AUTHOR AND EDITOR INFORMATION

Section 1 of 13  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT Scan
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 13  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT Scan
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Acknowledgments
• Multimedia
• References

Background

Neurofibromatosis (NF) is an autosomal dominant disorder, probably of neural crest origin, that affects all 3 germinal layers; therefore, it can involve any organ system. NF is not a single entity but a group of heterogeneous multisystemic neurocutaneous disorders involving both neuroectodermal and mesenchymal derivatives. Although 8 subtypes have been proposed to date, the National Institutes of Health (NIH) Consensus Development Conference has defined 2 distinct types: neurofibromatosis type 1 (NF1), or von Recklinghausen disease, which affects 85% of patients, and neurofibromatosis type 2 (NF2), or bilateral acoustic neuromas/vestibular schwannomas, which affects 10% of patients.^{1, 2, 3, 4, 5, 6, 7, 8, 9, 10}

Neurofibromas may affect any organ in the body. Discrete cutaneous and subcutaneous neurofibromas may develop at any time in life, but they occur infrequently before puberty. The total number of neurofibromas seen in adults with NF1 varies from a few to hundreds or even thousands. Additional cutaneous and subcutaneous neurofibromas continue to develop throughout life, although the rate of appearance may vary greatly from year to year.

Many women experience a rapid increase in the number and size of neurofibromas during pregnancy. Although the course of the pregnancy is normal in most women with NF1, serious complications can occur. Hypertension may first become symptomatic or, if preexisting, may become greatly exacerbated during pregnancy . Large pelvic or genital neurofibromas can complicate delivery, and cesarean delivery appears to be necessary more often in women with NF1 than in other women.¹¹

Hypertension is frequent in patients with NF1 and may develop at any age. In most patients, the hypertension is essential, but vascular dysplasia can occur in association with NF1 and may produce renal artery stenosis, coarctation of the aorta, or other vascular lesions associated with severe hypertension in adult patients with NF1.^{1, 9, 12, 13} Pheochromocytoma can cause severe hypertension in patients with NF1. Malignant neoplasms can occur in patients with NF1 at any age.

Intracranial manifestations of NF1 include development of optic pathway gliomas, cerebral gliomas, hydrocephalus, schwannomas of the cranial nerves, vascular dysplasias, hamartomas, craniofacial plexiform neurofibromas, and spongiotic myelinopathy. NF1 can involve the spine , musculoskeletal system, and the gastrointestinal (GI) tract,^{14, 15, 16} and NF1 is associated with neural crest tumors.¹⁷

Multisystemic involvement is common, and a variety of problems may present in childhood,¹⁸ including seizures and intellectual compromise, optic and acoustic involvement, intracranial and spinal tumors , and an increased incidence of malignancies, osseous defects and congenital dislocations, oral pathology, endocrine disorders, autonomic involvement, GI tract involvement, hypertension, and vascular anomalies.

Related Medscape topics:
Resource Center Hypertension
Resource Center Spinal Disorders

Related eMedicine topics:
Neurofibromatosis Type 2
Acoustic Neuromas/Vestibular Schwannomas

Pathophysiology

The NIH has developed criteria for the diagnosis of NF1 and NF2.⁵ The criteria for the diagnosis of NF1 are met in an individual if 2 or more of the following signs are found:

• Six or more café au lait macules larger than 5 mm in the greatest diameter in prepubertal children and larger than 1.5 cm in postpubertal individuals
• Two or more neurofibromas of any type or 1 plexiform neurofibroma
• Multiple freckles (Crowe sign) in the axillary or inguinal region
• A distinctive osseous lesion, such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudoarthrosis
• Optic glioma
• Two or more iris hamartomas (Lisch nodules) seen on slitlamp or biomicroscopy examination
• A first-degree relative (parent, sibling, offspring) with NF1, as diagnosed by using the above criteria.

However, the NIH criteria are often insufficient for diagnosis of NF1 in young children who have multiple café au lait spots, no other NF1 features, and no family history of NF1. The overwhelming majority of these children later are diagnosed with NF1 because many of the features are rare in infancy but increase in frequency with age.

Children who have inherited NF1 from an affected parent can usually be identified within the first year of life because the diagnostic criteria require just 1 feature in addition to a family history for NF1. This feature is usually multiple café au lait spots, which are present in infancy in more than 95% of patients with NF1. Development of multiple café au lait spots in a child with no family history without NF1 is insufficient to establish a diagnosis of NF1 if no other signs of the disease are present, although NF1 should be strongly suspected in these children, and they should receive clinical follow-up monitoring.¹⁹

A definite diagnosis of NF1 can be made in most children by age 4 years by using the NIH criteria. Various manifestations of NF1 appear at different characteristic times. For example, bone manifestations, such as cortical thinning, are congenital. Café au lait spots are often present at birth and increase in number during the first few years of life. Diffuse plexiform neurofibromas of the face and neck rarely appear after age 1 year, and plexiform neurofibromas of other parts of the body rarely develop after adolescence.

Optic gliomas develop during the first 4 years of life. Optic glioma is the most common intracranial tumor associated with NF1. It occurs in 12% of patients and is bilateral in 4%; 75% of optic gliomas occur in the first decade of life. The tumor spreads to the optic chiasm (in 25% of patients), optic tracts, and optic radiation. Malignant peripheral nerve sheath tumors (neurofibrosarcomas) usually occur in adolescents and adults.²⁰

Abdominal involvement in patients with NF1 has been described, including neurofibromas within the liver, mesentery, retroperitoneum, and GI tract. Large-bowel intussusception has been reported. Small-bowel leiomyomas, adenocarcinomas with neuroendocrine function, GI tract vasculopathy, GI tract bleeding, pseudo-obstruction, and protein-losing enteropathy also may occur.^{8, 14, 15, 16, 21}

Neurofibromas arise within or are attached to nerve trunks anywhere in the skin, as well as any conceivable internal site, including intracranial and intraspinal locations. Histologically, neurofibromas comprise all the components of the peripheral nerves, including fibroblasts, Schwann cells, and neurites. These cells are distributed in a loose myxoid stroma in which Schwann cells predominate with their elongated serpentine structure and their slender spindle-shaped nuclei. Neurofibromas in NF1 may undergo malignant degeneration in 3% of patients. Schwannomas are composed entirely of Schwann cells, and malignant transformation is extremely rare; however, when it occurs, it is associated with von Recklinghausen disease in 75% of patients.²²

Related Medscape topic:
CME  Surgery Insight: The Role of Surgery in the Management of Low-Grade Gliomas

Frequency

United States

NF1 is one of the most common autosomal dominant genetic disorders, with an incidence of 1 case per 3000-4000 people. One half of cases are caused by new mutations. The mutation rate in the NF1 gene (1 case per 10,000 population) is among the highest known for any human gene. The cause of the unusually high mutation rate in NF1 is unknown. In familial cases, expressivity of the disorder is variable, but the penetrance is 100%.²⁰

International

International frequency of NF1 appears to be the same as in the United States.

Mortality/Morbidity

Mean and median ages at death in patients with NF1 are 54.4 and 59 years, respectively, as compared with 70.1 and 74 years in the general US population. Results of proportionate mortality ratio analysis show that persons with NF1 are 34 times more likely to have a malignant connective or other soft-tissue neoplasm listed on the death certificate. Similarly, vascular disease is recorded more often on the death certificates of patients younger than 30 years with NF1 as compared with the general population. Malignant transformation of neurofibromas and schwannomas occurs in 3-15% of patients with NF1.²³

Age

Children who have inherited the NF1 gene from an affected parent can usually be identified within the first year of life because the diagnosis requires the presence of only 1 feature in addition to a family history for NF1. The manifestations of NF1 appear at characteristic times. Bone manifestations (eg, cortical thinning) are congenital. Café au lait spots often are present at birth and increase in number during the first few years of life. Diffuse plexiform neurofibromas of the face and neck rarely appear in children older than 1 year, and plexiform neurofibromas of other parts of the body rarely develop after adolescence. Optic gliomas develop in children as old as 4 years. Other malignant tumors may develop at any point in life.

Clinical Details

NF1 is a multisystemic disorder that may affect any organ in the body. Clinical presentation depends on the body system involved.

