Pathology of Brainstem Gliomas in Children

Pathophysiology

• Symptom evolution reflects aggressiveness of tumor: Symptoms of brainstem tumors are a function of tumor growth rate and location.  Benign tumors typically present with an insidious course over several months of gradual symptom progression. By comparison a shorter, more abrupt onset of symptoms is more indicative of higher-grade tumors (6, 16).
• Symptom pattern reflects extent of tumor: Diffusely growing tumors are associated with multiple, bilateral cranial neuropathies, long tract signs, and ataxia; hydrocephalus in these tumors is uncommon at initial presentation (6, 10, 16, 17). Focal gliomas often present with isolated cranial neuropathies, signs and symptoms of increased ICP, and ataxia. Rarely, hemiparesis may be a part of the clinical presentation (6, 10, 16, 17).
• Growth patterns: Benign tumors typically respect fiber tracts and pial borders.  In contrast, high-grade tumors grow and expand without respect for these anatomical boundaries of the surrounding tissues (18, 19).
• Hydrocephalus main feature of midbrain tumors: Midbrain tumors may present primarily with signs and symptoms of hydrocephalus.

Differential diagnosis of brainstem tumors

• Gliomas: Gliomas are the most common type of brainstem tumors.
• Other neuroepithelial tumors: PNET, ependymoma, ganglioglioma
• Other types of tumors: Hemangioblastoma, germ cell tumors (rarely involve midbrain), lymphoma, metastatic tumor
• Other types of lesions: Lipoma, inflammatory and infectious processes, vascular lesions (especially cavernous hemangioma), neuroepithelial cyst

Molecular/Genetic Pathology

• Diffuse intrinsic pontine glioma: Diffuse intrinsic pontine gliomas are genetically complex and distinct from both adult and pediatric supratentorial HGGs. Recent evidence points to PDGF and its receptors (PDGFR) as among the major driving forces of tumorigenesis in the majority of cases (79, 80, 81, 86, 92). Unlike the case in pediatric supratentorial high-grade gliomas, CDKN2A deletion is nonexistent in diffuse intrinsic pontine gliomas (82, 92), and amplification of CDK4 and CDK6 occurs only at a low rate (92).
• Little data on molecular genetics of brainstem tumors: There is a paucity of information about the molecular genetics of brainstem tumors with the exception of hemangioblastomas (see Pathology of Hemangioblastomas), which are very uncommon relative to astrocytomas.

Histopathology

In contrast to supratentorial or spinal cord gliomas, tumors occurring in the brainstem are typically defined by location rather than by histology and W.H.O. classification.

Diffuse intrinsic pontine gliomas

• Majority are high grade: About 70–90% of diffuse brainstem gliomas are anaplastic astrocytomas (W.H.O. Grade III) and glioblastoma multiformes (W.H.O. Grade IV) if biopsied before radiation therapy is given (20-22). The remainder are mainly fibrillary astrocytomas (W.H.O. Grade II). At autopsy, the vast majority of diffuse intrinsic pontine gliomas are high grade and may have disseminated within the neuraxis (31).

Dorsally exophytic gliomas

• Subependymal origin: Dorsally exophytic brainstem gliomas arise from subependymal glial tissue. In most cases, the majority of the tumor lies within the fourth ventricle.
• Low grade: Histologically, most of these tumors are low-grade gliomas that grow along the path of least resistance.  Rather than infiltrate the brainstem itself, most of tumors extend into the fourth ventricle and basal cisterns.
• Exception: Tumors that extend laterally and/or ventrally into the brainstem are usually more aggressive and of higher grade on pathological examination.

Cervicomedullary gliomas

• Brainstem or cord epicenter: The pathology of cervicomedullary brainstem gliomas is largely analogous to that of intramedullary spinal cord tumors. These tumors arise from either the medulla or high cervical spinal cord (8).
• Benign: Pathologically, tumors of the cervicomedullary junction tend to be benign and include low-grade gliomas, gangliogliomas, ependymomas, hemangioblastomas, and rarely lipomas.

Midbrain tumors

• Most are benign gliomas: Benign gliomas in the midbrain include pilocytic astrocytomas, fibrillary astrocytomas, and gangliogliomas.  Rarely, primitive neuroectodermal tumors arise in the area. In some reports, nonpilocytic low-grade astrocytomas were the most common type of focal midbrain gliomas (33). 
• Other lesions besides gliomas: Other lesions may include cavernomas, lymphomas, inflammatory processes and, rarely, germinomas, neuroepithelial cysts, and metastatic tumors.
• JPAs have Rosenthal fibers and bipolar cells: As is the case elsewhere in the brain, pilocytic astrocytomas (WHO grade I) appear biphasic with a mixture of compacted bipolar cells, multipolar cells with microcysts and eosinophilic granular bodies, rare mitoses, and associated Rosenthal fibers.
• Fibrillary astrocytomas have floating nuclei: Fibrillary astrocytomas (W.H.O. grade II) within the midbrain are composed of fibrillary neoplastic astrocytes with marked nuclear atypia (33). The cytoplasm is usually scant, giving the appearance of floating nuclei with infrequent mitoses.
• Anaplastic astrocytomas have mitoses: Anaplastic astrocytomas (W.H.O. grade III) show marked nuclear atypia and mitoses but lack microvascular proliferation or necrosis.
• Glioblastoma multiformes have necrosis: Glioblastoma multiforme (W.H.O. grade IV) demonstrates the features of anaplastic astrocytomas with the addition of pseudopallisading necrosis (24,25).