Neurofibroma

Neurofibroma is a benign peripheral nerve sheath tumour built from a mixture of Schwann cells, fibroblasts and perineural cells in a myxoid stromal matrix. It accounts for approximately 5% of all benign soft tissue tumours. It occurs in three clinical forms, localised (solitary), diffuse and plexiform, and each has its own associations, behaviour and treatment.

Who gets it. The solitary type presents at 20-40 years, while NF1-associated lesions appear from childhood. Males and females are affected equally. Any nerve can be involved, and the plexiform type favours large nerves and plexuses.

Why it matters. Plexiform neurofibromas are virtually pathognomonic for NF1, and in NF1 patients neurofibromas carry a significant risk of malignant transformation to MPNST. Unlike a schwannoma, a neurofibroma cannot be separated from its parent nerve, so excision means nerve sacrifice. Diffuse cutaneous neurofibromas cause significant morbidity and disfigurement.

Cellular composition. Neurofibromas arise from the peripheral nerve sheath and contain a heterogeneous cell population: Schwann cells, fibroblasts, perineural-like cells and mast cells, embedded in a myxoid collagenous matrix. This mixed composition distinguishes them from schwannomas, which contain only Schwann cells.

The NF1 gene. Patients with NF1 carry a germline mutation in the NF1 tumour suppressor gene on chromosome 17q11.2. It encodes neurofibromin, a RAS-GTPase activating protein (RAS-GAP) that inactivates RAS signalling, so loss of neurofibromin leaves the RAS-MAPK pathway constitutively active.

From neurofibroma to MPNST. The inherited germline NF1 mutation is the first hit and somatic loss of heterozygosity of NF1 is the second. Additional mutations in TP53, CDKN2A/B and SUZ12 then drive progression to a high-grade sarcoma; the intermediate steps are set out under atypical neurofibroma below.

The three forms differ in presentation, in how often they come with NF1 and in their malignant potential.

Localised (solitary). Localised neurofibromas (90%) present as single, slowly growing, painless nodules, typically in young to middle-aged adults. They arise within the dermis (cutaneous) or along peripheral nerves (intraneural), and most are sporadic.

What the localised lesion feels like. A soft, mobile subcutaneous or dermal nodule, typically 1-3cm, painless unless it compresses adjacent structures. A skin lesion may show the buttonhole sign, invaginating under pressure. It does not transilluminate, whereas a schwannoma may.

Diffuse. Diffuse neurofibromas are poorly defined, plaque-like thickenings of skin and subcutaneous tissue, typically in children and young adults and often on the head, neck or trunk. The skin is thickened and loses its normal texture, hyperpigmentation is common, and the lesion may cause hypertrophy of the underlying tissues. They are disfiguring, and their infiltrative growth makes complete excision difficult.

Plexiform. Plexiform neurofibromas are virtually pathognomonic for NF1. Sporadic plexiform lesions are described but rare, so one should prompt a full NF1 assessment rather than be taken as proof. They involve multiple nerve fascicles along the length of a nerve or plexus, creating the characteristic bag of worms, and are typically congenital or develop in early childhood.

What the plexiform lesion does. The rope-like masses are palpable along the nerve's distribution, often beneath hyperpigmented skin. They may cause limb overgrowth and elephantiasis, and can involve deeper structures such as the mediastinum and retroperitoneum.

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History. A solitary neurofibroma is typically a painless subcutaneous nodule found incidentally. A plexiform neurofibroma presents as a congenital or childhood mass; ask about a family history of NF1. Neurofibromas are usually asymptomatic unless compressive, and their growth is slow or stable.

Red flags for MPNST. These suggest malignant transformation and need urgent work-up:

• Rapid growth, a size increase over weeks to months in a previously stable lesion
• Pain, new in a previously painless lesion or worsening
• Neurological deficit, progressive motor weakness or sensory loss
• Systemic symptoms, weight loss and fatigue in advanced MPNST

Inspection. Note the size, location and overlying skin. Multiple lesions suggest NF1, as do café-au-lait spots, axillary or inguinal freckling (Crowe sign) and Lisch nodules (iris hamartomas) on slit-lamp examination.

Palpation. The mass is soft and non-tender; tenderness suggests MPNST. It cannot be separated from the nerve, unlike a schwannoma, and a Tinel sign may be present but is less prominent than with a schwannoma.

Neurological assessment. Examine the motor and sensory function of the affected nerve and document any deficit. Measure limb circumference if there is hypertrophy.

NF1 diagnostic criteria. NF1 is diagnosed when two or more of the following are present:

1. Six or more café-au-lait spots: over 5mm prepubertal or over 15mm postpubertal
2. Two or more neurofibromas of any type or one plexiform neurofibroma
3. Axillary or inguinal freckling
4. Optic glioma
5. Two or more Lisch nodules (iris hamartomas)
6. Distinctive osseous lesion: sphenoid dysplasia, tibial pseudarthrosis, or bowing
7. First-degree relative with NF1 by the above criteria

Schwannoma is the lesion most often confused with neurofibroma; MPNST is the one that must not be missed.

A neurofibroma is managed according to type, symptoms, functional threat and malignant red flags. Observe stable asymptomatic lesions; excise symptomatic localised tumours with explicit counselling about fascicular sacrifice; debulk plexiform disease selectively; and urgently investigate rapid growth, pain or deficit for ANNUBP/MPNST.

Initial assessment. Confirm the diagnosis on clinical examination and imaging, and determine the type: localised, diffuse or plexiform. Screen for NF1 if the lesion is plexiform or there are multiple lesions, and assess the symptoms: pain, neurological deficit and cosmetic concern.

Risk stratification. Risk guides the intensity of surveillance.

• Low risk: solitary, asymptomatic, stable size, no NF1
• Intermediate risk: diffuse type, cosmetic concern, no NF1
• High risk: plexiform with NF1, size over 5cm, rapid growth, pain

Conservative Management

Observation. Observation suits an asymptomatic localised neurofibroma, a stable plexiform neurofibroma in an NF1 patient, and small lesions (less than 3cm) without functional impact, provided there is no evidence of malignant transformation. Surgery is reserved for symptoms, cosmetic concern and diagnostic uncertainty.

Surveillance in NF1 with plexiform disease. These are the high-risk patients:

• Clinical examination every 6-12 months
• Baseline MRI with contrast at diagnosis
• Annual MRI for lesions over 3cm or symptomatic lesions
• PET-CT if there is concern for MPNST (SUV over 3.5 suspicious; the limits of that cut-off are discussed under Detecting Transformation)
• Patient education on the red-flag symptoms: pain, rapid growth, deficit

Surgical Management

Indications. Surgical decision-making balances symptom relief against the risk of neurological deficit from nerve sacrifice.

• Absolute: suspected malignant transformation (MPNST), progressive neurological deficit, severe pain unresponsive to conservative measures, diagnostic uncertainty (to rule out malignancy)
• Relative: symptomatic compression of adjacent structures, cosmetic disfigurement causing psychological distress, functional impairment (limited range of motion, daily activities), patient preference for an asymptomatic but growing lesion
• Contraindications: medical comorbidities precluding surgery, extensive plexiform neurofibroma where resection would cause severe deficit, multiple small asymptomatic lesions in NF1

Surgical Technique

Planning. MRI defines the anatomical extent and the nerve involved. Consent the patient for nerve sacrifice and the resulting deficit, mark the skin incision along the nerve's course, and consider nerve monitoring if nerve preservation is being attempted.

Excising a localised neurofibroma. The tumour is intrinsic to the nerve and cannot be shelled out like a schwannoma. The aim is a marginal margin, not a wide one, because the tumour is benign.

1. Incision and exposure. A longitudinal incision along the nerve's course; identify and protect normal nerve proximally and distally, and isolate the neurofibroma within the expanded nerve segment.
2. Tumour assessment. Assess whether the tumour can be separated from the nerve (unlikely); if it is intraneural, plan for fascicular sacrifice. Document preoperative motor and sensory function.
3. Resection. Sacrifice the involved fascicles, or the entire nerve if involvement is diffuse, and preserve uninvolved fascicles if possible (rare in practice).
4. Nerve reconstruction. Consider a nerve graft if a critical motor nerve is involved and the gap is long: a sural nerve interposition graft for gaps over 2cm, and direct repair only if tension is minimal. Most sensory nerves do not require reconstruction.
5. Closure. Haemostasis (neurofibromas can be vascular), layered closure without tension, and a drain only after extensive dissection.

Debulking plexiform disease. The goal is symptom relief, not cure, because complete resection is impossible. The mass is debulked while nerve function is preserved, subtotal resection is accepted to minimise deficit, and high recurrence is expected because the margins are incomplete.

Excising diffuse neurofibroma. The tumour is infiltrative, so it is excised widely with a margin, which may require skin grafting or flap reconstruction. Positive deep margins are accepted over critical structures, and recurrence is 20-40%.

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Reconstruction and Rehabilitation

Nerve deficits. Document the expected deficits: motor weakness, sensory loss and neuropathic pain. Occupational therapy addresses hand dysfunction, splinting supports motor deficits such as wrist drop and foot drop, and gabapentin or pregabalin treats neuropathic pain.

Soft tissue defects. The size of the defect and what it exposes decide the closure:

• Primary closure if minimal undermining is required
• Skin graft for shallow defects without exposed critical structures
• Local flaps (rotation, advancement) for moderate defects
• Free tissue transfer for large defects or exposed neurovascular structures

Rehabilitation. Early mobilisation prevents stiffness, desensitisation helps hypersensitive scars, and strengthening exercises begin once healed. For patients with NF1 and disfigurement, neuropsychological support is part of rehabilitation.

Novel and Emerging Therapies

MEK inhibition. Selumetinib inhibits MEK in the RAS-MAPK pathway. It is indicated for progressive, symptomatic plexiform neurofibromas in children with NF1, where it achieves a 70% partial response with tumour volume reduction, and it received FDA approval in 2020 for paediatric NF1 plexiform neurofibroma.

Under investigation.

• mTOR inhibitors: sirolimus trials for plexiform neurofibromas
• HDAC inhibitors: epigenetic modulation trials
• Immunotherapy: PD-1 inhibitors for MPNST
• Gene therapy: NF1 gene replacement (preclinical)

Localised. The prognosis is excellent with complete excision, and recurrence is less than 5% if marginal margins are achieved. Malignant transformation in sporadic lesions is less than 1%, and no systemic surveillance is required.

Diffuse. The overall prognosis is good, but infiltrative growth makes complete excision difficult and local recurrence is high. The malignant transformation risk is low (less than 5%), and clinical surveillance for recurrence is recommended.

Plexiform in NF1. These tumours cannot be completely excised without major neurological deficit and require lifelong MPNST surveillance; selumetinib may reduce tumour burden and symptoms. NF1-associated MPNST carries a poor prognosis, with 5-year survival of approximately 21% against 42% for sporadic MPNST, so early detection is critical.

A stepwise progression. Transformation is a multistep progression, not a single leap: a benign plexiform neurofibroma does not usually jump straight to high-grade MPNST. It passes through an atypical neurofibroma and then an atypical neurofibromatous neoplasm of uncertain biologic potential (ANNUBP), a consensus-defined intermediate.

What defines ANNUBP. It shows atypical features short of MPNST: cytological atypia, loss of the normal neurofibroma architecture, hypercellularity, and/or a low but definite mitotic rate. It lacks the high mitotic count and the necrosis of MPNST.

The molecular step. On top of the biallelic NF1 loss that defines the neurofibroma, progression to atypical neurofibroma/ANNUBP is driven by loss of the CDKN2A/CDKN2B (p16) tumour-suppressor locus. Further hits (TP53, SUZ12/PRC2, EGFR amplification) then complete the step to high-grade MPNST, and loss of H3K27me3 on immunohistochemistry is a useful marker of that final transition.

Why the category matters. ANNUBP is regarded as a premalignant lesion, so it is managed differently from both a benign neurofibroma and an MPNST. Rather than simple observation (benign) or wide oncological resection with radiotherapy (MPNST), it is generally treated by complete marginal (macroscopically clear) excision to prevent progression, with pathology of the whole lesion to exclude a co-existing MPNST. Its imaging correlate is often a distinct nodular lesion arising within a plexiform neurofibroma.

The SUV over 3.5 threshold used in the surveillance protocol is a crude test. Whole-body MRI quantifies tumour burden, and FDG-PET uses a tumour-to-liver ratio, not just SUVmax.

The distinct nodular lesion. The earliest imaging sign of atypical change within a plexiform neurofibroma is a discrete, well-defined nodule that stands out from the surrounding plexiform tissue, often with loss of the target sign, a more homogeneous or solid signal, and larger size. Atypical neurofibroma/ANNUBP and early MPNST arise in these nodules, so they are the lesions to biopsy or excise.

