Neurofibromas are characteristic of NF1. Cutaneous neurofibromas are present in 95% of patients, although they are not life-threatening. Deep neurofibromas are neoplasms of the peripheral nerve sheath and are divided into nodular neurofibromas (dependent on a single nerve fascicle) and PNF (dependent on several fascicles).

PNF are pathognomonic of NF1 and are present in 40–60% of patients. These tumours can affect the skin and subcutaneous tissue, causing aesthetic alterations, or they can involve deeper structures, leading to skeletal changes. On the other hand, they may degenerate into malignant transformation.

Fig 1: 12-year-old male with a left malar and zygomatic plexiform neurofibroma causing noticeable facial aesthetic alteration.

Regarding the early diagnosis of PNF, European guidelines such as ERN GENTURIS recommend performing whole-body MRI in asymptomatic adolescent patients with NF1, as this is the stage of life when PNF most commonly develops. This recommendation is based on the availability and speed of current imaging techniques, the rapid tumour growth and development of morbidity during childhood and adolescence, and the increasing number of therapeutic agents that may effectively halt neurofibroma growth. Additionally, the presence of the 17q11 microdeletion increases the risk of developing internal tumours.

Fig 2: 12-year-old male. Whole-body MRI in a patient with NF1 transitioning from childhood to adolescence. No PNF observed, only millimetric neurofibromas in the left thigh.

For already diagnosed PNF, the guidelines recommend individualised monitoring led by multidisciplinary medical teams. Furthermore, symptomatic PNF requires more frequent monitoring and shorter intervals between imaging tests.

Fig 3: 13-year-old male. Part of a whole-body MRI of an adolescent with NF1. Slow growth and progression of an extensive PNF in the subcutaneous cellular tissue of the lumbosacral region.

Table 2: Summary of the ERN GENTURIS Recommendations for PNF.

Differentiating nodular neurofibromas from PNF is crucial in imaging studies. Nodular neurofibromas are better defined and usually more superficial, making them suitable for ultrasound (US), computed tomography (CT), and MRI. They typically appear as well-defined, oval lesions adjacent to the peripheral nerve, displaying the "target sign," with a hyperintense margin on T2-weighted sequences and a hypointense centre. After gadolinium administration, they show homogeneous enhancement of the central component.

On the other hand, PNFs present as confluent, infiltrative, multinodular masses with a mass effect on adjacent structures, making MRI the imaging modality of choice. They may display multiple target signs and show heterogeneous enhancement after gadolinium administration. A structured report can categorise them based on their morphology and signal intensity (homogeneous, heterogeneous, or mixed patterns), depth (superficial, deep, or mixed), and relationship with adjacent structures (diffuse or well-defined).

Fig 4: 12-year-old male with PNF in the left popliteal fossa showing the "target sign" in T2 and STIR sequences.

Fig 5: 6-year-old male with right dorsal PNF showing heterogeneous signal intensity, a mixed depth pattern, and a diffuse relationship with adjacent structures. It is located in the upper thoracic region, positioned posteriorly in the right paravertebral area, with a subpleural imprint and intercostal extension. The tumor affects the dorsal and paravertebral musculature, as well as the subcutaneous adipose tissue.

Regarding complications, various bone abnormalities are associated with mesodermal dysplasia and extrinsic pressure from neurofibromas.

Among these, scoliosis is the most common, present in 21% of patients. Scoliosis can be non-dystrophic, following a course similar to that of the general population, or dystrophic, which occurs earlier, progresses rapidly, and has a worse prognosis. Dystrophic scoliosis involves four to six vertebral bodies and is associated with vertebral scalloping, neuroforaminal widening, transverse process spindling, and rib pencilling.

Fig 6: 17-year-old female with dystrophic scoliosis secondary to PNF and dystrophy associated with NF1, involving more than six vertebral bodies, with associated foraminal widening and sharpening of the transverse processes.

Other bone alterations associated with PNF include posterior vertebral fusions, thinning of vertebral components, widening of the neural foramina, rib deformities, and anterolateral deformities of the tibia and fibula.

Fig 7: 15-year-old male with lumbosacral plexiform NFs involving the nerve roots and expansion of the conjunction foramina.

Fig 8: 13-year-old female with left middle dorsal intercostal neurofibromas causing rib deformities.

Fig 9: 17-year-old male with plexiform NFs in both lower limbs. On the right, located posterolaterally to the tibial shaft; on the left, in the posterior region of the leg, ankle, and hindfoot. Correction of asymmetry of the lower limbs. Non-ossifying fibroma (NOF) in the proximal region of the left tibia.

Fig 10: 12-year-old female. Left occipital PNF extending to the posterosuperior part of the neck. Cutaneous involvement is present, with soft tissue thickening and deep extension surrounding the ipsilateral sternocleidomastoid muscle. It causes rotatory subluxation between C1 and C2 towards the left.

PNF can degenerate into malignant neoplasms in 2% of cases, transforming into high-grade sarcomas (MPNSTs).

MPNSTs can present asymptomatically but are typically associated with symptoms such as persistent pain, rapid growth, hardening, or new-onset neurological deficits. Despite their low incidence, they are the leading cause of death in NF1 patients.

If MPNST is suspected, regional MRI should be performed. MPNSTs show atypical signs on MRI, such as increased mass size, peripheral enhancement, increased perilesional edema, and intratumoral cystic lesions. If two or more atypical signs are present, the suspicion of malignant transformation is high.

Table 3: Atypical signs of PNF on MRI.

However, PET-CT or biopsy is often required for a definitive diagnosis. PET-CT is the most accurate imaging test, with MPNSTs appearing as hypermetabolic lesions with an SUVmax greater than 3.5.

Fig 11: 16-year-old male with malignant right sacral plexiform NF spreading to the neuroaxis. Dural ectasia present. Hypermetabolic right pelvic masses that, in the patient's clinical context, are consistent with malignancy in neurofibromas.

Historically, the treatment for PNF has been surgical.

Indications for surgical treatment include the potential for malignant transformation, neurological deficits, aesthetic alterations, and respiratory difficulties (especially in PNF of the neck and mediastinum).

Fig 12: 14-year-old male. Plexiform NF on the right side, following the course of the brachial plexus, from the origin of the cervical roots to the supraclavicular, axillary, arm, and elbow regions. Residual right paravertebral NF (anterior surgical resection).

Studies have shown that the highest rate of benefits is achieved when treating PNF that causes respiratory alterations due to extrinsic compression and aesthetic changes.

However, a high recurrence rate of PNF after surgery, along with multiple functional and neurological sequelae, has also been demonstrated.

Therefore, it has been concluded that new, effective medical therapies are necessary for the treatment of PNF.

Currently, Selumetinib, a MEK inhibitor, has been approved for treating inoperable and symptomatic PNF. Selumetinib has demonstrated tumour reduction with a partial response in 70% of patients, with 59% of those showing durability after one year, and symptom relief lasting up to four years.

This drug is not absent of adverse effects, though most are mild (e.g., gastrointestinal symptoms, asymptomatic increase in CPK, paronychia, acneiform eruptions). To date, the drug dose has only been reduced in 39% of patients due to an asymptomatic reduction in left ventricular ejection fraction (LVEF).