Pathology of Central Nervous System Tumors Occurring During Infancy

Pathophysiology

• Difficult to classify due to immaturity of cells reflecting infancy of patient: Tumors in infants are often so large at presentation, with histologically undifferentiated cell type, that accurate identification of their site of origin can be elusive. With the advent of molecular cellular identifiers, subtypes of disease and therefore patterns of growth and response to therapy are becoming apparent.

AT/RTs

• Posterior fossa site of origin: Tumors are found throughout the CNS, but the posterior fossa site is most common. Rorke (14) found 66% in their series of 52 patients in this site.
• CNS metastasis: Tumors may be disseminated at presentation with seeding along CSF pathways.
• Systemic metastasis: Tumors do present outside the CNS; in fact the entity was first described as a subset of pediatric renal tumors. Metastases to or from the CNS are possible.

Neuroblastomas

• Spinal site of origin: Derived from primitive neural crest cells, vertebral and foramenal involvement is understandable. 7–15% of patients present with a paraspinal mass with or without cord compression (8).

Desmoplastic infantile gangliogliomas

• Supratentorial: Tumors are superficial in the cerebrum.
• Cystic: Cystic components are common.
• Large: These tumors tend to be large, firm, multilobulated, and well demarcated (14, 19, 22).

Molecular/Genetic Pathology

The concept that conatal tumors might be associated with germline mutations in tumor suppressor genes has been entertained since the mid-portion of the 20th century, following seminal work of authors such as Armitage and Doll (1) and Knudson (9), who noted statistical data consistent with as few as two somatic mutations resulting in tumorogenesis.

AT/RTs

• Chromosome 21: Abnormalities on chromosome 22 have been identified in > 50% of patients with AT/RTs, with other abnormalities such as deletions affecting chromosomes 6, 13, and 17 (13).
• Chromosome 22: The specific genetic abnormality identified on chromosome 22 is deletion of a gene at 22q11.2, hSNF5/INI1. This gene appears to be a tumor suppressor (20, 24). The presence of the INI -1 deletion in tumors of PNET-like histology is accepted by most to be diagnostic of AT/RT.

Neuroblastomas

• Chromosome 2: Amplification of the N-Myc gene of chromosome 2 in tumor tissue may confer high-risk status, although clinical series differ in the observation of risk association (8, 18).
• DNA ploidy: DNA ploidy is also a feature of these tumors that increases risk. 

Desmoplastic infantile gangliogliomas

• Abnormal karyotype: Karyotypic abnormalities including isochromosome 1q, polyploidy, and telomere associations are described (20).

Histopathology

AT/RTs

• Rhabdoid cell: The tumor, as its name suggests, is characterized by rhabdoid cells with an eccentrically placed nucleus.
• Difficult to differentiate from PNET: More than 70% contain fields indistinguishable from PNET, which explains prior classification in this group.

Desmoplastic infantile gangliogliomas

• Mixture of ganglion cells and astrocytes: Desmoplastic infantile gangliogliomas contain a mixture of astrocytes within a dense fibrous stroma. By definition they contain ganglion cells. 
• Pleomorphic nuclei with high mitotic rate: Histological appearance with pleomorphic nuclei and high mitotic index confer the appearance of an anaplastic tumor.  Biological activity, however, is of an indolent course, with surgical excision often being curative (14).

Medulloepitheliomas

• Tubules with pseudostratification: Composed of canalicular structures. Typically there is a pseudostratification of cells with mitoses toward the abluminal border.
• Cell differentiation: There may be component differentiation along glial, neuronal, or mesenchymal lines, with the tumor being described as the most primitive primary CNS tumor (14, 16).