Whole-body MRI. In NF1 with a high plexiform burden, whole-body MRI (STIR or fat-suppressed sequences) maps the total internal tumour volume and screens the whole body for distinct nodular lesions that a symptom-driven, single-region scan would miss. It is useful for baseline burden and serial surveillance.

Reading FDG-PET. Metabolically active tumour is suspicious for transformation, but a single SUVmax cut-off has false positives and negatives. Ferner (PMID 17932395) found qualitative PET sensitivity of 0.89 and specificity of 0.95, yet showed that SUVmax does not predict grade, and the quoted 2.5/3.5 cut-offs come from later pooled work, not that paper. The tumour-to-liver SUV ratio (and delayed or dual-time-point imaging) discriminates benign from malignant better than SUVmax alone.

Where to biopsy. A metabolically hot distinct nodular lesion is the target for image-guided biopsy of the most active area, not blind sampling of the whole plexiform mass. Biopsy a clinically worrying lesion whatever the number.

No single test is definitive. Benign neurofibromas can enhance and be mildly FDG-avid, and biopsy can undersample a heterogeneous transforming lesion. Imaging guides but does not replace the correlation of clinical red flags, targeted biopsy and specialist (sarcoma-MDT) pathology.

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Global Epidemiology

• NF1 incidence: approximately 1 in 2500-3000 live births worldwide; one of the most common autosomal dominant disorders, with no consistent racial or ethnic predilection
• Penetrance: nearly complete by adulthood, but expression is highly variable even within families; roughly 50% of cases are de novo mutations
• Plexiform neurofibroma: present in 30-50% of NF1 patients on whole-body MRI; the dominant source of malignant transformation risk

Side-by-Side Guidance

Registry and Cohort Evidence

• There is no dedicated arthroplasty-style implant registry for neurofibroma; the key population evidence comes from national NF1 registers and cancer registries (e.g. the NW England population study, French and German NF reference cohorts) that established the 8-13% lifetime MPNST risk and the poor survival of NF1-associated MPNST.
• Pharmacovigilance and post-marketing data for selumetinib are tracked through regulator and trial-network registries rather than orthopaedic implant databases.

High- vs Limited-Resource Practice Variation

• Well-resourced settings: access to whole-body MRI, FDG-PET, MEK inhibitor therapy and dedicated multidisciplinary NF1/sarcoma clinics enables structured surveillance and early MPNST detection.
• Limited-resource settings: surveillance relies more on clinical examination and targeted ultrasound/MRI; MEK inhibitors are frequently unavailable or unaffordable, so management of plexiform disease remains observation and selective surgical debulking, with later-stage MPNST presentation.
• Universally, patient education on red-flag symptoms (new pain, rapid growth, neurological deficit) is the single most transferable, low-cost surveillance tool.

ANNUBP, the malignant grey zone. The category of atypical neurofibromatous neoplasm of uncertain biologic potential (defined by CDKN2A/B loss and atypia short of MPNST) is now recognised by WHO. Thresholds for resection and surveillance of these premalignant lesions are not standardised.

How aggressive plexiform surgery should be. Debulking relieves symptoms, but recurrence is high and complete excision risks major deficit. With effective MEK inhibition, the balance between upfront surgery and medical therapy for symptomatic plexiform disease is shifting and remains debated.

Optimal imaging for transformation. FDG-PET (SUVmax cut-offs and tumour-to-liver ratio) improves MPNST detection but with false positives, and whole-body MRI quantifies tumour burden. The ideal surveillance interval and modality combination are not settled.

Duration and role of MEK inhibitors. Selumetinib shrinks plexiform neurofibromas, but optimal treatment duration, rebound after cessation, adult efficacy and whether it reduces MPNST risk are all unresolved.

Related pages: Neurofibromatosis for the syndrome, the 2021 revised diagnostic criteria and the wider surveillance programme; Schwannoma for the lesion this is most often confused with — it shells out from the nerve and stains diffusely for S100, where a neurofibroma does neither; Malignant Peripheral Nerve Sheath Tumour for the transformation this page screens against, including the ANNUBP intermediate category; Nerve Sheath Tumors of the Spine for the spinal and dumbbell presentations; and MRI Neurography for the imaging signs, remembering that no imaging feature reliably separates benign from malignant.

