Schwann cells

There are two kinds of Schwann cells, myelinating and nonmyelinating.

While myelinating Schwann cells cover large diameter (>1 micrometer) peripheral nervous system (PNS) axons with myelin, nonmyelinating Schwann cells encapsulate small diameter PNS axons with their cytoplasmic processes.

This conglomeration of nonmyelinating Schwann cells and axons is called a Remak bundle.

While nonmyelinating Schwann cells are the origin of neurofibromas, the mutations that make them susceptible to this transformation occur in Schwann cell precursors during early nerve development.

Tumorigenesis

Mutated nonmyelinating Schwann cells do not form normal Remak bundles. Instead, they fail to properly surround and segregate target axons.

It is unknown at this time why, if both types of Schwann cells exhibit bilallelic inactivation of the NF1 gene, only the nonmyelinating variety give rise to neurofibromas.

Once a nonmyelinating Schwann cell has suffered inactivation of its NF1 genes, through genetic mutation and DNA damage caused by environmental factors, it begins to proliferate rapidly.

This condition is called hyperplasia, which is cell growth beyond what is normally seen. However, despite increased numbers of nonmyelinating Schwann cells, there is no neurofibroma yet.

In order for the neurofibroma to develop, cells that are heterozygous for the NF1 gene must be recruited to the site.

It has been hypothesized that the proliferating nonmyelinating Schwann cells secrete chemoattractants such as the KIT ligand, and angiogenic factors such as the heparin-binding growth factor midkine.

These chemicals promote the migration of different kinds of cells that are heterozygous for the NF1 gene into the hyperplastic lesions created by the nonmyelinating Schwann cells.

These cell types include fibroblasts, perineurial cells, endothelial cells, and mast cells.

The mast cells then secrete mitogens or survival factors that alter the developing tumor microenvironment and result in neurofibroma formation.

Dermal and plexiform neurofibromas do differ in later development stages, but the details are unclear at this point.

Once a plexiform neurofibroma has formed, there is a chance that it will undergo transformation into a malignant peripheral nerve sheath tumor (MPNST).

The formation of malignant cancers from neurofibromas is associated with the loss of expression of the CDKN2A or TP53 gene in non-myelinating Schwann cells that also exhibit biallelic inactivation of the NF1 gene.

Tumors

Schwann cells are the neoplastic element in neurofibromas.