Skin

Discrete cutaneous and subcutaneous neurofibromas may develop at any time but are infrequent before puberty. Total numbers of cutaneous and subcutaneous neurofibromas seen in adults vary from a few to thousands. Additional cutaneous and subcutaneous neurofibromas continue to develop throughout life, although the rate of appearance may vary greatly from year to year. Many women experience a rapid increase in the number and size of neurofibromas during pregnancy. Other cutaneous lesions include café au lait spots, elephantoid overgrowth of skin and subcutaneous tissue, breast enlargement, and other cutaneous lesions, such as hemangiomas, xanthogranulomas, red-blue macules, giant hairy nevi, and depigmented macules.²⁴

Related Medscape Topics: 
Resource Center Dermatologic Surgery
Resource Center Skin Cancer

GI tract

GI tract involvement includes neurofibromas within the liver, mesentery, retroperitoneum, large bowel (with possible intussusception), rectum, and jejunum, as well as small-bowel leiomyomas, small-bowel adenocarcinoma with neuroendocrine function, GI tract vasculopathy and bleeding, pseudo-obstruction, and protein-losing enteropathy. Patients may present with abdominal pain, nausea, abdominal distention, diarrhea, constipation, bowel perforation, or GI tract bleeding.^{14, 15, 16, 21, 25}

Cardiovascular system

Hypertension is frequent in NF1 and may develop at any age. In most patients, the hypertension is essential, but vascular dysplasia can occur in NF1, which may produce renal artery stenosis, coarctation of the aorta, or other vascular lesions associated with hypertension. Pheochromocytoma can cause severe hypertension in adult patients with NF1. Other cardiovascular abnormalities that have been reported in patients with NF1 include congenital heart defects (with a 10-fold increase in pulmonary valve stenosis, atrial septal defect, and ventricular septal defect).^{9, 12, 13}

Further abnormalities reported include complete heart block, aortic coarctation, regressive cardiomyopathy in infancy, idiopathic hypertrophic subaortic stenosis, coronary heart disease associated with myocardial infarction or coronary artery spasm, and intestinal angina due to compression of GI blood supply by a neurofibroma.

Musculoskeletal system

Spinal rotational anomalies can include kyphoscoliosis, bowed legs, skull defects and anomalies of skull shape, pulsating or nonpulsating exophthalmos, orbital displacement, edema of the eyelids, ptosis, macrodactyly, postaxial polydactyly, and thoracic cage deformities, such as pectus excavatum and pseudoarthrosis of bones.

Endocrine and metabolic functions

Hyperparathyroidism, multiple endocrine adenomatosis type 2B (also termed multiple endocrine neoplasia type 2B [MEN 2B], pheochromocytoma, medullary carcinoma of the thyroid and multiple neuromas, sexual precocity, gigantism, osteomalacia/rickets, hypoglycemia, hypertrophy of the clitoris or labia or penis, irregular menses, infertility, ovarian cysts, early menopause, or hyperprolactinemia may occur.

Central nervous system, eye, and otologic functions

Learning disabilities, behavioral disorders, seizures, mental retardation, hyperactivity, moyamoya phenomenon, childhood hypertensive strokes, eyelid neurofibromas, congenital glaucoma, buphthalmos, retinal detachment, retinal phakoma,²⁶ hypertelorism, abnormal hearing, and neurofibromas of the external and middle ears may occur.

Associated neoplasms

MEN 2B, optic pathway glioma, cerebral glioma, CNS hamartomas, small-bowel leiomyoma/leiomyosarcoma, meningiomas (intracranial and spinal), sarcomas, various types of carcinomas, leukemia, lymphoma, melanoma, pheochromocytoma, neuroblastoma, nonossifying fibromas, adrenal cortical adenomas, and sarcomatous changes in a neurofibroma may occur.

Preferred Examination

The preferred examination depends on the clinical problem to be investigated and the organ involved. Although plain radiographs may be sufficient for evaluating skeletal lesions, sonography and MRI may be the investigation of choice for peripheral nerve tumors and tumors of solid intra-abdominal organs or for associated renal artery stenosis. CT and MRI are preferred with spinal or intracranial lesions. Radionuclide scans are useful when functional imaging is needed in associated tumors such as a pheochromocytoma.^{16, 27, 28, 29, 30}

Limitations of Techniques

Limitations depend on the organ being investigated and the suspected pathology. Plain radiographs are excellent at showing skeletal abnormalities of both the axial and appendicular skeleton. Similarly, chest radiography remains a useful technique for demonstrating thoracic cage abnormalities and pulmonary fibrosis. For intracranial, intrathoracic, or intra-abdominal pathology, cross-sectional imaging is more appropriate, and the modality chosen is tailored to the problem.