1. WHO Classification of Tumours Editorial Board. Soft Tissue and Bone Tumours. WHO Classification of Tumours. 5th ed. Lyon: IARC Press; 2020.

2. Ferner RE, Huson SM, Thomas N, et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet. 2007;44(2):81-88. doi:10.1136/jmg.2006.045906

3. Gross AM, Wolters PL, Dombi E, et al. Selumetinib in children with inoperable plexiform neurofibromas. N Engl J Med. 2020;382(15):1430-1442. doi:10.1056/NEJMoa1912735

4. Evans DG, Baser ME, McGaughran J, et al. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet. 2002;39(5):311-314. doi:10.1136/jmg.39.5.311

5. Rodriguez FJ, Folpe AL, Giannini C, Perry A. Pathology of peripheral nerve sheath tumors: diagnostic overview and update on selected diagnostic problems. Acta Neuropathol. 2012;123(3):295-319. doi:10.1007/s00401-012-0954-z

6. Xu GZ, Li YH, Zhao DP, et al. Comparison of dumbbell-shaped schwannomas and neurofibromas in the upper extremities. Acta Neurochir (Wien). 2009;151(6):653-661. doi:10.1007/s00701-009-0280-8

7. Woodruff JM, Godwin TA, Erlandson RA, et al. Cellular schwannoma: a variety of schwannoma sometimes misinterpreted as a malignant tumor. Am J Surg Pathol. 1981;5(8):733-744.

8. Beert E, Brems H, Daniëls B, et al. Atypical neurofibromas in neurofibromatosis type 1 are premalignant tumors. Genes Chromosomes Cancer. 2011;50(12):1021-1032. doi:10.1002/gcc.20921

9. Mautner VF, Asuagbor FA, Dombi E, et al. Assessment of benign tumor burden by whole-body MRI in patients with neurofibromatosis 1. Neuro Oncol. 2008;10(4):593-598. doi:10.1215/15228517-2008-011

10. Salamon J, Veldhoen S, Apostolova I, et al. 18F-FDG PET/CT for detection of malignant peripheral nerve sheath tumours in neurofibromatosis type 1: tumour-to-liver ratio is superior to an SUVmax cut-off. Eur Radiol. 2014;24(2):405-412. doi:10.1007/s00330-013-3020-x

11. Farid M, Demicco EG, Garcia R, et al. Malignant peripheral nerve sheath tumors. Oncologist. 2014;19(2):193-201. doi:10.1634/theoncologist.2013-0328

12. Dunn GP, Spiliopoulos K, Plotkin SR, et al. Role of resection of malignant peripheral nerve sheath tumors in patients with neurofibromatosis type 1. J Neurosurg. 2013;118(1):142-148. doi:10.3171/jns.2012.9.JNS101610

13. Stucky CC, Johnson KN, Gray RJ, et al. Malignant peripheral nerve sheath tumors (MPNST): the Mayo Clinic experience. Ann Surg Oncol. 2012;19(3):878-885. doi:10.1245/s10434-011-1978-7

14. Dombi E, Baldwin A, Marcus LJ, et al. Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas. N Engl J Med. 2016;375(26):2550-2560. doi:10.1056/NEJMoa1605943

15. Fisher MJ, Avery RA, Allen JC, et al. Functional outcome measures for NF1-associated optic pathway glioma clinical trials. Neurology. 2013;81(21 Suppl 1):S15-S24. doi:10.1212/01.wnl.0000435745.95155.b8

16. Needle MN, Cnaan A, Dattilo J, et al. Prognostic signs in the surgical management of plexiform neurofibroma: the Children's Hospital of Philadelphia experience, 1974-1994. J Pediatr. 1997;131(5):678-682. doi:10.1016/s0022-3476(97)70092-1

17. Bhargava R, Parham DM, Lasater OE, et al. MR imaging differentiation of benign and malignant peripheral nerve sheath tumors: use of the target sign. Pediatr Radiol. 1997;27(2):124-129. doi:10.1007/s002470050082

18. Jett K, Friedman JM. Clinical and genetic aspects of neurofibromatosis 1. Genet Med. 2010;12(1):1-11. doi:10.1097/GIM.0b013e3181bf15e3