Schwannoma, Neurofibroma & Phakomatoses

Schwannomas and neurofibromas are the two major peripheral nerve sheath tumors arising from Schwann cells. Schwannomas are encapsulated, well-differentiated tumors composed entirely of Schwann cells; neurofibromas are unencapsulated tumors with mixed Schwann cell, fibroblast, and perineurial components. Both have benign and malignant forms, and both are characteristic of specific neurocutaneous syndromes — NF1 (neurofibromatosis type 1) and NF2 (neurofibromatosis type 2) — that are themselves important to recognize. This page covers schwannomas, neurofibromas, and the phakomatoses.

Schwannoma

Pathology

  • Encapsulated by epineurium; arises eccentrically from nerve.
  • Antoni A regions: compact, cellular areas with palisading nuclei forming Verocay bodies (alternating eosinophilic anuclear zones and nuclear palisades).
  • Antoni B regions: loose, hypocellular myxoid areas.
  • Verocay bodies: characteristic palisading pattern in Antoni A.
  • Variable hyaline-thickened vessels with thrombosis.
  • S100 + SOX10 positive (Schwann cell markers); strongly so.
  • EMA: capsule positive.
  • Other types: cellular schwannoma (more cellular, can be confused with sarcoma), plexiform schwannoma, melanotic schwannoma.

Locations

  • Vestibular schwannoma (acoustic neuroma): most common; cerebellopontine angle; CN VIII.
  • Trigeminal schwannoma.
  • Spinal nerve roots (dorsal root preferred; often dumbbell shaped extending through foramina).
  • Peripheral nerves of trunk, limbs.
  • Visceral nerves (rare).

Clinical

  • Vestibular schwannoma: progressive unilateral hearing loss + tinnitus + sometimes facial weakness (CN VII) + cerebellar signs.
  • Spinal schwannoma: pain, sensory or motor deficits in nerve root distribution.
  • Slowly growing; benign in most cases.

Imaging

  • Well-circumscribed enhancing mass attached to nerve.
  • Vestibular schwannoma: enlarges internal auditory canal; CPA mass.
  • Spinal: dumbbell extending through neural foramen.

Treatment

  • Surgery: complete resection often curative.
  • Stereotactic radiosurgery for vestibular schwannoma: alternative to surgery in selected cases.
  • Observation for small asymptomatic tumors.
  • Bevacizumab for vestibular schwannomas in NF2 (slows growth, improves hearing in some).

Neurofibroma

Pathology

  • Unencapsulated; involves the entire nerve trunk.
  • Mixed cellular composition: Schwann cells, fibroblasts, perineurial cells, mast cells.
  • Wavy nuclei in loose myxoid or collagenous stroma.
  • Shredded carrot collagen pattern.
  • “Wagner-Meissner-like bodies” in some.
  • S100 positive (less uniform than schwannoma); CD34 positive in fibroblasts.

Subtypes

  • Localized cutaneous neurofibroma: small skin lesions; common in NF1.
  • Diffuse neurofibroma: infiltrating dermal lesion.
  • Plexiform neurofibroma: involves multiple branches of a nerve; “bag of worms”; almost pathognomonic of NF1; risk of malignant transformation to MPNST (8-13% lifetime).
  • Intraneural neurofibroma: within a single nerve.

Treatment

  • Resection for symptomatic; cosmetic management for skin lesions.
  • Plexiform neurofibromas: difficult complete resection.
  • Selumetinib (MEK inhibitor): approved 2020 for inoperable plexiform neurofibroma in NF1 children.
  • Monitor for malignant transformation (rapid growth, pain).

Malignant Peripheral Nerve Sheath Tumor (MPNST)

  • Sarcomatous transformation, often from preexisting plexiform neurofibroma (especially in NF1).
  • Aggressive; high-grade sarcoma.
  • S100 often weak or focal (loss with malignancy).
  • H3K27me3 loss in many cases.
  • Treatment: wide surgical resection + radiation; chemotherapy variable role.

Neurofibromatosis Type 1 (NF1)

Genetics

  • Autosomal dominant; NF1 gene on chromosome 17q11.2.
  • Neurofibromin protein: tumor suppressor; negative regulator of RAS.
  • ~50% sporadic mutations.

Clinical Features

  • Café-au-lait macules: ≥ 6 of certain size.
  • Cutaneous neurofibromas: increase in number with age.
  • Plexiform neurofibromas.
  • Lisch nodules: iris hamartomas.
  • Axillary or inguinal freckling.
  • Optic pathway glioma: pilocytic astrocytoma; childhood.
  • Brainstem glioma.
  • Distinctive skeletal abnormalities: sphenoid wing dysplasia, tibial pseudarthrosis.
  • First-degree relative with NF1.

Associated Tumors and Conditions

  • MPNST.
  • Pheochromocytoma.
  • Glomus tumor.
  • Juvenile myelomonocytic leukemia (JMML).
  • Gastrointestinal stromal tumors (GIST).
  • Breast cancer.
  • Learning disabilities, ADHD.

Neurofibromatosis Type 2 (NF2)

Genetics

  • Autosomal dominant; NF2 gene on chromosome 22q12.
  • Merlin (schwannomin) protein; tumor suppressor.

Clinical Features

  • Bilateral vestibular schwannomas (pathognomonic when present).
  • Multiple meningiomas.
  • Multiple schwannomas (peripheral nerves, spinal nerve roots).
  • Ependymomas (often spinal).
  • Juvenile posterior subcapsular lens opacity (cataract).
  • Retinal hamartomas.
  • NO café-au-lait macules or Lisch nodules.