DIFFERENTIALS

Section 3 of 13  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT Scan
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Acknowledgments
• Multimedia
• References

Other Problems to Be Considered

Neurofibromatosis type 2 - Bilateral acoustic neuromas, first-degree relatives with unilateral acoustic neuroma, neurofibroma, meningioma, and glioma, schwannoma, and juvenile posterior subcapsular lenticular opacity

Neurofibromatosis–Noonan syndrome - NF1 with some associated features of Noonan syndrome

Proteus syndrome - Congenital neurocutaneous disorder associated with thickening of palms and soles, hyperkeratosis, lipomas (subcutaneous and abdominal), hamartomas, hemangiomas, and lymphangiomas

Jaffe-Campanacci syndrome - Café au lait spots, mental retardation, hypogonadism, precocious puberty, disseminated nonossifying fibromas, fractures, and kyphoscoliosis

Multiple endocrine neoplasia 2B - Multiple mucosal neuromas, pheochromocytoma, and ganglioneuromatosis

Klippel-Trenaunay syndrome - Port-wine stains, elongation and widening of the bones of a limb (with limb hemihypertrophy), cortical thickening, and various vascular anomalies

Bannayan-Riley-Ruvalcaba syndrome - Macrocephaly, mesodermal and hamartomatous tumors (subcutaneous, intracranial, visceral, intestinal, skeletal thoracic)

McCune-Albright syndrome - Patchy cutaneous pigmentation, sexual precocity, and polyostotic fibrous dysplasia

Hemihypertrophy - Range of asymmetry from enlargement of 1 digit to an entire half of the body associated with skin abnormalities and hamartomatous lesions

Autosomal dominant familial angiolipomatosis - Large subcutaneous angiolipomata

Watson syndrome - Characteristic facies, extensive skeletal abnormalities, congenital heart disease, liver and biliary tree anomalies, and renal function anomalies

Elephant man - Definite diagnosis not yet established for this patient, but NF1 and Proteus syndrome are possibilities

Hip dislocations

Moyamoya disease

Polyostotic fibrous dysplasia (PFD)- Café-au-lait spots occur in 50% of patients, particularly in those patients who also have endocrinopathy.  The café-au-lait spots in PFD typically have irregular borders ("coast of Main" lesions), whereas the café-au-lait spots in NF1 have smooth, well-defined borders ("coast of California" lesions). Café-au-lait spots in PFD are also darker and fewer in number.³¹

RADIOGRAPH

Section 4 of 13  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT Scan
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Acknowledgments
• Multimedia
• References

Findings

• Skull
  • Many skull abnormalities are well demonstrated on plain radiographs. These include macrocephaly, absence of the greater and lesser wings of the sphenoid, absence of the orbital floor, hypoplasia of the lesser wings of the sphenoid, enlarged orbits, enlargement of cranial foramina, enlargement of orbital margins, sclerosis in the vicinity of the optic foramen (optic nerve sheath meningioma), facial asymmetry, hypoplasia of the paranasal sinuses, mandibular abnormalities, mandibular hypoplasia with flattening of the external contour, thinning of the ramus, coronoid hyperplasia, widening of the lateral and medial coronoid spaces, and calvarial defects adjacent to the lambdoid suture.
  • Multiple frontobasal osseomeningeal defects causing cerebrospinal fluid (CSF) rhinorrhea and meningoencephalocele can occur, and the osseous defects may be depicted on plain radiographs.
  • Dural calcifications, especially at vertex.
  • Macrocephaly due to hydrocephalus or increased white matter volume.
• Chest
  • Plain radiograph findings include inferior rib notching, twisted and ribbonlike ribs in the upper thoracic cage, posterior mediastinal masses secondary to intrathoracic meningoceles, mediastinal and lung masses secondary to neurofibromas, and dumbbell neurofibromas.
  • Reported changes of lung parenchyma include progressive pulmonary interstitial fibrosis leading to formation of bullae and honeycomb lung.
  • The incidence of spontaneous pneumothorax and hemothorax is increased.
  • Changes of interstitial lung disease and pulmonary hypertension may be seen, such as dilatation/enlargement of the central pulmonary arteries and peripheral pruning of vessels.
• Spine
  • A sharply angled kyphoscoliosis centered at the thoracolumbar junction is seen in 50% of patients. The kyphosis is more pronounced than the scoliosis, and the incidence increases with advancing age.
  • Enlargement of the intervertebral foramina, scalloping of the vertebral bodies (anterior, posterior, lateral), hypoplasia of the vertebral pedicles, wedged-shaped vertebrae, spondylolisthesis, spinal clefts, osteolysis, and spindling of the transverse processes may be depicted.
  • Spinal fusion may be complicated by pseudoarthrosis and curve progression.
  • Spinal segments may be unstable, leading to subluxation or dislocation.
• Appendicular skeleton
  • Bowing or an S-shaped deformity of long bones, hyperplasia or hypoplasia of long and short bones, pseudoarthrosis, erosions, periosteal dysplasia, intramedullary longitudinal osteosclerotic streaks, single or multiple cystic bone lesions, and focal gigantism may be depicted.
  • Joint abnormalities reported include protrusio acetabuli, dislocation of the hip, dislocation of the radius and ulna, absence of a patella, and neuropathic arthropathy of the knee.
• GI tract
  • Abdominal involvement in NF1 has been described, including neurofibromas within the stomach, small and large bowels, and rectum.
  • Barium series may show intraluminal mass lesions due to a neurofibroma indistinguishable from other polypoid lesions.
  • Intussusception of the bowel may be present with intestinal obstruction.
  • Rarely, bowel obstruction simulating Hirschsprung disease may occur, secondary to plexiform neurofibroma of the colon.
  • Plexiform neurofibromas may cause a mass effect on adjacent barium-filled bowel loops.
  • Small-bowel leiomyoma, small-bowel adenocarcinoma with neuroendocrine function, stromal tumors, and carcinoid tumors are other reported associations.
  • Pseudo-obstruction has been reported.
  • A barium small-bowel series may show features consistent with malabsorption resulting from protein-losing enteropathy.
  • Biliary strictures and bile duct intraluminal neurofibromas are rarely associated and may be revealed on percutaneous cholangiography or endoscopic retrograde cholangiopancreatography (ERCP).³²
• Urinary tract
  • The renal collecting system and bladder may be intrinsically involved by neurofibromas or extrinsically compressed or displaced by neurofibromas.
  • Plain radiography has little to contribute besides showing a soft-tissue mass, but intravenous urography may provide useful information regarding the nature and site of obstruction and function.

Degree of Confidence

Radiographic findings of NF1 are nonspecific, but a fairly confident diagnosis can be made in the appropriate clinical setting when the index of clinical suspicion is high.

False Positives/Negatives

Many neurofibromas may not be depicted on plain radiographs. NF shares many skeletal abnormalities with other syndromes; therefore, the differential diagnosis is extensive.

CT SCAN

Section 5 of 13  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT Scan
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Acknowledgments
• Multimedia
• References

Findings

Peripheral soft-tissue NF

• CT scans demonstrate solid fusiform masses in the distribution of nerves, with central areas of low attenuation and calcification. These masses may present in the paravertebral, laryngeal, mediastinal, abdominal, and pelvic/ischiorectal fossae. The masses usually are well defined with attenuation values of approximately 30-40 Hounsfield units (HU).
• Plexiform neurofibromas are depicted as widespread sheets of nodular tissue, with attenuation values identical to the fusiform form (30-40 HU).
• Paraspinal neurofibromas may be seen at every level, may vary in size, may be dumbbell shaped, or may comprise fusiform/spherical soft-tissue masses with attenuation values of approximately 20-30 HU. Dumbbell-shaped neurofibromas may enlarge the exiting foramina.
• A characteristic appearance may be seen of mesenteric plexiform neurofibromas trapping mesenteric fat within an entangled network, with attenuation values of approximately 15-30 HU.
• Nonneoplastic cerebral and cerebellar calcification and choroid plexus calcification are depicted well on cranial CT scans.
• Hydrocephalus in NF1 may be due to benign aqueduct stenosis or a glioma of the tectum/tegmentum of the mesencephalon.
• Intracranial nerve sheath tumors are not depicted as well on CT scans as they are on MRI, but associated bone erosions are seen well on CT.
• Meningiomas with associated changes in the calvarium/skull are depicted well.
• Dural calcifications may be seen, especially at vertex.
• Macrocephaly due to hydrocephalus or increased white matter volume may be seen 
• Extrinsic bladder involvement, intrinsic infiltrative processes, or extrinsic compression of the renal collecting system by a neurofibroma may be revealed on CT scans as masses of low attenuation.
• CT has a role in the investigation of thoracic, abdominal, and pelvic complications of NF1.

Degree of Confidence

CT scans and MRIs are excellent at depicting most primary lesions and associated tumors and complications of NF1. Some pathology is better imaged by using MRI, such as optic nerve glioma and intraspinal abnormalities. However, even with optic nerve gliomas, osseous erosions may be depicted better on CT scans.^{27, 28, 29}

False Positives/Negatives

Neurofibromas can occur as an isolated anomaly and in association with NF2. Certain congenital bone lesions may mimic bone involvement associated with NF1, such as fibrous dysplasia. A number of syndromes can mimic NF1 (see Differentials).

