical, pathological, and molecular variables in therapeutic stratification schemes for medulloblastoma, we also provide the first outcome data based on a clinical trial cohort and novel data on how molecular subgroups are distributed across the range of disease.

Supplementary material

401_2011_800_MOESM1_ESM.docx (4.7 mb)
Supplementary Figure 1: Classic medulloblastoma. Most tumors demonstrate sheets of small densely packed round cells with a high nuclear:cytoplasmic ratio (a), although 14% of classic medulloblastomas in this series contained elongated cells arranged in a vague fascicular pattern (b). A small proportion (7%) of classic tumors showed nodules of differentiated neurocytic cells (c), without surrounding desmoplasia (d; reticulin stain). Other manifestations of focal neuronal differentiation included dense aggregates of tiny neurocytes (e) or irregular regions of neurocytes and ganglion cells against a neuropil-like matrix (f). Non-desmoplastic nodular regions (g) and dense neurocytic clusters (h) express neuronal proteins, such as synaptophysin (illustrated). All foci of neuronal differentiation had a low growth fraction, as estimated by Ki-67 immunolabeling in illustrated for this neurocytic cluster (i). Foci of astrocytic differentiation are exceptional (j). (DOCX 4811 kb)
401_2011_800_MOESM2_ESM.docx (3.1 mb)
Supplementary Figure 2: Desmoplastic medulloblastoma. The archetypal desmoplastic/nodular medulloblastoma contains scattered nodules of neurocytes against a neuropil-like matrix (a). Nodules are separated by reticulin-rich desmoplastic regions (b; reticulin stain). The MBEN is characterized by large irregular nodules that dominate the tumor’s architecture (c). In the MBEN, strikingly monomorphic neurocytes may form ribbons in elongated nodules and are often separated from a nodule’s periphery by an anuclear zone (d). Strong expression of NEU-N characterizes intranodular neurocytes (e), while there is a marked disparity in growth fraction between nodular and internodular regions (f; Ki-67 immunoreactivity). Paucinodular medulloblastomas show widespread desmoplasia, among which small nodules can be detected (g). The nodules do not have the low cell density of the MBEN, and a neurocytic morphology is subtle, but expression of neuronal proteins can be demonstrated (h; NEU-N immunoreactivity). Intranodular anaplasia may be a feature of some D/N medulloblastomas (i), as may invasion of nodules by embryonal cells (j). (DOCX 3133 kb)
401_2011_800_MOESM3_ESM.docx (2.1 mb)
Supplementary Figure 3: Large cell/anaplastic medulloblastoma. Anaplastic medulloblastomas show marked cytological pleomorphism, with molding of polyhedral nuclei against one another, cell wrapping, and high mitotic and apoptotic counts (a, b, c). Despite no obvious morphological differentiation, anaplastic tumors usually express neuronal markers, including neurofilament proteins, which are rarely expressed in classic tumors (d; NFP immunoreactivity). The large cell phenotype is different from anaplastic morphology and demonstrates groups of uniform large cells with prominent nucleoli (e). A few tumors from infants demonstrated sheets of uniform round cells with one or two prominent nucleoli (f). (DOCX 2130 kb)
401_2011_800_MOESM4_ESM.docx (749 kb)
Supplementary Figure 4: Idiosyncratic perivascular niche phenotype. A perivascular arrangement of anaplastic embryonal cells gives way to a more differentiated phenotype, with neurocytic cells against a neuropil-like matrix, away from blood vessels (a, b). (DOCX 748 kb)
401_2011_800_MOESM5_ESM.doc (212 kb)
Supplementary Figure 5: Interphase FISH. Monosomy 6 (a). PTCH1 (green signal) loss (b). Isodicentric 17q (c). MYC amplification (d). (DOC 211 kb)
401_2011_800_MOESM6_ESM.xls (60 kb)
Supplementary Table 1 (XLS 60.5 kb)

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • David W. Ellison
    • 1
  • James Dalton
    • 1
  • Mehmet Kocak
    • 2
  • Sarah Leigh Nicholson
    • 3
  • Charles Fraga
    • 1
  • Geoff Neale
    • 4
  • Anna M. Kenney
    • 5
  • Dan J. Brat
    • 6
  • Arie Perry
    • 7
  • William H. Yong
    • 8
  • Roger E. Taylor
    • 9
  • Simon Bailey
    • 10
  • Steven C. Clifford
    • 10
  • Richard J. Gilbertson
    • 11
  1. 1.Department of Pathology MS# 250St. Jude Children’s Research HospitalMemphisUSA
  2. 2.Department of BiostatisticsSt. Jude Children’s Research HospitalMemphisUSA
  3. 3.Department of PathologyNewcastle University Hospitals NHS TrustNewcastle-upon-TyneUK
  4. 4.Hartwell Center for Bioinformatics and BiotechnologySt. Jude Children’s Research HospitalMemphisUSA
  5. 5.Cancer Biology and GeneticsSloan Kettering InstituteNew YorkUSA
  6. 6.Department of PathologyEmory University School of MedicineAtlantaUSA
  7. 7.Department of PathologyUCSFSan FranciscoUSA
  8. 8.Department of PathologyUCLALos AngelesUSA
  9. 9.South West Wales Cancer Centre, Singleton HospitalSwanseaUK
  10. 10.Northern Institute for Cancer ResearchUniversity of NewcastleNewcastle-upon-TyneUK
  11. 11.Department of Developmental BiologySt. Jude Children’s Research HospitalMemphisUSA

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