Pathology of Intramedullary Spinal Cord Tumors in Children

Pathophysiology

The biology of IMSCTs in children leads to a predictable pathophysiology. The typical benign tumor will cause focal dysfunction that evolves slowly, while the unusual malignant tumor quickly involves the entire width of the spinal cord at the level of involvement.

• Symptom evolution: Symptoms evolve as a function of the rate of growth of the tumor and its location. Most IMSCTs are benign and grow slowly, so that symptoms evolve insidiously. Ependymomas arise centrally and so have evenly distributed symptoms bilaterally.  Other tumors arise eccentrically and have symptoms that tend to lateralize (10). 

• Growth patterns: Benign tumors respect fiber tracks. Cervical tumors curve dorsally at the decussations of the fiber tracks in the lower medulla (18). Exophytic tumors are very unusual and, when present, are frequently malignant.

Cervicomedullary spinal cord tumor: The tumor has been directed dorsally due to its rostral growth being blocked by the decussating sensory and motor fibers within the medulla oblongata.

Molecular/Genetic Pathology

Over the past several decades, the genetics and resulting molecular pathology have slowly come to light for many of the tumors affecting the spinal cord.

• Astrocytomas: The knowledge about the genetics of astrocytic IMSCTs is limited given the small number of pediatric cases in the literature that describe the genetic mutations present in the analyzed tumors.  Additionally, most reports of analysis of pediatric IMSCTs lump the results with analysis of tumors of similar histology arising in other areas of the CNS.  There is one study that reports a fusion of the BRAF–KIAA1549  genes in 6 of 8 pediatric patients with intramedullary pilocytic astrocytomas of the spinal cord (50).
• Ependymomas: Intramedullary spinal cord ependymomas occur in 30% of patients with NF2. It has been widely reported that it is not uncommon to see genetic aberrations in the NF genes on chromosome 22 in patients found to have intramedullary spinal cord ependymomas (38).
  
• Gangliogliomas: To date there are no studies available that authoritatively discuss the molecular genetics of intramedullary spinal cord gangliogliomas. 
• Hemangioblastomas: Intramedullary spinal cord hemangioblastomas occur in 20% of patients with VHL disease. Deletions and mutations have been reported for the VHL gene both in patients with sporadic intramedullary cord hemangioblastomas and in those with associated VHL disease (38).

Histopathology

• Astrocytomas: Slightly more than 40% of IMSCTs will be astrocytomas. Roughly 70% will be benign. Historically it was felt that nearly 80% of IMSCTs in children were astrocytomas with nearly half being pilocytic. When a large series (117 children) of IMSCT specimens were reviewed using immunohistochemistry it was found that nearly half of tumors labeled as astrocytomas were in fact gangliogliomas and very few of the remaining astrocytomas were pilocytic (33). It is now known that the majority of intramedullary spinal cord astrocytomas are the fibrillary type. All fibrillary astrocytomas have infiltrative margins and arise eccentrically.

Astrocytoma:

• Gangliogliomas: Gangliogliomas and other mixed glial-neuronal tumors comprised 35% of the tumors in Miller’s analysis of Epstein’s series (33). They tended to occur in younger children than did the astrocytomas.  Gangliogliomas rarely occur in adults. Their hallmark is large neuronal cells within the tumor that have vesicles gathered about the nucleus which react to synaptophysin, an immunostain that reacts with synaptic vesicle membranes. The margins of these tumors are infiltrative, and they arise eccentrically.

Ganglioglioma:

• Ependymomas:  Ependymomas account for only 10 – 15% of IMSCTs in children and adolescents (33). There are three grades in the W.H.O. system with grade 1 being myxopapillary ependymomas, grade 2 benign ependymomas, and grade 3 malignant ependymomas. There appears to be no difference in the biology of the three grades. These tumors tend to establish a plane between themselves and the surrounding spinal parenchyma, and their zone of infiltration is only 1 – 3 cells thick on microscopic examination. They arise centrally in the cord, growing from the central canal.

Ependymoma:

• Oligodendrogliomas and mixed gliomas: Oligodendrogliomas and mixed gliomas occur in very small numbers in children. Oligodendrogliomas vary from having the fried egg cell appearance of the typical oligodendroglioma to an astrocytoma with scattered oligodendrocytes of varying density. These tumors occur in such small numbers that there is insufficient knowledge about their biology. They arise eccentrically and infiltrate like astrocytomas and gangliogliomas.

• Hemangioblastomas: Hemangioblastomas are vascular tumors that microscopically show multiple, closely packed blood channels surrounding richly vacuolated cells with eosinophilic cytoplasm and hyperchromatic nuclei (48). They can be either mural nodules within a larger cyst or a solid intramedullary mass. Not uncommonly they share blood supply with the surrounding spinal cord.

Hemangioblastoma:

• Cavernous hemangiomas: Cavernous hemangiomas or cavernous malformations are small collections of vessels that appear purplish in color, much like a mulberry. On microscopic examination they consist only of blood vessels with vessel walls varying from single layer capillary type to much thicker walls made up of layers of collagen fibers but no elastic fibers or muscle. There is no intervening tissue between the vessels, but there can be associated hematomas and calcium.

Cavernous malformation: