Page 8 - Read Online

Page 4 of 15 Brown. Rare Dis Orphan Drugs J. 2025;4:21 https://dx.doi.org/10.20517/rdodj.2025.14

staining, and the need for distinction may not be clinically apparent to the pathologist as both are benign
tumors. If the patient does not yet have a genetic diagnosis and/or does not carry the typical features of
NF1, two distinct tumors can be submitted for next-generation sequencing of somatic mutation analysis
with attention to alterations of chromosome 22q11. If > 1 tumors have different mutations or alterations
involving the NF2 gene and no identified alteration of NF1, this would indicate non-NF2-related
schwannomatosis rather than NF1. Diagnosticians should carefully consider the possibility of
schwannomatosis as a diagnosis for individuals who do not have an identified germline NF1 mutation and
who do not fully meet diagnostic requirements for NF1, but who harbor internal nerve sheath tumors and
have at least one resected skin lesion identified as a “neurofibroma” based on H&E.

THE EXTRACELLULAR MATRIX INCREASES INTERSTITIAL PRESSURE
The ECM makes up ~50% of the dry weight of the tumor, which is about half of that in skin but twice the
concentration found in peripheral nerve endoneurium. The concentration of glycosaminoglycans,
particularly hyaluronic acid, is up to 10 times higher in CNs than in the surrounding skin . In CNs,
[13]
collagen is organized into densely packed, haphazardly splayed bundles, interspersed with intermittent
elastin or reticular fibers that surround disorganized, spindle-shaped tumor cells. CNs are physically
characterized by high internal tissue tension despite lacking a true capsule. This internal pressure becomes
evident during resection at the skin plane, wherein the residual hypodermal tumor often protrudes or
“balloons” outward through the incision, driven by the newly created pressure gradient.

CNs are mostly composed of ECM, including fibrillary collagen types (COL) I, II, III, IV, V, network
collagen type VI (COLVI) and basement membrane collagen type XV, plasma-derived fibronectin,
hyaluronic acid, and Laminin isotype subunit A [14,15] . COLI and COLIII have a filamentous ultrastructure
and are involved in fibrosis, and COLIII confers a promitotic cellular phenotype and may contribute to
[16]
drug resistance . Cultured fibroblasts from CNs primarily produce COLI > COLIII, whereas COLIV is
secreted by Schwann-like tumor cells into a basement membrane-like structure coating each cell . In
[13]
normal skin, COLVI typically resides between the basement membrane and the interstitium. It is produced
by Schwann cells to guide remyelination after nerve injury [17,18] and is required for the organization of
acetylcholine receptors at the neuromuscular junction . COLVI is also found abundantly in normal skin at
[19]
the dermal-epidermal border, where it contributes to the near-impenetrable skin barrier to environmental
exposures, as well as within skeletal muscle, the cerebral meninges, and in disease states such as
glioblastoma and Alzheimer’s disease [20,21] .

ECM components are differentially produced by Schwann-derived tumor cells, perineurial cells, and
tumor-associated fibroblasts that release autocrine and paracrine stromal cell-derived factor-1 (SDF1) and
[22]
transforming growth factor beta (TGFβ) to increase ECM deposition . During synthesis, COLVI is first
woven into a triple helical monomer and then joined into disulfide-bonded dimers and tetramers before
secretion into the extracellular space, where subunits associate non-covalently to form a net-like beaded
meshwork. Intracellular collagen-synthesizing and -modifying enzymes such as lysyl hydroxylases and
prolyl hydroxylases are overexpressed in CNs. The abundant ECM generates a more rigid tumor
microenvironment through collagen crosslinking with elastin. ECM binding also enhances focal adhesion
kinase (FAK) and integrin signaling. Moreover, the macrostructure of the ECM impairs the diffusion of
large molecules and leads to anisotropy and sequestering of pro-tumorigenic growth factors close to tumor
cells. Within CNs, the subchains COL6A1, A2, and A3 are most abundantly expressed by CN-associated
fibroblasts . COLIV is present in a patchy discontinuous pattern focused at the tumor periphery,
[14]
potentially because of hypoxia or altered diffusion parameters at the tumor core. The hyper-coiled, heavily
cross-linked, and chemically stable collagen components of the ECM have a half-life longer than the average