MRI

Section 6 of 13  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT Scan
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Acknowledgments
• Multimedia
• References

Findings

• MRI is the modality of choice for imaging neural sheath tumors, which can be demonstrated by following the course of the nerve from which the tumor arises.
• Intracranial neural sheath tumors are isointense to brain tissue on T1-weighted images and hyperintense to brain tissue on T2-weighted images.
• Tumors enhance intensely following contrast administration.
• Tumors tend to be smoothly marginated.
• Larger tumors are heterogeneous.
• Tumors occasionally present at the base of the brain and may spread through the basal foramina.
• Intraparenchymal brain abnormalities include isointense or hyperintense foci on T2-weighted images in the cerebellar white matter, dentate nucleus, basal ganglia, periventricular white matter, optic nerve, and optic pathways. These lesions are isointense on T1-weighted images and usually have no mass effect. (The lesions are classed as hamartomas but are probably demyelinating lesions because they may resolve.) They become visible between ages 2 and 10 years, then regress by the second decade. If the T2 lesions show enhancement, glioma development should be suspected.
• Rarely, hyperintensities and mild mass effect have been reported in the globus pallidus on T1-weighted images.
• Optic gliomas, which are the most common intracranial lesion in NF1, and gliomas of other parts of the brain may be demonstrated.
• Gliomatosis cerebri may be seen, which is an unusual confluence of astrocytomas.
• Hydrocephalus in NF1 may be due to benign aqueduct stenosis or a glioma of tectum/tegmentum of the mesencephalon.
• Dural calcifications may be seen, especially at vertex. 
• Macrocephaly due to hydrocephalus or increased white matter volume may be seen.
• Nerve sheath tumors are the most common intradural neoplasms. Schwannomas usually arise from the dorsal sensory root. They are almost always solitary and sporadic in NF1, but multiple schwannomas occur in NF2. Intradural neurofibromas are almost always multiple in NF1.
• Although schwannomas and neurofibromas are histologically different, they exhibit similar MRI appearances. Both schwannomas and neurofibromas are hypointense or mildly hypointense compared to the spinal cord on T1-weighted images and are heterogeneously hyperintense on T2-weighted images. The tumors may extend into the neural foramina.
  • Within schwannomas, areas of hypointensity due to collagen deposition, hemorrhage, and densely packed Schwann cells frequently are seen.
  • After the administration of contrast material, peripheral enhancement of schwannomas predominates.
  • Neurofibromas enhance more homogeneously.
  • Enhancement patterns and T2-weighted images can help differentiate schwannomas from meningiomas, but the same confidence cannot be transferred to differentiating schwannomas from neurofibromas.
• MRI allows noninvasive identification of intradural neurofibromas and helps determine their relationship to the neural foramina, canal, and thecal sac spinal cord. 
• The target sign (bright on T2, with dark collagen centrally) is highly suggestive of a peripheral neurofibroma on MRI. It may be seen with plexiform neurofibromas as well.
• Paraspinal neurofibromas may be dumbbell shaped, fusiform, or spherical. They are slightly hyperintense relative to muscle on T1-weighted images, with a hyperintense periphery and a hypointense core on T2-weighted images.
• A lateral thoracic meningocele, which is known to be associated with NF1, is depicted well on MRIs and is seen as a CSF-filled sac extending through a widened neural foramina.
• Other CNS abnormalities associated with NF1 are depicted well on MRIs and include prominent CSF spaces, arachnoid cysts, arachnoid pouches, frontobasal meningocele, craniofacial plexiform neurofibromas, and intracranial lipoma.
• Extrinsic bladder involvement, an intrinsic infiltrative process, and extrinsic compression of the renal collecting system by a neurofibroma are depicted well, with a markedly increased signal within the compressing mass on T2-weighted images and a slightly increased signal intensity on T1-weighted images relative to muscle.
• Cardiovascular abnormalities, such as a superior vena cava aneurysm, obstruction, lymphatic obstruction, left atrial wall aneurysm, aneurysm of the coronary arteries, aneurysm of other major or minor vessels, and stenoses of cranial, renal, celiac axis, and superior mesenteric arteries, are depicted well with magnetic resonance angiography (MRA) or contrast-enhanced dynamic MRA.

Degree of Confidence

MRI is the modality of choice because the course of the nerve from which the tumor arises can be detected, and MRI can depict neural sheath tumors. MRI also depicts optic nerve gliomas better than CT.^{27, 28, 29}

False Positives/Negatives

Schwannomas and neurofibromas cannot always be differentiated. When solitary, the tumor usually is regarded as a schwannoma; when multiple, tumors usually are diagnosed as neurofibromas.

ULTRASOUND

Section 7 of 13  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT Scan
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Acknowledgments
• Multimedia
• References

Findings

• Solitary neurofibromas are mostly hyperechoic with coarse internal echoes and lobulated margins.
• Nonplexiform neurofibromas in NF1 appear as hypoechoic fusiform masses, and although they do not have a histologic capsule, they present with relatively regular and well-defined margins.
• Small intratumoral cystic areas due to myxoid degeneration may be present in schwannomas.
• When a sudden increase in tumor size is detected, malignant transformation should be considered.
• Paraspinal neurofibromas may appear as well-circumscribed cylindrical lesions.
• Abdominal involvement that may be depicted on sonography includes NF and tumor growth in the liver, mesentery, and the retroperitoneum, in addition to mesenteric leiomyomatosis and gastric and bowel tumors.
• Biliary obstruction may be demonstrated on ultrasound images, and tumor spread into the liver along the portal vein has been shown as infiltrative hypoechoic masses around the porta hepatis and intrahepatic portal branches.
• Similarly, obstructive uropathy caused by neurofibroma may be depicted on ultrasound images.
• Duplex color and spectral Doppler ultrasonography are useful diagnostic modalities for revealing the vascular complications of NF1, such as aneurysms and stenoses.

Degree of Confidence

The diagnosis of nerve sheath tumors with sonography depends on depiction of a mass along the presumed course of a nerve in association with neurologic signs. Thus, sonography is reliable only when a definite relationship can be demonstrated between a mass and a nerve origin.²⁹

False Positives/Negatives

Peripheral lymphadenopathy may superficially resemble neurofibromas. Lesions within other solid or cystic intra-abdominal organs need to be differentiated from other masses.

NUCLEAR MEDICINE

Section 8 of 13  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT Scan
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Acknowledgments
• Multimedia
• References

Findings

Radionuclide isotope bone scans can be useful in the investigation of intraosseous lesions and pseudofractures because differentiation from metastases may be possible. Technetium-99m diethylenetriamine pentaacetic acid (DTPA) has been shown to accumulate in benign soft-tissue tumors of NF. Positron emission tomography has been used to image the uptake of fluorodeoxyglucose in the malignant transformation of a neurofibroma.^{33, 34}

Degree of Confidence

The role of nuclear medicine is complementary, and the findings are seldom diagnostic.

False Positives/Negatives

Although radionuclide scans are sensitive in detecting bone pathology, the appearances are nonspecific, and positive findings may occur in a variety of bone pathologies.

ANGIOGRAPHY

Section 9 of 13  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT Scan
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Acknowledgments
• Multimedia
• References

Findings

Angiography remains the criterion standard for providing both anatomic and functional information on vascular aneurysms, occlusions, and arteriovenous shunts.

Degree of Confidence

Aneurysms and stenoses are depicted well on angiographic images, which remain the criterion standard for vascular investigation.

False Positives/Negatives

Although angiography is highly sensitive in the diagnosis of aneurysms and stenoses, findings only occasionally help in specifying the cause.

INTERVENTION

Section 10 of 13  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT Scan
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Acknowledgments
• Multimedia
• References

Fine-needle aspiration biopsy can be performed in nerve sheath tumors in which the diagnosis is not clear. The excruciating pain triggered by the insertion of the needle is a clue to the diagnosis of nerve tumors.

Medical Legal Pitfalls

Related Medscape topic:
Resource Center Medical Malpractice and Legal Issues

Special Concerns

• Pregnant patients¹¹
• • Many women experience a rapid increase in the number and size of neurofibromas during pregnancy.
  • Although the course of the pregnancy in most women with NF1 is normal, serious complications can occur.
  • Hypertension may first become symptomatic; or if it is preexisting, it may be greatly exacerbated during pregnancy.
  • Large pelvic or genital neurofibromas can complicate delivery, and cesarean delivery appears to be necessary more often in women with NF1 than in other women.
• Pediatric patients^{17, 18}
• • NIH criteria are often insufficient for the diagnosis of NF1 in young children with multiple café au lait spots, no other NF1 features, and no family history of NF1.
  • Optic gliomas are one of the cardinal features of NF1, and these may be the first manifestation in the absence of other features of NF1.
  • NF1 may be manifested by a hypertensive childhood stroke.

ACKNOWLEDGMENTS

Section 11 of 13  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT Scan
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Acknowledgments
• Multimedia
• References

The authors and editors acknowledge Dr. Faiq Khan Malik, MBBS, for his contributions to this article.

MULTIMEDIA

Section 12 of 13  

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT Scan
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Acknowledgments
• Multimedia
• References

Media file 1:  Frontal skull radiograph in a patient with NF1 shows asymmetry of the orbits but a normal sphenoid ridge.
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Media file 2:  Plain radiograph in a patient with NF1 shows a left lambdoid defect (same patient as in Image 1).
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Media file 3:  (Left) Plain radiograph of the left forearm in a 15-year-old boy shows hypoplasia and deformity of the radius and ulna. Note the intramedullary sclerotic streaks within the radius and periosteal dysplasia. (Right) Compare these findings with the normal right forearm, and note the unrelated exostosis of the distal radius.
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Media file 4:  Chest radiograph in a 56-year-old man with NF1 shows apical neurofibromas and ribbon or notched ribs. Note the myodil within the spinal canal from a previous myelography performed because of previous spinal root problems. Myodil or Pantopaque (iophendylate) is an oily contrast medium that was used for myelography in the 1960s and 1970s, but its use was abandoned because of the risk of arachnoiditis.
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Media file 5:  Chest radiograph in a 62-year-old patient with NF1 shows interstitial fibrosis in the middle and lower zones. Note the multiple surface neurofibromas.
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Media file 6:  Plain radiograph of the pelvis in a 28-year-old woman shows gross deformity of the left hemipelvis and the left upper femur.
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Media file 7:  Sagittal T1-weighted unenhanced MRI scan in a 28-year-old woman shows dural ectasia and a large lobulated anterior sacral meningocele (M) (same patient as in Image 6).
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Media file 8:  Sagittal T2-weighted MRI in a 28-year-old woman shows dural ectasia and a large lobulated anterior meningocele (same patient as in Images 6-7).
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Media file 9:  A 66-year-old woman with NF1 presented with paresthesia down the right arm. T1-weighted transaxial MRI through the cervical spine shows a low-signal-intensity mass extruding through the right foraminal canal at the C5-6 vertebral level; the mass appears to be eroding the vertebral body. The final diagnosis was a neurofibroma.
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Media file 10:  T2-weighted transaxial MRI in a 66-year-old woman shows a moderately hyperintense neurofibroma (N) (same patient as in Image 9).
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Media file 11:  CT scan through the orbits in a patient with NF1 shows a right optic glioma.
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Media file 12:  A 7-year-old girl with a family history of NF1 had been blind for 18 months. T2-weighted transaxial MRI shows bilateral optic nerve gliomas (arrows), as well as a right temporal lobe and left brainstem lesions, which may represent additional gliomas or spongiform white matter changes of NF1.
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Media file 13:  T1-weighted MRI in a 7-year-old girl with a family history of NF1 who had been blind for 18 months shows bilateral optic nerve gliomas (arrows) (same patient as in Image 12).
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Media file 14:  Axial sonogram through the right iliac fossa in a 28-year-old man with NF1shows a hypoechoic dumbbell-shaped neurofibroma.
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Media file 15:  T1-weighted coronal MRI of the abdomen in a 28-year-old man shows a low-signal dumbbell-shaped right iliac fossa tumor, confirmed to be a neurofibroma at laparotomy (same patient as in Image 14). The patient also had sickle cell trait and presented with hematuria from a left-sided medullary cell renal carcinoma.
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Media file 16:  Upper GI barium series in a 56-year-old woman with NF1 shows multiple filling defects along the greater curve of the stomach due to neurofibromas. Note the multiple subcutaneous neurofibromas in the right upper quadrant.
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Media file 17:  Upper GI barium series in a 56-year-old woman shows multiple polypoid filling defects throughout the small bowl due to neurofibromas (same patient as in Image 16). Note the subcutaneous neurofibromas projected over the right hypochondrium.
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REFERENCES

Section 13 of 13

• Authors and Editors
• Introduction
• Differentials
• Radiograph
• CT Scan
• MRI
• Ultrasound
• Nuclear Medicine
• Angiography
• Intervention
• Acknowledgments
• Multimedia
• References

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Article Last Updated: Jan 23, 2008