Neurofibroma pathophysiology

Neurofibromas arise from the nonmyelinating-type Schwann cells and can occur anywhere in the body. Gene involved in the pathogenesis of plexiform neurofibroma is NF1 which codes for neurofibromin that leads to loss of RAS control causing increased activity of downstream RAS pathways involved in increased cell growth and survival. Plexiform neurofibroma may be caused by the bi-allelic inactivation of the neurofibromatosis type I tumor suppressor gene. On gross pathology, a nonencapsulated superficial mass is the characteristic finding of localised or diffuse neurofibroma; whereas the “bag of worms” appearance is the characteristic finding of plexiform neurofibroma. On microscopic histopathological analysis, nerve fibers, schwann cells, spindle cells with wavy nuclei without pleomorphism, shredded carrot collagen, moderate increase of cellularity vis-a-vis normal dermis, blood vessels, mast cells, pseudomeissnerian bodies, and varying degrees of myxoid degeneration are characteristic findings of neurofibroma. However, plexiform neurofibroma shows a characteristic target sign on histopathology, representing a central core of collagenous and fibrillary tissue with peripheral less densely cellular myxoid tissue. Electron microscopy of neurofibromas shows Schwann cells enclosing axons in plasmalemmal invaginations (mesaxons).

• Neurofibromas arise from the nonmyelinating-type Schwann cells.^[1][2][3]
• Plexiform neurofibromas can grow from nerves in the skin or from more internal nerve bundles, and can be very large.
• About 10% of plexiform neurofibromas undergo transformation into a malignant peripheral nerve sheath tumor (MPNST).^[4]
• In 2006, Yang et al demonstrated a critical neurofibroma microenvironment interaction that includes SCF–stimulated Nf1+/− mast cells potentiating Nf1+/− fibroblast functions.^[5]
• Nearly one-half of the dry tumor weight is made up of collagen secreted by fibroblasts, which comprise the major cellular portion of neurofibroma.
• Fibroblasts migrate, proliferate, and synthesize collagen in response to transforming growth factor β (TGF-β).
• Fibroblast bioactivity is TGF-β dependent.
• Nf1+/− mast cell is the critical effector in the paracrine induction of neurofibroma pathogenesis.
• TGF-β–dependent Nf1+/− fibroblast hyperactivity is a result of increased kinase activity of c-abl secondary to increased Ras–GTP.

• Gene involved in the pathogenesis of plexiform neurofibroma is NF1.
• The NF1 gene is composed of 60 exons spanning 350kb of genomic data, and maps to chromosomal region 17q11.2.^[6]
• This gene codes for neurofibromin which is a large 220-250 KDa cytoplasmic protein that is composed of 2,818 amino acids with three alternatively spliced exons (9a, 23a, and 48a) in the encoding gene.
• The functional part of neurofibromin is GAP, or GTPase-activating protein.
• GAP accelerates the conversion of the active GTP-bound RAS to its inactive GDP-bound form, inactivating RAS and reducing RAS-mediated growth signaling.
• Loss of RAS control leads to increased activity of other signaling pathways including RAF, ERK1/2, PI3K, PAK, MAPK, SCF/c-kit and mTOR-S6 kinase. It is suspected that this increased activity of downstream RAS pathways might work together to increase cell growth and survival.^[7][8]

• Neurofibromas can occur anywhere in body. Gross features of different types of neurofibromas include the following:

Localised neurofibroma and Diffuse neurofibroma

• Superficial mass
• Not encapsulated

Soft tissue neurofibroma

• Not encapsulated, softer (more gelatinous) than schwannoma.
• Superficial tumors are small, pedunculated nodules protruding from skin (molluscum pendulum).
• Deeper tumors are larger, may cause tortuous enlargement of peripheral nerves (plexiform neurofibromas).

Plexiform neurofibroma

• “Bag of worms” appearance^[9]
• Associated with grossly enlarged and tortuous nerves
• Deep tumors are often large
• Highly vascularized and locally invasive

• Made of nerve fibers, schwann cells (cells that cover the nerve fibers), blood vessels, inflammatory white blood cells (mast cells), and connective tissue (fibroblasts and loose material called extracellular matrix)
• Multiple enlarged fascicles of randomly oriented thin spindled nerve sheath cells are embeded in a stromal mucin and wire-like collageneous matrix within fibrous connective tissue^[2]
• Spindle cells have hyperchromatic, elongated, wavy, buckled, small and bland nuclei with indistinct scant cytoplasm
• No pleomorphism
• Tactile-like bodies are also detected
• Varying degrees of myxoid degeneration
• Unencapsulated
• Moderate increase of cellularity vis-a-vis normal dermis
• Uniphasic, low to moderate cellularity (generally hypocellular)
• Occasional mast cells, and lymphocytes, rare foam cells.^[3]
• Thin and thick collagen strands (“shredded carrot collagen”)
• Nerve fibers run through a neurofibroma (making excision more difficult with increased likelihood of nerve damage)
• Nerve frequently not grossly identifiable
• Features of specific differentiation (e.g. pseudomeissnerian bodies) may be present occassionally
• Low mitotic index
• No clear division between Antoni A and B areas within the tumor
• No well formed verocy bodies
• No epithelial component
• No distinct lobulation
• Seldom cystic
• Cellularity and organization are generally insufficient to produce palisading

• Localized hyperchromatic atypical cells (“ancient change“) with:
  • Large, pleomorphic nuclei
  • Cytoplasmic intranuclear inclusions
  • Smudgy chromatin
  • Inconspicuous nucleoli
• Absent or very low mitotic activity
• Low to moderate cellularity
• Often large, long standing lesions

• Proliferation of all elements of peripheral nerves.
• Schwann cells with wire like collagen fibrils (wavy serpentine nuclei, pointed ends), stromal mucosubstances, mast cells, Wagner-Meissner corpuscles, Pacinian corpuscles, axons (highlight with silver or acetylcholinesterase stain, NSE, neurofilament), fibroblasts and collagen.
• Perineurial cells in plexiform types, mitotic figures are rare.
• Less of a fascicular pattern than fibromatosis.
• May be infiltrative, have myxoid areas, contain melanin pigment, have epitheloid morphology.
• Rarely has skeletal differentiation (neuromuscular hamartoma).
• No Verocay bodies
• No nuclear palisading
• No hyalinized thickening of vessel walls

• Nodular or diffuse
• Diffuse cases are also known as elephantiasis neurofibromatosa; characterized by an overgrowth of epidermal and subcutaneous tissue.
• Hypocellular with myxoid background; contains Schwann cells, fibroblasts and mast cells
• Occasional nuclear palisading
• Rarely is pigmented due to melanocytes
• No biphasic pattern of schwannoma
• Target sign on histopathology represents a central core made up of collagenous and fibrillary tissue with peripheral less densely cellular myxoid tissue.^[10]

• Schwann cells enclose axons in plasmalemmal invaginations (mesaxons).

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