Primitive Neuroectodermal Tumors of the Central Nervous System Clinical Presentation

Updated: May 31, 2018
  • Author: Subrata Ghosh, MD, MBBS, MS; Chief Editor: Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS  more...
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Presentation

History

No pathognomonic signs or symptoms exist. The onset at presentation is insidious.

The observed symptoms are due to the neuroanatomical location of the tumor or are a consequence of increased intracranial pressure. They include the following:

  • Irritability, lethargy, and decreased social interaction (60%)

  • Intermittent vomiting (40%)

  • Headache (40%) (usually worse in the morning)

  • Visual blurring/change (30%)

  • Nausea - Unusual as a distinct symptom, unless the tumor infiltrates the floor of the fourth ventricle (5%)

  • Imbalance (40%)

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Physical

Physical characteristics include the following:

  • Papilledema (60%)

  • Ataxia (50%)

  • Nystagmus with or without gaze palsy (40%)

  • Lower cranial nerve palsy (20%)

  • Dysdiadochokinesia, hypotonia, dysmetria, particularly in lateralized lesions of the cerebellum (20%)

  • Increased head circumference in children younger than 2 years (30%)

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Causes

Isolated PNET is sporadic in nature, and only 14 familial cases have been reported in the literature.

Loss of the short arm of chromosome 17 (17p13.3) is the most frequent abnormality (particularly with medulloblastoma, in which it is found in 30-40% of cases), the presence of which also affects prognosis. This site is, however, distinct from the common tumor suppressor gene, TP53. Other genetic loci of interest in the pathogenesis of medulloblastoma include PAX genes and sonic hedgehog (SHH) genes, the roles of which are under intense investigation.

17p loss, MYC amplification/expression, and 1q gain are associated with poor prognosis; in contrast, monosomy 6, mutation of CTNNB1, and trkC expression identify tumors with a favorable outcome. [7]

Multiple signaling pathways have been associated with medulloblastoma formation and growth. These include the developmental pathways Hedgehog, (Hh) Notch, and Wnt, as well as the receptor tyrosine kinases (RTK) c-Met, erbB2, IGF-R, and TrkC, and the oncoprotein Myc. [8]

Studies on molecular characterization have identified 4-6 subgroups of medulloblastoma on the basis of molecular differences. [9] Despite the disparity in the number of subtypes, the studies have substantial common ground. All describe a subtype with aberrant sonic hedgehog pathway signaling (often PTCH1 mutations), which has a high incidence among desmoplastic tumors. Another subtype has aberrant signaling in the wingless (WNT) pathway (frequently, CTNNB1 mutations), a classic histology that commonly affects older children. Additionally, a less favorable subtype emerged from the latest studies, which associates MYC overexpression and amplification with poor prognostic features, such as high prevalence of metastatic disease and large-cell anaplastic histology.

The most current international consensus recognizes 4 core medulloblastoma subgroups namely, SHH, WNT, Group 3, and Group 4. This is adopted based on the knowledge of genomic complexity of medulloblastoma as analyzed by recent high-throughput genomic technology. [10]

Karyotypically, almost all PNETs are abnormal.

Certain conditions have increased associations with PNETs. They include the following:

  • Gorlin syndrome, also known as nevoid basal cell carcinoma syndrome, is an autosomal dominant disorder with mutations of the PTCH gene. [11] It is characterized by a combination of neoplastic and malformative disorders including nevoid basal cell carcinoma, jaw keratocysts, skeletal abnormalities, ovarian fibromas, and ectopic calcifications. Approximately 5% of mutation carriers develop medulloblastoma at an early age.

  • Turcot syndrome is a heterogenous group of autosomal dominant disorders with occurrence of multiple colorectal neoplasms and medulloblastomas or glioblastomas.

  • Li-Fraumeni syndrome is an autosomal dominant disorder characterized by multiple tumors in children, including soft-tissue sarcomas, osteosarcomas, breast cancer, leukemias, and a higher incidence of brain tumors than in the general population.

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