Treatment

  • Multidisciplinary management.
  • Hearing preservation strategies (early intervention, hearing aids, cochlear implants, auditory brainstem implants).
  • Bevacizumab for progressive vestibular schwannomas.
  • Surgical resection and radiosurgery as indicated.

Schwannomatosis

  • Multiple schwannomas WITHOUT vestibular schwannomas (or with unilateral).
  • SMARCB1 or LZTR1 mutations.
  • Often presents with chronic pain.

Other Neurocutaneous Syndromes

Tuberous Sclerosis Complex (TSC)

  • Autosomal dominant; TSC1 (hamartin) or TSC2 (tuberin) mutations.
  • Cortical tubers, subependymal nodules, SEGA.
  • Cardiac rhabdomyomas, renal angiomyolipomas, lymphangioleiomyomatosis.
  • Skin: facial angiofibromas, ash-leaf macules, shagreen patches.
  • Seizures, autism, intellectual disability.
  • mTOR inhibitors (everolimus, sirolimus) transformative for SEGA, angiomyolipoma, refractory seizures.

Von Hippel-Lindau (VHL)

  • VHL gene; tumor suppressor.
  • Hemangioblastomas of cerebellum, brainstem, spinal cord, retina.
  • Renal cell carcinoma.
  • Pheochromocytoma.
  • Endolymphatic sac tumors.

Sturge-Weber Syndrome

Discussed in vascular malformations page. Leptomeningeal angioma + port-wine stain + seizures + cortical calcifications. GNAQ somatic mutation.

PHACE Syndrome, Cowden, Other

Rare neurocutaneous syndromes; specific molecular causes; characteristic features.

🔍 Did You Know?

The 2020 approval of selumetinib for inoperable plexiform neurofibromas in NF1 was a landmark in pediatric oncology. Plexiform neurofibromas — large, often disfiguring tumors that involve multiple branches of a nerve, sometimes called “bag of worms” — were previously treatable only with surgery, which was often incomplete because of nerve involvement. They can cause severe pain, disfigurement, and functional impairment, and ~8-13% of plexiform neurofibromas transform to malignant peripheral nerve sheath tumor (MPNST) over the patient’s lifetime. Selumetinib, a MEK inhibitor, blocks the RAS-MAPK pathway that is hyperactivated in NF1 (because of NF1 gene loss of function — NF1 normally restrains RAS). In the SPRINT trial (2020), pediatric patients with inoperable NF1 plexiform neurofibromas showed dramatic responses: ~70% partial response, with reduction in tumor volume, pain, and disfigurement. The treatment is generally well-tolerated. The approval marked the first specific therapy for NF1-associated tumors and opened a new era: NF1, once a syndrome managed largely through observation and surgical management of complications, is now a treatable condition with targeted therapy for at least one of its major manifestations. Trials are extending to gliomas and other NF1-related tumors. The lesson: identifying the molecular driver of a genetic syndrome can open targeted therapies that transform clinical management. NF1 is a classic example, and similar developments are emerging for NF2 (bevacizumab), TSC (mTOR inhibitors), and other neurocutaneous syndromes.

Pitfalls and Pearls

  • Schwannoma: encapsulated; Antoni A + B + Verocay bodies; S100/SOX10 strongly positive.
  • Neurofibroma: unencapsulated; mixed Schwann + fibroblast + perineurial; wavy nuclei + shredded carrot collagen.
  • Plexiform neurofibroma: “bag of worms”; NF1 pathognomonic; 8-13% lifetime MPNST risk.
  • Vestibular schwannoma + bilateral: NF2 pathognomonic.
  • Vestibular schwannoma + unilateral: usually sporadic.
  • MPNST: malignant; H3K27me3 loss; loss of S100; often from preexisting plexiform NF.
  • NF1 diagnostic criteria: café-au-lait + freckling + Lisch + cutaneous NF + skeletal + first-degree relative; need 2 of 7.
  • NF2 diagnostic criteria: bilateral vestibular schwannomas OR family history + unilateral + other.
  • Schwannomatosis: SMARCB1, LZTR1; multiple schwannomas without VS.
  • Selumetinib (MEK inhibitor): NF1 plexiform NF; approved 2020.
  • Bevacizumab: NF2 vestibular schwannomas.
  • Everolimus / sirolimus: TSC SEGAs and angiomyolipomas.
  • Optic pathway glioma + NF1: classical pediatric presentation; observation often first; selumetinib/carboplatin if progression.
  • Hemangioblastoma + VHL: cerebellum, brainstem, spinal cord, retina.
  • Sturge-Weber: port-wine stain + leptomeningeal angioma + seizures; GNAQ somatic.

References

  1. Louis DN, Perry A, Wesseling P, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021;23(8):1231-1251.
  2. Hirbe AC, Gutmann DH. Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol. 2014;13(8):834-843.
  3. Evans DG. Neurofibromatosis type 2 (NF2): a clinical and molecular review. Orphanet J Rare Dis. 2009;4:16.
  4. Gross AM, Wolters PL, Dombi E, et al. Selumetinib in children with inoperable plexiform neurofibromas. N Engl J Med. 2020;382(15):1430-1442.
  5. Plotkin SR, Stemmer-Rachamimov AO, Barker FG 2nd, et al. Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N Engl J Med. 2009;361(4):358-367.
  6. Krueger DA, Care MM, Holland K, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med. 2010;363(19):1801-1811.